Antithrombotic Therapy in Peripheral Arterial Occlusive Disease

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review and metaanalysis10 of randomized trials of exercisetherapy in patients with claudication suggests that exerciseimproves maximal walking time by 150%. One must judgesymptomatic antithrombotic therapy in this context. Fur-thermore, while risk factor modification is not well studiedin patients with PAOD, observational data and generali-zation from trials11,12 in persons with other manifestationsof cardiovascular disease support the importance of treat-ing key risk factors such as smoking, diabetes, dyslipide-mia, and hypertension.1

1.1 Antiplatelet therapy

Antiplatelet therapy may modify the natural history of chronic lower-extremity arterial insufficiency, as well aslower the incidence of associated cardiovascular events.No convincing data from properly designed large trialsdemonstrate that antithrombotic therapy will delay orprevent 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 Anti-thrombotic Trialists’ Collaboration metaanalysis13 foundthat 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 withintermittent claudication, those having peripheral bypass,endarterectomy, and those having peripheral angioplasty all benefited to a similar degree. For all conditions, aspirinat 80 to 325 mg/d was at least as effective as any otherregimen, including higher-dose aspirin therapy, which ismore prone to cause side effects and GI complications.

1.1.1 Aspirin

The antiplatelet trialists analysis13 showed that for allconditions, aspirin at 80 to 325 mg/d was at least aseffective as any other regimen, including higher-doseaspirin therapy, which is more prone to cause side effectsand GI complications. Data from a single randomizedcontrolled trial (RCT)14 suggest that aspirin, alone orcombined with dipyridamole, will delay the progression of established arterial occlusive disease as assessed by serialangiography. This may have been an effect on inhibitingthrombotic occlusion of stenotic vessels rather than retard-ing stenosis progression.

In another study of 54 patients with intermittent clau-dication, the combination of aspirin and dipyridamole wasfound to increase the pain-free walking distance andresting limb blood flow.15 An RCT16 of 296 patients withintermittent claudication found an improved coagulationprofile and ankle/brachial index with therapy, but did notreport if walking distance improved with combined ther-apy. The Physicians Health Study,17 a primary preventionstudy, found that aspirin, 325 mg every other day, de-creased the need for peripheral arterial reconstructivesurgery; however, no difference was noted between theaspirin and placebo groups in the development of inter-mittent claudication.

Other chapters in these guidelines describe the com-pelling 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 allpatients with PAOD who do not have clinically manifestdisease have occult coronary or cerebrovascular disease.Aspirin is less effective than ticlopidine and clopidogrel(see below). However, the marginal benefit of these otherdrugs is small, and aspirin is much less expensive. Theseare the rationales for our recommendation for aspirin overclopidogrel.

Recommendation

1.1.1. We recommend lifelong aspirin therapy (75 to325 mg/d) in comparison to no antiplatelet therapy inpatients with clinically manifest coronary or cerebrovascu-lar disease (Grade 1A ) and in those without clinically manifest coronary or cerebrovascular disease (Grade1C).

1.1.2 Ticlopidine

One metaanalysis18 demonstrated that patients withintermittent claudication treated with ticlopidine had asignificant reduction in fatal and nonfatal cardiovascularevents in comparison with patients treated with placebo.Ticlopidine has also shown a modest beneficial effect forrelieving symptoms, increasing walking distance, and im-proving lower-extremity ankle pressure indices in patients

with intermittent claudication (see chapter by Patrono etal in this Supplement).19–20 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 leukope-nia and thrombocytopenia, requiring close hematologicmonitoring. Because of these side effects, clopidogrel hasreplaced ticlopidine as the thienopyridine of choice.

Recommendation

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

1.1.3 Clopidogrel

Clopidogrel is a thienopyridine, the chemical structureof which is similar to ticlopidine, that exerts an irreversibleantiplatelet effect primarily directed against adenosinediphosphate-induced stimulation of platelet function (seechapter by Patrono et al in this Supplement). In a large,multicenter RCT22 of 19,185 patients, investigators com-pared the relative efficacy of clopidogrel and aspirin inreducing the risk of a composite end point of ischemicstroke, MI, or vascular death. The study population com-prised patients with recent ischemic stroke, recent MI, orPAOD. The overall incidence of composite end points waslower in the group treated with clopidogrel (5.32%/yr)than with aspirin (5.83%; p 0.043). A subgroup analysissuggested that a larger benefit of clopidogrel over aspirinin patients with symptomatic PAOD than those with

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T a b l e

1 — P A O D

P a t i e n t s

S e c t i o n

P o p u l a t i o n

I n t e r v e n t i o n s o r E x p o s u r e s

O u t c o m e

M e t h o d o l o g y

1 . 1 . 1 – 1 . 1 . 3

C h r o n i c l i m b i s c h e m i a a n d

c l a u d i c a t i o n

A n t i p l a t e l e t t h e r a p y ( c l o p i d o g r e l , t i c l o p i d i n e , a s p i r i n )

S u r v i v a l ; i s c h e m i c s t r o k e ,

M I , v a s c u l a r d e a t h , w a l k i n g

d i s t a n c e

R C T s

1 . 1 . 4 – 1 . 1 . 5



C i l o s t a z o l , p e n t o x i f y l l i n e

I m p r o v e m e

n t i n m a x i m u m

w a l k i n g d i s t a n c e , a b s o l u t e

c l a u d i c a t

i o n d i s t a n c e , w a l k i n g i m p a i r m e n t q u e s t i o n n a i r e ,

h e a l t h - r e

l a t e d q u a l i t y o f l i f e

R C T s

1 . 1 . 6



P r o s t a g l a n d i n s

I m p r o v e m e

n t i n m a x i m u m

w a l k i n g d i s t a n c e , a b s o l u t e

c l a u d i c a t


h e a l t h - r e


R C T s

1 . 1 . 7

C h r o n i c l i m b i s c h e m i a

K e t a n s e r i n , s u l o c t i d i l ,

f i s h

o i l s u p p l e m e n t a t i o n ,

n a f t i d r o f u r y l , p i c o t a m i d

e ,

h e p a r i n s , w a r f a r i n

S u r v i v a l ; c o

m p o s i t e e n d p o i n t o f i s c h e m i c s t r o k e ,

M I ,

v a s c u l a r

d e a t h , i m

p r o v e m e n t i n m a x i m u m

w a l k i n g d i s t a n c e ,

a b s o l u t e

c l a u d i c a t


h e a l t h - r e


R C T s

2 . 1 – 2 . 2

A c u t e l i m b i s c h e m i a

A n t i c o a g u l a t i o n ,

i n t r a - a r t e

r i a l t h r o m b o l y t i c t h e r a p y

L i m b s a l v a g e , s u r v i v a l

R C T s ;

o b s e r v a t i o n a l

s t u d i e s

3 . 1

V a s c u l a r s u r g e r y

I n t r a o p e r a t i v e h e p a r i n a n t i c o a g u l a t i o n

G r a f t p a t e n

c y ,

f a t a l / n o n f a t a l M I

R C T s

3 . 2 . 1

I n f r a i n g u i n a l p r o s t h e t i c b y p a s s

A s p i r i n , c l o p i d o g r e l , t i c l o p i d i n e , w a r f a r i n

G r a f t p a t e n

c y ,

l i m b s a l v a g e , s u r v i v a l

R C T s

3 . 2 . 2

I n f r a i n g u i n a l v e i n b y p a s s

A s p i r i n , c l o p i d o g r e l , t i c l o p i d i n e , w a r f a r i n

G r a f t p a t e n

c y ,

l i m b s a l v a g e , s u r v i v a l

R C T s

3 . 2 . 3

I n f r a i n g u i n a l b y p a s s a t h i g h t h r o m b o t i c

r i s k

A s p i r i n p l u s w a r f a r i n

G r a f t p a t e n

c y ,

l i m b s a l v a g e

R C T s

4 . 1 .

C a r o t i d e n d a r t e r e c t o m y

A s p i r i n

S t r o k e ,

M I ,

d e a t h

R C T s

5 . 0

A s y m p t o m a t i c a n d r e c u r r e n t c a r o t i d

s t e n o s i s

A s p i r i n

S t r o k e ,

M I ,

d e a t h

R C T s

6 . 0

L o w e r - e x t r e m i t y e n d o v a s c u l a r

p r o c e d u r e s

A n t i p l a t e l e t a g e n t s ( a l l ) , a

n t i c o a g u l a t i o n

L i m b s a l v a g e , a r t e r i a l p a t e n c y , s t r o k e ,

M I , d e a t h

R C T s

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cardiac or cerebrovascular disease. Subgroup analysis isoften misleading, and we are inclined to trust the overallestimate of clopidogrel effectiveness in all patients with

vascular disease.

Recommendation

1.1.3. We recommend clopidogrel in comparison to noantiplatelet therapy (Grade 1C) but suggest that aspirin

be used instead of clopidogrel (Grade 2A ).

Underlying values and preferences: This recommendationplaces a relatively high value on avoiding large expendi-tures to achieve small reductions in vascular events.

1.1.4 Cilostazol

Cilostazol is a type III phosphodiesterase inhibitor thatsuppresses platelet aggregation and is a direct arterial

vasodilator. Its mechanism of action as a treatment forclaudication is not fully understood. We found no system-atic reviews on this drug for PAOD. Several publishedclinical trials that have evaluated the efficacy of cilostazolas a therapeutic agent for intermittent claudication.

In the first of these published trials,23 239 patientsrandomly assigned to receive a 16-week course of cilosta-zol or placebo, the cilostazol group showed an increase inabsolute claudication distance (ACD) of 47%, while thecontrol group improved by 13% (p 0.001). Functionalstatus assessment also showed improvement with cilosta-zol compared with control subjects, although there weresignificantly 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 threegroups, cilostazol, pentoxifylline, or placebo for 24 weeks;at 24 weeks, the treatment was changed to placebo for allgroups, and follow-up was continued for 6 more weeks.There was a more significant decrease in ACD aftercessation of cilostazol therapy than with either pentoxifyl-line or placebo. The increase in ACD from baseline wassimilar in both the cilostazol and pentoxifylline groups(109% and 94%, respectively).

In a trial26 of 516 patients randomly assigned to cilosta-zol (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 walkingdistance, respectively, while with a dose of 100 mg bidshowed a 51% and 59% improvement, respectively, com-pared 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 infunctional outcomes with cilostazol, and no difference inthe incidence of adverse events in the three groups. Sideeffects noted in each of the studies included headache,loose and soft stools, diarrhea, dizziness, and palpitations.

Cilostazol is more effective than pentoxifylline, as illus-trated in a study of 698 patients randomized to pentoxi-fylline (400 mg tid), cilostazol (100 mg bid), or placebo for24 weeks.27 In comparison to pentoxifylline, cilostazol

produced a significant increase in walking distance foronset of claudication (218 m for cilostazol vs 202 m forpentoxifylline, 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 pentoxi-fylline).

Cilostazol thus appears to be an appropriate therapy for

patients with disabling claudication who are not candidatesfor revascularization. However, its high cost, modest effecton walking distance, lack of demonstrated benefit inimproving health-related quality of life, and the salutary effects of exercise therapy and risk factor modificationargue against its routine use in patients with less-disablingintermittent claudication.

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

Recommendation1.1.4. For patients with disabling intermittent claudica-

tion who do not respond to conservative measures (riskfactor modification and exercise therapy) and who are notcandidates for surgical or catheter-based intervention, wesuggest cilostazol (Grade 2A ). We suggest that cliniciansnot use cilostazol in those with less-disabling claudication(Grade 2A ).

Underlying values and preferences: The recommendationagainst cilostazol for those with less-disabling claudicationplaces a relatively low value on small possible improve-ments in function in the absence of clear improvement inhealth-related quality of life.

1.1.5 Pentoxifylline

Pentoxifylline is a weak antithrombotic agent; its puta-tive mechanisms of action include an increase in RBCdeformity, and decreases in fibrinogen concentration,platelet adhesiveness, and whole-blood viscosity.28–30 Onemetaanalysis31 suggests that pentoxifylline improves walk-ing distance by 29 m compared with placebo, although theimprovement was approximately 50% in the placebogroup, and use of pentoxifylline improved walking distance

by an additional 30%. Moreover, clinical trials have shownconflicting results. Some32–37 have concluded that pentoxi-fylline was significantly more effective than placebo inimproving treadmill-walking distance, but others38–43

could not demonstrate consistent benefit. In many trials,patients treated with placebo also demonstrated signifi-cant improvement. Thus, the actual improvement in walk-ing distance attributable to pentoxifylline is often unpre-dictable and may not be clinically important compared

with the effects of placebo.44 In summary, the evidence fora beneficial effect of pentoxifylline is not strong enough tosuggest an important role in the treatment of patients withPAOD.45,46



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Recommendation

1.1.5. We recommend against the 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 topatients with advanced chronic arterial insufficiency inhopes of relieving rest pain and healing ischemic ulcers. Ina study 47 of 80 patients with intermittent claudication, IV administration of a PGE1 produced a dose-related im-provement 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 threeischemic ulcers not healing for 3 weeks with standard care

who were randomized to receive either PGE1 or a placebofor 72 h through a central venous catheter, PGE1 wasfound to be ineffective. In a small, randomized openstudy,49 PGE1 administered IV and combined with anintensive exercise regimen produced dramatic and sus-tained improvement in symptom-free walking distance incomparison with exercise alone or exercise combined withIV-administered pentoxifylline. The largest data set comesfrom a multicenter RCT50 in which 1,560 patients withchronic critical ischemia of the leg were randomly as-signed to receive either a daily IV infusion of PGE1 ornothing (open-label study) during their hospital stay. Atdischarge, there was a greater reduction in compositeoutcome events in the PGE1 group than in the controlsubjects (63.9% vs 73.6%; relative risk, 0.87; p 0.001),but this difference was not statistically significant at 6months (52.6% vs 57.5%; relative risk, 0.92; p 0.074).AS-013, a PGE1 prodrug, was evaluated in a small ran-domized trial51 of 80 patients with claudication, and wasassociated with an increase of 35 m in maximal walkingdistance after 8 weeks of treatment, compared with aslight decrease in placebo-treated control subjects. Thisdifference was statistically significant (p 0.01), althoughthe 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 ulcerhealing or rest pain.52 However, selective intra-arterialPGI2 was found to relieve rest pain and promote healing of ulcers to a significantly greater degree than did placebotreatment in 30 nondiabetic patients, half of whom hadthromboangiitis obliterans (Buerger disease).53 In anotherdouble-blind trial,54 PGI2 administered IV to nondiabeticpatients with severe arterial insufficiency produced sig-nificantly greater relief (lasting up to 1 month) of restpain than did placebo, but there was no correlation

with changes in ankle-to-brachial pressure index, or ulcerhealing.

Beraprost, an orally active PGI2 analog, was evaluatedin the Beraprost et Claudication Intermittente-2 trial55 of 549 patients with a pain-free walking distance of 50 to300 m. After 6 months, more patients receiving beraprost(40 g 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 weremodest and probably not clinically significant. The inci-dence of cardiac death, MI, coronary revascularization,stroke, transient ischemic attack (TIA), or leg ischemiarequiring intervention was similar in both groups.

Recommendation

1.1.6. For limb ischemia, we suggest clinicians not use

prostaglandins (Grade 2B).

Underlying values and preferences: The recommendationplaces a low value on achieving small gains in walkingdistance in the absence of demonstrated improvement inquality of life.

1.1.7 Other agents

Other agents with putative antithrombotic activity thathave been subjected to RCTs but were found to beineffective in the treatment of intermittent claudicationinclude the following: the antiserotonin agent ketanserin,56

suloctidil,57 fish oil supplementation,58 and naftidrofu-ryl.59–60 Other ineffective drugs for intermittent claudica-tion (such as nifedipine, l-carnitine, etc) are not discussed,as there is little evidence for the role as antithromboticagents.

Picotamide, an antiplatelet agent that inhibits throm-boxane-A2 synthase and antagonizes thromboxane-A2 re-ceptors, has been evaluated in one, small, blinded RCT61

in patients with PAOD. Treatment with picotamide sig-nificantly reduced the overall incidence of major andminor cardiovascular events. In a blinded, placebo-controlled RCT,62 patients treated with picotamideshowed no progression of carotid atherosclerosis (as mea-sured by B-mode ultrasound) compared with placebo-treated control subjects. There are no data on whether thisagent 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 acolloidal 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 walk-ing distance in two studies.64,65

A Cochrane review 66 assessed the effects of anticoagu-lant 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, amputa-tion-free survival, and side effects. Thirteen trials wereinitially considered eligible for inclusion in the review.Only three studies (two evaluating VKA, one evaluatingUFH) met the high quality methodologic inclusion criteriaand were included in the primary analysis, while four otherstudies were included in the sensitivity analysis. No signif-icant difference was observed between UFH treatmentand control groups for pain-free walking distance ormaximum walking distance at the end of treatment. Thereview found no data to indicate that LMWHs benefit

walking distance. No study reported a significant effect on



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overall mortality or cardiovascular events, and the pooledodds ratios were not significant for these outcomes. Majorand minor bleeding events were significantly more fre-quent in patients treated with VKAs compared to control,

with a nonsignificant increase in fatal bleeding events. Nomajor bleeding events were reported in the study evalu-ating UFH, while a nonsignificant increase in minorbleeding events was reported. In conclusion, no benefit of UFH, LMWH, or VKA has been established for intermit-tent claudication. An increased risk of major bleedingevents has been observed especially with VKAs. TheCochrane review 66 concluded that the use of anticoagu-lants for intermittent claudication cannot be recom-mended.

Recommendation

1.1.7. In patients with intermittent claudication, werecommend against the use of anticoagulants (Grade1A ).

2.0 Acute Limb IschemiaThe major causes of acute arterial insufficiency are

arterial thrombosis, embolus, and trauma. Extreme vaso-spasm (eg, ergot induced) and arterial dissection areunusual causes. Most traumatic occlusive events are asso-ciated with transection, laceration, or occlusion fromexternal compression such as a fracture or dislocation; butin some instances, thrombosis occurs from blunt trauma.Iatrogenic vascular trauma, most often from diagnosticand therapeutic catheter placement, is a common cause of acute arterial occlusion. In most patients early surgery isrequired, with appropriate repair of the injured vessel. If thrombosis occurred, use of the Fogarty balloon catheterto remove thrombi is often required and is usually effec-tive. Anticoagulation with UFH is variably used at the timeof operation, but may be contraindicated because of otherinjuries. Outcome is related to the seriousness of associ-ated injuries and duration of ischemia; successful vascularrepair can be achieved in most cases.

Nontraumatic acute occlusion is mainly embolic orthrombotic. The large majority of emboli arise from theheart in patients with valvular disease and/or atrial fibril-lation, with prosthetic valves, or with mural thrombi in aninfarcted or dilated left ventricle. Noncardiac sources of embolism include arterial aneurysms, ulcerated athero-sclerotic plaque, recent (endo)vascular procedures, para-doxic emboli from venous thrombi, and rarely arteritis or

vascular trauma. Approximately two thirds of noncerebralemboli enter vessels of the lower extremity and half of these obstruct the iliofemoral segment, while the remain-der involve the popliteal and tibial vessels. The upper-extremity and renal plus visceral vessels each receiveapproximately 15% of emboli.67,68

Thrombotic occlusions of arteries are usually associated with advanced atherosclerosis, and arteries often havepreexisting and developed collateral blood supply. For thisreason, final occlusion may not be a dramatic event and issometimes silent; it is not an emergent process in many patients. Thrombosis also occurs in vascular grafts and

with other degenerative or inflammatory diseases or withtrauma. The upper extremity better tolerates arterialocclusion because of rich collateral blood supply: gangreneor ischemic rest pain is rare in the absence of distalembolization. Hypovolemia, hyperviscosity, and hyperco-agulability as observed in shock, thrombocytosis, polycy-themia, and malignant disorders predispose to thromboticarterial occlusion. Arterial thrombosis most frequently involves the lower extremities.

Therapeutic management will depend on whether theocclusion is caused by embolism in a healthy artery vsthromboembolism in an atheromatous artery. Promptembolectomy through surgical intervention is the usualtechnique to remove emboli from healthy arteries. Theintroduction of the Fogarty balloon catheter 40 years agodramatically decreased the mortality and the amputationrate from arterial embolism. Percutaneous thromboembo-lectomy with the aid of an aspiration catheter or of athrombectomy device is a recent alternative. Literature oneither of these new techniques is descriptive and wasrecently reviewed.69,70 No randomized comparison be-tween the different options is available. Traditionally,thromboembolism in a severely diseased artery or in a

vascular graft causing acute ischemia symptoms has beenthe domain of the vascular surgeon as well, but optimalmanagement needs to be determined.

2.1 Heparin

Patients presenting with acute limb ischemia secondary to thromboembolic arterial occlusion usually receiveprompt anticoagulation with therapeutic dosages of UFHin order to prevent clot propagation and to obviate furtherembolism. The logic of this common clinical practice is notquestioned, even though no formal studies have estab-lished unequivocally a beneficial role of any antithrom-botic agent in patients with acute embolic occlusion. Theexpected adverse effect of perioperative anticoagulanttherapy is an increased risk of wound complications,particularly hematomas. The major role for continuedanticoagulant therapy (UFH followed by VKA) after em-bolization is to prevent embolic recurrence if the source of embolism cannot be eradicated or corrected.

Recommendation

2.1. In patients with acute arterial emboli or thrombosis, we recommend treatment with immediate systemic anti-coagulation with UFH to prevent thrombotic propagation(Grade 1C). We also recommend systemic anticoagula-tion with UFH followed by long-term VKA to preventrecurrent 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 re-store perfusion is a potential alternative to surgical revas-cularization in acute limb ischemia of thromboembolicorigin. Systemic thrombolysis with IV administration of a



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thrombolytic agent was used in the 1960s and 1970s andhas been completely abandoned and replaced by catheter-directed thrombolysis. With this technique, a catheter ispositioned intra-arterially and advanced into the thrombusfor local delivery of the thrombolytic agent. Several infu-sion methods can be used. Initially, streptokinase was themost widely used agent, but later it was superseded inclinical use by urokinase and recombinant tissue-type

plasminogen activator (rt-PA). Dosages schemes vary con-siderably; an overview of reported dosages was publishedin a recent consensus document.71 rt-PA was mainly usedin Europe, but since the suspension of urokinase sales in1998, it has been administered in the United States as

well. In addition, new agents are being investigated. Forinstance, reteplase, a nonglycosylated mutant of alteplase,

was tested in a few small series:72,73 doses of 0.5 up to 2U/h produced thrombus dissolution rates and bleedingrates that appear comparable to published data with otherthrombolytic agents, but a direct comparison is not avail-able.

A new approach is the use of the platelet glycoproteinIIb-IIIa antagonist abciximab as adjuvant therapy tothrombolysis with the hope of improving lytic efficacy andclinical outcome. A pilot trial74 randomized 70 patients tourokinase plus abciximab or to urokinase plus placebo.At 90 days, amputation-free survival was 96% in theurokinase-abciximab group vs 80% in the urokinase-placebo group. Thrombolysis occurred faster in the formergroup, but the rate of nonfatal major bleeding was alsohigher.74

Only a few randomized studies compared thrombolyticagents directly. An open trial75 compared intra-arterialstreptokinase to intra-arterial and IV rt-PA in 60 patients

with recent onset or deterioration of limb ischemia; ini-tial angiographic success was superior with intra-arterialrt-PA (100%) than with intra-arterial streptokinase (80%;p 0.04) or IV rt-PA (45%; p 0.01), the 30-day limbsalvage rates being 80%, 60%, and 45%, respectively.Another randomized trial76 in 32 patients showed signifi-cantly faster lysis with rt-PA than with urokinase, but the24-h lysis rate and the 30-day clinical success rate weresimilar. The Surgery vs Thrombolysis for Ischemia of theLower Extremity (STILE) study 77 included a comparisonof rt-PA and urokinase; patients assigned to thrombolytictreatment received at random one of the two drugs, andthe main report mentions similar efficacy and safety forboth agents.

A German study 78 randomized 120 patients with throm-botic infrainguinal arterial occlusion to treatment withurokinase or rt-PA, and noted a slight improvement insuccessful lysis in all segments treated with rt-PA(p 0.05), but local hematomas were more common. TheProurokinase Versus Urokinase for Recanalization of Pe-ripheral Occlusions, Safety and Efficacy trial79 comparedthree doses of recombinant prourokinase to tissue cultureurokinase with complete lysis as a primary end point; thehighest 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 fibrin-ogen level. In assessing all of these data, there is at present

no convincing scientific proof of superiority of any agentfor catheter-directed thrombolysis in terms of efficacy andsafety.

Although the extensive literature on catheter-directedthrombolysis is largely descriptive, five prospective ran-domized studies compared this treatment method tosurgical intervention.77,80,81,84,85 Two meta-analyses86,87 areavailable and conclude that there is a similar mortality and

amputation rate for thrombolysis and surgery; thromboly-sis reduces the need for open major surgical proceduresbut causes more bleeding and distal embolization.

In a small trial,80 surgical thrombectomy was comparedto 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 patientstreated with alteplase, and half of them subsequently underwent percutaneous transluminal angioplasty. Twoearly reocclusions occurred. Thrombectomy also resultedin an immediate restitution of blood flow in six of ninecases.

Ouriel et al81 compared initial thrombolysis comple-mented with percutaneous transluminal angioplasty or/ and surgery vs immediate surgery in 114 patients withlimb-threatening ischemia of 7 days in duration, due tonative artery or graft occlusion. Thrombolysis resulted indissolution of the occluding thrombus in 70% of thepatients. 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 tofewer cardiopulmonary complications in hospital (84% vs58% at 1 year, p 0.01).

The STILE trial77 randomized 393 patients with non-embolic native artery or bypass graft occlusion in the lowerlimbs within the past 6 months to either optimal surgicalprocedure or intra-arterial catheter-directed thrombolysis

with rt-PA or urokinase. The primary end point was acomposite outcome of death, major amputation, ongoingor recurrent ischemia, and major morbidity. At 1 month,the primary end point was reached for 36.1% of surgicalpatients and 61.7% of thrombolysis patients (p 0.0001).This difference was primarily due to ongoing/recurrentischemia (25.7% vs 54.0%; p 0.0001); lysis was unsuc-cessful in 28% of the patients assigned to thrombolysisbecause of failure of proper catheter placement, an inex-plicably high rate. However, in a secondary analysis thatstratified patients by duration of ischemia, thrombolysisresulted in improved amputation-free survival at 6 monthsand shorter hospital stay in patients with acutely ischemiclimbs ( 14 days), whereas surgical revascularization wasmore effective for more chronic ischemia ( 14 days).77

Two additional publications82,83 analyzed the STILEtrial on an intention-to-treat basis for the 30-day, 6-month,and 1-year results in patients with native artery and graftocclusion 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,



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diabetes, and critical ischemia. Only 20% of those patientshad an onset or progression of ischemic symptoms of 14days 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 thesurgical group compared to lysis, predominantly due to areduction in ongoing/recurrent ischemia. However, 39%randomized to lysis failed catheter placement and re-quired 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)84,85 investigators prospectively compared recom-binant urokinase vs surgery in acute arterial occlusion( 14 days). In a first dose-ranging trial,84 they evaluatedthe safety and efficacy of three doses of recombinanturokinase in comparison with surgery in 213 patients. Theamputation-free survival rate at 1 year was 75% in 52patients treated initially with recombinant urokinase at4,000 IU/min, and 65% in 58 surgically treated patients, anonsignificant difference. The 4,000 IU/min dosage ap-peared the most appropriate thrombolytic regimen (com-pared with 2,000 IU/min and 6,000 IU/min) for the first4 h because it maximized lytic efficacy against the bleedingrisk. This optimal dosage regimen (4,000 IU/min for theinitial 4 h followed by 2,000 IU/min for up to 48 h) wasnext 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 notsignificant. Thrombolysis reduced the need for opensurgical procedures (315 vs 551 at 6 months) withoutincreased risk of amputation or death.

Overall, the randomized trials provide no clear-cutanswer to the dilemma which of the two treatments(thrombolysis or surgical intervention) to prefer. They selected heterogeneous patient populations and studiedcomplicated endpoints. The risk of intracranial bleedingremains a major burden for thrombolytic treatment inacute limb ischemia; in three American prospective ran-domized 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 theuse of thrombolysis in the management of lower-limbarterial occlusion.71 In native artery occlusion, a manage-ment strategy incorporating thrombolysis followed by correction of the causative lesion was proposed as anappropriate strategy in patients with ischemia of 14 daysin duration. Immediate surgical revascularization is to bepreferred if thrombolysis would lead to an unacceptabledelay in effective reperfusion. In patients with irreversibleischemia, primary amputation is indicated. For occluded

bypass grafts, the therapeutic options are either surgicalrevision and thrombectomy, catheter-directed thromboly-sis, or insertion of a new graft. Factors to consider intherapeutic decision making are the age and nature of thegraft, the duration and degree of ischemia, and theavailability of vein for a new distal bypass. In patients witha recent occlusion of a well-established graft, the workingparty proposed thrombolytic therapy as a primary treat-ment modality. Thrombolysis may eventually clear thethrombosed 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 proce-dure.88

Recommendation

2.2. In patients with short-term ( 14 days) thromboticor embolic disease with low risk of myonecrosis andischemic nerve damage developing during the time toachieve revascularization by this method, we suggestintra-arterial thrombolytic therapy (Grade 2B).

Underlying values and preferences: This recommendationplaces relatively little value on small reductions in theneed for surgical intervention and relatively high value onavoiding large expenditures and possible major hemor-rhagic complications.

3.0 Vascular Grafts

The superior patency of vein grafts is supported primar-ily by a single, multicenter, randomized trial published in1986,89 which compared saphenous vein grafts with ex-panded polytetrafluoroethylene prostheses for lower-extremity arterial reconstructions. The primary patency rate at 4 years for infrapopliteal bypasses with saphenous

vein was 49%, significantly better than the 12% patency rate with polytetrafluoroethylene bypasses (p 0.001).Although demonstrating clear differences between veinand prosthetic bypasses, this trial is also notable because itdocumented that even expert surgeons had failure ratesthat were alarmingly high. Other studies90,91 show im-proved patency rates, with no major differences betweenreversed and nonreversed in situ vein grafts in which the

valves are rendered incompetent. In the absence of venousconduits, placement of arterial prostheses may be neces-sary, and most randomized trials evaluating availablematerials indicate that human umbilical vein grafts haveslightly better patency than polytetrafluoroethylene.92–94

The variable patency of all lower-extremity arterial by-passes, regardless of the type of bypass conduit, suggeststhe need for adjunctive antithrombotic therapy.

There are similarities and differences in the pathophys-iology of thrombotic occlusion of vein grafts and arterialprostheses.95 Both are subject to early occlusion fromtechnical problems that reduce or disturb blood flow.Antithrombotic therapy might prevent or delay some of these occlusions. Both are also vulnerable to intermediateand late occlusions from neointimal hyperplasia and pro-gression of atherosclerosis in the native vascular beds.However, the sites of neointimal hyperplasia differ for vein



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grafts and for vascular prostheses. In vein grafts, theprocess can be either diffuse, leading to progressiveluminal reduction of the entire graft, or focal, causingisolated stenoses at anastomoses or valve sites.95,96 Vascu-lar prostheses, in contrast, are subject to the developmentof neointimal hyperplasia at anastomoses in which theprocess stems from the adjacent artery. Patency of veingrafts and vascular prostheses is also adversely affected by progressive inflow and outflow atherosclerosis that re-duces flow through the conduit.

The principal difference between thrombotic occlusionof vein bypasses and that of prosthetic bypasses has to do

with surface thrombogenicity. Because they are lined withendothelium, vein grafts are inherently less thrombogenicthan vascular prostheses that rarely develop a completeendothelial lining. Vein grafts may lose variable amountsof their endothelial lining during harvesting and implan-tation, which may contribute to early occlusion. Thissuggests the rationale for early antithrombotic therapy thatcould be discontinued after healing at anastomotic sitesand repavement of the graft with endothelium. Arterialprostheses, however, are highly thrombogenic at the timeof implantation and remain so. Studies97,98 with 111In-labeled platelets in humans demonstrate marked uptake of labeled platelets on femoropopliteal bypass prostheses of Dacron or polytetrafluoroethylene, but little or no uptakeon vein bypasses in the same position.

3.1 Intraoperative anticoagulation during vascular reconstructions

IV UFH is traditionally administered prior to clampingarteries and interrupting flow. The goals are to preventstasis thrombosis in the often-diseased proximal and distal

vessels, and to avoid the accumulation of thrombi atanastomoses and other sites of vascular injury. Random-ized trials of this therapy are probably not justified, andthe primary question remains what should be the optimalintensity of anticoagulation during the procedure. Follow-ing the guidelines developed by cardiologists and inter-

ventional radiologists, some surgeons will monitor UFHdosage and responses using a point-of-care coagulationtesting device such as the activated clotting time.99 In theabsence of direct monitoring, a fairly intense level of anticoagulation is generally recommended during surgery,because of the wide variability in responses to UFH. Arational UFH regimen is to administer 100 to 150 U/kg IV before application of cross-clamps, and to supplement thisevery 45 to 50 min with 50 U/kg until cross-clamps areremoved and circulation is reestablished. The timing of the supplemental doses is based on the half-life of UFH(50 to 80 min).

Even in aortic surgery, in which some surgeons do notconsider UFH essential, anticoagulation may prevent re-mote thromboses. In an RCT100 of 284 patients undergo-ing elective abdominal aortic aneurysm repair, there wasno difference in the incidence of blood loss, transfusionrequirement, or arterial thrombosis in either group. How-ever, those treated with UFH sustained fewer fatal (1.4%

vs 5.7%; p 0.05) and nonfatal MIs (2.0% vs 8.5%;p 0.02) than those who did not receive UFH.

Controversy also exists as to whether protamine isbeneficial or safe for restoring hemostatic competenceafter routine peripheral vascular surgery. Protamine com-monly causes adverse hemodynamic effects; in diabeticsreceiving neutral protamine Hagedorn insulin, anaphylac-tic reactions may occur in 0.6 to 3.0% of patients.101–103

Reversal of UFH with protamine may not necessarily reduce postoperative bleeding. In a single-center, ran-domized, double-blind study 104 of 120 patients undergoingperipheral vascular surgery, protamine produced no dif-ference in blood loss, bleeding complications, or transfu-sion requirement compared with those administered sa-line solution. One caveat is that the surgeons in this trial104

used a dose of UFH (90 U/kg) that is lower than thatsuggested above, albeit with satisfactory results. Also,rapid reversal of UFH anticoagulation with protamine may increase the risk of thrombosis, at least in carotid endar-terectomy. In a small trial105 of 64 patients randomized toreceive protamine or no reversal, the amount of wounddrainage was significantly less, and neck swelling was thesame. Two patients receiving protamine suffered internalcarotid artery thrombosis compared with none in thecontrol group, although this difference was not statistically significant. UFH reversal with protamine sulfate is subjectto wide practice variations among surgeons; the desirabil-ity of reversal or nonreversal has not been established.

Recommendation

3.1. For patients undergoing major vascular reconstruc-tive procedures, we recommend UFH at the time of application of vascular cross-clamps (Grade 1A ).

3.2 Prolonging the patency of grafts

3.2.1 Antiplatelet agentsIn 1975, the first RCT106 showed the protective action

of aspirin on thromboembolic events in patients afterperipheral bypass surgery. Six trials of antiplatelet therapy in patients with peripheral bypass grafts were described inthe Sixth ACCP Consensus Conference on AntithromboticTherapy.107 These trials and others were pooled in thesecond part of the metaanalysis by the 1994 AntiplateletTrialists’ Collaboration.108 All unconfounded randomizedtrials of antiplatelet therapy available before March 1990,in which vascular graft or native arterial patency wasstudied systematically, were included. In a metaanalysis of those 11 studies, a significant risk reduction of graftocclusion of 32% in patients who received platelet inhib-itors was demonstrated.108

A metaanalysis109 performed in 1999 of trials in infrain-guinal bypass surgery found five trials110–114 comparingaspirin (alone or combined with other antiplatelet therapy)against placebo. In 423 patients treated with antiplateletdrugs, 120 bypasses occluded (28.4%), compared with 144occlusions in 393 randomized control subjects (36.6%).109

The relative risk was 0.78 (95% confidence interval [CI],0.64 to 0.95), with a proportional risk reduction of 22%.This corresponds with an absolute risk reduction of 8.2%.

Antiplatelet therapy affects prosthetic and vein graftsdifferently. A favorable effect of antiplatelet therapy was



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demonstrated in the trials111–113 studying patients withprosthetic grafts, whereas trials110,114 in which at least 70%had venous grafts were inconclusive. This stronger bene-ficial effect of aspirin on prosthetic grafts was also sup-ported in a short-term (6 weeks) trial by Clyne et al,115

who demonstrated a benefit of aspirin and dipyridamoletreatment in patients with prosthetic grafts, whereas nobenefit was seen in the vein graft bypass group. Thebeneficial effect of antiplatelet therapy on prosthetic graftpatency was confirmed in a recent overview analysis.116 Inthe Antiplatelet Trialists’ Collaboration overview 108 of allantiplatelet studies, neither direct nor indirect compari-sons of the effects of different regimens (aspirin, dipyrid-amole, sulfinpyrazone, ticlopidine and suloctidil) on vas-cular patency provided convincing evidence that oneantiplatelet regimen was more effective than another. Inthe Dutch Bypass, Oral Anticoagulants or Aspirin (BOA)study 117 (see below), which randomized a large number of patients undergoing lower-extremity bypass (vein andprosthetic) to VKA vs aspirin, aspirin was found to signif-icantly improve patency of prosthetic grafts.

Ticlopidine, an inhibitor of adenosine diphosphate-induced platelet activation, has also been shown to beeffective in improving the patency of femoropoplitealand femorotibial bypasses. In a randomized, multicenter,placebo-controlled trial118 of 243 patients, primary patency at 24 months was 82% in the ticlopidine group and 63% inthe placebo group (p 0.002). In clinical use, ticlopidinehas now been superceded by the chemically related drugclopidogrel, for which new trials are underway. At present,there are no definitive data to recommend clopidogrel toimprove patency.

Controversy still remains as to whether antiplatelettherapy is best started preoperatively or postoperatively,although the weight of evidence suggests inhibition of platelet function is best established prior to the vascularinjury. Two of three trials112,113 of aspirin showed a benefitin graft patency when the drug was started preoperatively,and the third trial114 showed no benefit when antiplatelettherapy was begun postoperatively. This third trial114 hadthe largest percentage of vein grafts, which are thought tobe less thrombogenic. Data from the literature119–122 onthe patency of aortocoronary saphenous vein grafts sup-ports the concept of beginning antiplatelet therapy prior tosurgery.

Recommendation

3.2.1. In patients undergoing prosthetic infrainguinalbypass, we recommend aspirin (Grade 1A ).

3.2.2 VKAs

Two randomized trials123,124 have compared the efficacy of VKAs to no antithrombotic therapy in patients afterinfrainguinal bypass surgery. Kretschmer and col-leagues123 studied the effect of long-term treatment with

VKA (target international normalized ratio [INR], 2.4 to4.8) on vein graft patency, limb salvage, and survival inpatients operated on for claudication or critical ischemia.Patency was determined by Doppler ultrasonography, and

angiography when indicated. In 66 treated patients, 13grafts occluded (19.7%), compared with 23 occlusions in64 control subjects (35.9%), a relative risk of 0.55 (95% CI,0.30 to 0.99), with a proportional risk reduction of 45%.The corresponding absolute risk reduction by VKA was16.2%. Limb loss was also significantly less common in theanticoagulated group (6.1%) than in the control group(20.3%). Among the anticoagulated patients, 27 patients

(40.9%) died during 10 years of follow-up, compared with37 subjects (57.8%) in the control group (relative risk,0.71; 95% CI, 0.49 to 1.01), with an absolute risk reductionof 16.9%. The study reported one fatal GI hemorrhage inthe treated group.

A second trial124 included a more heterogeneous groupof 116 patients undergoing various vascular reconstruc-tions ( ie, vein or prosthetic bypass and endarterectomy).Intention-to-treat analysis showed no difference in pa-tency rate, limb salvage, and survival at the first, second,and third year of follow-up between the anticoagulatedgroup and the control group. These conflicting results withthe trial by Kretschmer et al123 may have been due to thelower level of anticoagulation (target INR, 1.8 to 2.8) inthe latter trial, and by the differences in graft materials:

vein in the first trial, and prosthetic grafts or endarterec-tomy in more than half of the patients in the second trial.

Four trials117,125–127 comparing VKA with aspirin inpatients after infrainguinal bypass surgery or thromboen-darterectomy have been reported. In 1979, Schneider etal125 reported a trial of 91 patients with a vein femoropop-liteal bypass and 122 patients after thromboendarterec-tomy. They were randomized to treatment with eitheraspirin (1,000 mg/d) or aspirin plus dipyridamole (225mg/d) or VKA (target range not reported). The overall2-year patency rate did not differ significantly in thegroups. However, subgroup analysis of patients after veinbypass surgery demonstrated a better patency rate in thegroup treated with VKAs compared with both antiplateletgroups, 87% vs 65% (p 0.005). In the subgroup of patients undergoing thromboendarterectomy, antiplatelettherapy proved to be favorable compared to VKA; patency rates were 80% and 51%, respectively (p 0.002).

The Dutch BOA study randomized a total of 2,690patients from 80 centers to VKA therapy (target INR, 3 to4.5) or aspirin, 80 mg/d.117 All patients in the BOA study

who required an infrainguinal bypass graft for obstructivearterial disease were eligible for inclusion, and the meanfollow-up was 21 months. The VKA group had 308 graftocclusions, compared to 322 occlusions in the aspiringroup (hazard ratio, 0.95; 95 CI, 0.82 to 1.11), suggestingno overall benefit of one treatment over the other. Thehazard ratios of VKA vs aspirin were essentially the samein patients with femoropopliteal (hazard ratio, 0.97; 95%CI, 0.81 to 1.16), and femorocrural bypass grafts (hazardratio, 0.95; 95% CI 0.70 to 1.30). However, analysisstratified for graft material showed a lower risk of veingraft occlusion in anticoagulated patients than in thosereceiving aspirin (hazard ratio, 0.69; 95% CI, 0.54 to 0.88).Seventeen patients would require treatment to preventone occlusion. Conversely, the risk of prosthetic graftocclusion was lower in patients treated with aspirin (haz-ard ratio, 1.26; 95% CI, 1.03 to 1.55). Fifteen patients



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randomized trial of 301 patients comparing very-low-doseaspirin therapy, 50–100 mg/d, with placebo after carotidendarterectomy.133 Therapy was started 1 week to 3months after operation, and no significant benefit of

very-low-dose aspirin therapy was detectable. However,the timing of perioperative aspirin therapy may be critical,

with late postoperative initiation of therapy being too lateto be beneficial. This is suggested by a randomized,

double-blind trial134

of aspirin, 75 mg/d, vs placebo in 232patients; therapy was started preoperatively and was asso-ciated with a marked reduction in intraoperative andpostoperative stroke.

The ASA and Carotid Endarterectomy Trial135 was amulticenter, randomized, double-blind clinical trial in

which 2849 patients scheduled for carotid endarterectomy were randomly assigned to one of four aspirin doses (81mg, 325 mg, 650 mg, and 1,300 mg). Aspirin was startedbefore surgery and continued for 3 months. The combinedrate of stroke, MI, and death was lower in the low-dosegroups (81 mg and 325 mg) than in the high-dose groupsat 30 days (5.4% vs 7.0%, p 0.07) and at 3 months (6.2%

vs 8.4%, p 0.03). Since many patients would be receiv-ing higher doses of aspirin prior to randomization into thestudy, and surgery would be performed prior to washout of the previous dose platelet effect, a separate efficacy analysis was performed of patients previously receiving 650 mg of aspirin and who were randomized 2 daysbefore surgery. In the efficacy analysis, there were 566patients in the low-dose group, and 550 patients in thehigh-dose group. The combined rate of stroke, MI, anddeath occurred less frequently in the low-dose group thanin the high-dose group at both 30 days and 3 months (3.7%

vs 8.2%, p 0.002; 4.2% vs 10.0%, p 0.0002).135

Based on these considerations, perioperative aspirin

therapy, 75 to 325 mg/d, is appropriate therapy in patientsundergoing carotid endarterectomy. Therapy should bestarted at the time of clinical presentation and continuedthrough the perioperative period. Bleeding complications,particularly wound hematomas, occur in 1.4 to 3.0% of patients undergoing carotid endarterectomy, and are as-sociated with incomplete reversal with protamine of intra-operative UFH, hypertension, and perioperative antiplate-let therapy.136,137 If intraoperative UFH is not fully reversed or continuous UFH anticoagulation is adminis-tered postoperatively, perioperative aspirin therapy wouldpotentially increase the incidence of hematomas and otherbleeding complications.

Recommendation

4.1. We recommend that aspirin, 75 to 325 mg, be givenpreoperatively and continued indefinitely in patients un-dergoing carotid endarterectomy (Grade 1A ).

5.0 Asymptomatic and Recurrent CarotidStenosis

It is unknown whether aspirin therapy will prevent ordelay the onset of TIAs and strokes in patients withasymptomatic cerebrovascular disease. Indirect evidence

from the Veterans Administration asymptomatic carotidstenosis study 138,139 suggests that aspirin may be beneficialin patients with advanced stenosis who do not undergocarotid endarterectomy. A surprising 16% of patientsrandomized to medical therapy were intolerant and had todiscontinue aspirin. The incidence of neurologic events

was significantly higher among patients who stoppedtaking aspirin.

The long-term protective effects of aspirin on strokerate for asymptomatic patients with 50% carotid steno-sis is unclear. In a blinded, placebo-controlled trial in

which 372 asymptomatic patients with 50% carotidstenosis were randomized to either aspirin (325 mg/d) orplacebo, no difference in stroke rate or incidence of acomposite end point of ischemic events was observed at amean follow-up of 2.3 years.140 The clinical application of these findings, particularly concerning the use of aspirin inthese patients as a means of preventing cardiac events, istempered by the relatively short follow-up period and by the exclusion of patients with symptomatic cerebrovascu-lar disease, recent MI, and unstable angina.

Significant stenoses recurring at the site of endarterec-tomy are found in as many as 10 to 19% of patients aftercarotid endarterectomy.141 Data from retrospective stud-ies142,143 suggest that antiplatelet therapy does not reducethe incidence of recurrent carotid artery stenosis. Arandomized trial144 confirmed that treatment with aspirinand dipyridamole does not prevent symptomatic or asymp-tomatic recurrent stenosis after carotid endarterectomy.Although there are no data to recommend aspirin treat-ment for patients with asymptomatic or recurrent carotidstenosis in order to prevent progression or symptomdevelopment, these patients have a high prevalence of associated coronary and PAOD. Therefore, antiplatelettherapy may improve long-term cardiovascular outcomes.

Recommendation

5.0. In nonoperative patients with asymptomatic orrecurrent carotid stenosis, we recommend lifelong aspirin,75 to 162 mg/d (Grade 1C).

6.0 Lower-Extremity Endovascular Procedures

Recommendations for optimal antithrombotic therapy for lower-extremity arterial balloon angioplasty are ham-pered by the lack of agreement over the proper role of these endovascular procedures, and a lack of data fromsuitable RCTs. There is general consensus that translumi-nal angioplasty is appropriate for focal stenotic lesions of the iliac and femoropopliteal arteries, particularly whenthe indication for limb revascularization is intermittentclaudication rather than critical ischemia, and in nondia-betic patients with relatively preserved tibial artery run-off.145 There is less agreement regarding the suitability of transluminal angioplasty for more diffuse and extensivepatterns of occlusive disease.

Complicating the matter even further is the technologic“moving target” of catheter-based interventions. The useof self-expanding metallic stents can salvage what other-

wise might be an unacceptable technical outcome from



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balloon angioplasty alone. The routine use of stents,however, has not been shown to improve the results of lower extremity balloon angioplasty.145,146 Newer devicessuch as medication-coated stents are being tested in thelower-extremity arterial circulation.147 Based on the prom-ising early results seen with coronary stenting,148 suchdevices might find a role in the peripheral arterial vascularbed. It cannot be assumed then, that results from clinical

trials evaluating antithrombotic therapy for balloon angio-plasty alone will necessarily extrapolate to its use withexisting and newer stent devices.

Life-long antiplatelet therapy is recommended for allpatients with PAOD on the basis of their increased risk of coronary and cerebrovascular events. Given this, the pri-mary issue governing the proper use of antithrombotictherapy in conjunction with lower-extremity balloon an-gioplasty and stenting is that of agent and dosage.

Whether antiplatelet therapy improves patency of lower-extremity angioplasty is a separate question, and hasbeen addressed in two RCTs149,150 comparing combina-tions of aspirin and dipyridamole with placebo. In asingle-center trial149 of 199 patients undergoing lower-extremity angioplasty, patients were randomized to acombination of dipyridamole (225 mg) plus high-doseaspirin (990 mg), dipyridamole with low-dose aspirin (300mg), or placebo Only patients undergoing successfulballoon angioplasty of femoropopliteal arterial segmentatherosclerotic obstructive lesions were randomized. Clin-ical and angiographic follow-up showed an improvementin both treatment groups in comparison with placebo;however, only the high-dose aspirin group achieved astatistically significant improvement.

In another RCT150 from 12 centers, 223 patients under-going balloon angioplasty of iliac and femoropoplitealsegments were randomized to either placebo or a combi-nation of aspirin (50 mg) and dipyridamole (400 mg).Primary patency and overall results were the same in bothgroups, thus showing no benefit with antiplatelet therapy.Limitations of this study include a higher percentage of patients undergoing treatment of more favorable iliaclesions in the placebo group (65% vs 51%); adjunctive useof metallic stents was not performed, as is commonly donenow in clinical practice with the advent of low-profile,self-expanding, flexible stents.

It is not uncommon for combinations of anticoagulationand antiplatelet therapy to be used in patients undergoingfemoropopliteal, and tibial artery balloon angioplasty. Thisdoes not appear to be supported by the results of the threeRCTs151–153 published regarding this issue; a total of 438patients were randomized in the three studies. In all threestudies,151–153 the arterial patency rates were slightly lowerin the anticoagulation groups, but this was not statistically significant in any of the studies. Also, there tended to bemore bleeding complications in the anticoagulationgroups, including one fatal intracerebral hemorrhage.

Combinations of thienopyridines (ticlopidine, clopi-dogrel) with aspirin are also used in clinical practice asantithrombotic therapy for lower-extremity balloon angio-plasty and stenting, particularly when the treated arteriesare in the femoropopliteal segments, and in the smaller-diameter tibial arteries. As yet, such combinations have

not been studied in RCTs. Interest in the use of aspirin with either ticlopidine or clopidogrel has undoubtedly been stimulated by the favorable results reported withaspirin and ticlopidine in comparison with aspirin aloneand aspirin with warfarin after coronary artery stenting.154

There are important differences between lower-extremity arterial interventions and those in the coronary circulationto call into question the validity of such an extrapolation.Nonetheless, given the relatively high rate of failure of lower-extremity intervention and the increasing use of stents in these interventions, investigation aimed at study-ing such combinations of antiplatelet therapy in thissetting is needed.

In summary, antiplatelet therapy with aspirin is indi-cated for all patients undergoing lower-extremity balloonangioplasty (with or without stenting), as it is currently recommended for all patients with PAOD. There areinsufficient data to recommend any additional antiplateletor antithrombotic agents for iliac artery angioplasty andstenting. Similarly, insufficient data exist to recommendadditional antithrombotic agents in the setting of femoro-popliteal or tibial arterial angioplasty and stenting. Specif-ically, the addition of anticoagulation to antiplatelet ther-apy does not appear to convey any advantage, and likely increases the risk of bleeding complications. Based on thedata from the coronary circulation, it is reasonable toconsider combinations of aspirin and thienopyridines inhigh-risk, small-diameter tibial artery angioplasty.

Recommendation

6.0. For all patients undergoing lower-extremity balloonangioplasty (with or without stenting), we recommendlong-term aspirin, 75 to 162 mg/d (Grade 1C).

Summary of Recommendations

1.0 Chronic Limb Ischemia

1.1 Antiplatelet therapy

1.1.1 Aspirin

1.1.1. We recommend lifelong aspirin therapy, 75 to325 mg/d, in comparison to no antiplatelet therapy inpatients with clinically manifest coronary or cerebrovascu-lar disease (Grade 1A ) and in those without clinically manifest coronary or cerebrovascular disease (Grade

1C).

1.1.2 Ticlopidine

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

1.1.3 Clopidogrel

1.1.3. We recommend clopidogrel in comparison to noantiplatelet therapy (Grade 1C), but suggest that aspi-rin be used instead of clopidogrel (Grade 2A ).Underlying values and preferences: This recommendation



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places a relatively high value on avoiding large expendi-tures to achieve small reductions in vascular events.

1.1.4 Cilostazol

1.1.4. For patients with disabling intermittent claudica-tion who do not respond to conservative measures (riskfactor modification and exercise therapy) and who are not

candidates for surgical or catheter-based intervention, wesuggest cilostazol (Grade 2A ). We suggest that cliniciansnot use cilostazol in those with less-disabling claudication(Grade 2A ).

Underlying values and preferences: The recommendationagainst cilostazol for those with less-disabling claudicationplaces a relatively low value on small possible improve-ments in function in the absence of clear improvement inhealth-related quality of life.

1.1.5 Pentoxifylline

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

1.1.6 Prostaglandins

1.1.6. For limb ischemia, we suggest clinicians not useprostaglandins (Grade 2B).

Underlying values and preferences: The recommendationplaces a low value on achieving small gains in walkingdistance in the absence of demonstrated improvement inquality of life.

1.1.7 Other agents

1.1.7. In patients with intermittent claudication, werecommend against the use of anticoagulants (Grade1A ).

2.0 Acute Limb Ischemia

2.1 Heparin

2.1. In patients with acute arterial emboli or thrombosis, we recommend treatment with immediate systemic anti-

coagulation with UFH to prevent thrombotic propagation(Grade 1C). We also recommend systemic anticoagula-tion with UFH followed by long-term VKA to preventrecurrent embolism in patients undergoing embolectomy (Grade 1C).

2.2 Thrombolysis

2.2. In patients with short-term ( 14 days) thromboticor embolic disease with low risk of myonecrosis andischemic nerve damage developing during the time toachieve revascularization by this method, we suggestintra-arterial thrombolytic therapy (Grade 2B).

Underlying values and preferences: This recommendationplaces relatively little value on small reductions in theneed for surgical intervention and relatively high value onavoiding large expenditures and possible major hemor-rhagic complications.

3.0 Vascular Grafts

3.1 Intraoperative anticoagulation during vascular reconstructions

3.1 For patients undergoing major vascular reconstruc-tive procedures, we recommend UFH at the time of application of vascular cross-clamps (Grade 1A ).

3.2 Prolonging the patency of grafts

3.2.1 Antiplatelet agents

3.2.1. In patients undergoing prosthetic infrainguinal by-pass, we recommend aspirin (Grade 1A ).

3.2.2 Vitamin K antagonists3.2.2. We suggest that VKA not be used routinely in

patients undergoing infrainguinal femoropopliteal or distal vein bypass (Grade 2A ).

Underlying values and preferences: This recommendationattributes relatively little value to small increases in long-term patency and relatively high value to avoiding hemor-rhagic complications.

3.2.3 VKA plus aspirin

3.2.3. For routine patients undergoing infrainguinalbypass without special risk factors for occlusion, we rec-ommend against VKA plus aspirin (Grade 1A ). For thoseat high risk of bypass occlusion and limb loss, we suggest

VKA plus aspirin (Grade 2B).

Underlying values and preferences: These recommenda-tions place high value on the avoidance of bleedingcomplications but recognize that there are circumstances

where the threat of limb loss and major disability may supercede this risk.

4.0 Carotid Endarterectomy4.1 Aspirin

4.1. We recommend that aspirin, 75 to 325 mg/d, begiven preoperatively and continued indefinitely in patientsundergoing carotid endarterectomy (Grade 1A ).

5.0 Asymptomatic and Recurrent CarotidStenosis

5.0. In nonoperative patients with asymptomatic orrecurrent carotid stenosis, we recommend lifelong aspirin,75 to 162 mg/d (Grade 1C).



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6.0 Lower Extremity Endovascular Procedures

6.0. For all patients undergoing lower-extremity balloonangioplasty (with or without stenting), we recommendlong-term aspirin, 75 to 162 mg/d (Grade 1C).

References

1 Reunanen A, Takkunen H, Aromaa A. Prevalence of inter-mittent claudication and its effect on mortality. Acta MedScand 1982; 211:249–256

2 Jelnes R, Gaardsting O, Hougaard Jensen K, et al. Fate inintermittent claudication: outcome and risk factors. BMJ1986; 293:1137–1140

3 Skau T, Jonsson B. Prevalence of symptomatic leg ischaemiain a Swedish community: an epidemiological study. Eur J

Vasc Surg 1993; 7:432–4374 Criqui MH, Fronek A, Barrett-Connor E, et al. The preva-

lence of peripheral arterial disease in a defined population.Circulation 1985; 71:510–515

5 Newman AB, Siscovick DS, Manolio TA, et al. Ankle-armindex as a marker of atherosclerosis in the cardiovascularhealth study. Circulation 1993; 88:837–845

6 Cox GS, Hertzer NR, Young JR, et al. Nonoperative treat-ment of superficial femoral artery disease: long-term follow-up. J Vasc Surg 1993; 17:172–182

7 Cronenwett JL, Warner KG, Zelenock GB, et al. Intermit-tent claudication. Arch Surg 1984; 119:430 –436

8 Howell MA, Colgan MP, Seeger RW, et al. Relationship of severity of lower limb peripheral vascular disease to mortal-ity and morbidity: a six-year follow-up study. J Vasc Surg1989; 9:691–697

9 Ogren M, Hedblad B, Isacsson SO, et al. Non-invasively detected carotid stenosis and ischaemic heart disease in men

with leg arteriosclerosis. Lancet 1993; 342:1138–114110 Leng GC, Fowler B, Ernst E. Exercise for intermittent

claudication. Cochrane Database Syst Rev (database online).

Issue 2, 200011 Regensteiner JG, Hiatt WR. Current medical therapies for

patients with peripheral arterial disease: a critical review.Am J Med 2002; 112:49 –57

12 Hiatt WR. Medical treatment of peripheral arterial diseaseand claudication. N Engl J Med 2001; 344:1608–1621

13 Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy forprevention of death, myocardial infarction, and stroke inhigh risk patients. BMJ 2002; 324:71–86

14 Hess H, Mietaschik A, Deichsel G. Drug-induced inhibitionof platelet function delays progression of peripheral occlu-sive arterial disease: a prospective double-blind arterio-graphically controlled trial. Lancet 1985; 1:416 –419

15 Libretti A, Catalano M. Treatment of claudication with dipy-ridamole and aspirin. Int J Clin Pharmacol Res 1986; 6:59 –60

16 Giansante C, Calabrese S, Fisicaro M, et al. Treatment of intermittent claudication with antiplatelet agents. J Int MedRes 1990; 18:400–407

17 Goldhaber SZ, Manson JE, Stampfer MJ, et al. Low-doseaspirin and subsequent peripheral arterial surgery in thePhysicians’ Health Study. Lancet 1992; 340:143–145

18 Boissel JP, Peyrieux JC, Destors JM. Is it possible to reducethe risk of cardiovascular events in subjects suffering fromintermittent claudication of the lower limbs? Thromb Hae-most 1989; 62:681–685

19 Arcan JC, Panak E. Ticlopidine in the treatment of periph-eral occlusive arterial disease. Semin Thromb Haemost1989; 15:167–170

20 Balsano F, Coccheri S, Libretti A, et al. Ticlopidine in thetreatment of intermittent claudication: a 21-month double-blind trial. J Lab Clin Med 1989; 114:84–91

21 Bergqvist D, Almgren B, Dickinson JP. Reduction of therequirement for leg vascular surgery during long-term treat-ment of claudicant patients with ticlopidine: results from theSwedish Ticlopidine Multicentre Study (STIMS). Eur J VascEndovasc Surg 1995; 10:69–76

22 CAPRIE Steering Committee. A randomized, blinded, trial

of clopidogrel versus aspirin in patients at risk of ischaemicevents (CAPRIE). Lancet 1996; 348:1329 –133923 Money SR, Herd JA, Isaacsohn JL, et al. Effect of cilostazol

on walking distances in patients with intermittent claudica-tion caused by peripheral vascular disease. J Vasc Surg 1998;27:267–275

24 Dawson DL, Cutler BS, Meissner MH, et al. Cilostazol hasbeneficial effects in treatment of intermittent claudication:results from a multicenter, randomized, prospective, dou-ble-blind trial. Circulation 1998; 98:678 –686

25 Dawson DL, DeMaioribus CA, Hagino RT, et al. The effectof withdrawal of drugs treating intermittent claudication.Am J Surg 1999; 178:141–146

26 Beebe HG, Dawson DL, Cutler BS, et al. A new pharma-cologic treatment for intermittent claudication: results of a

randomized, multicenter trial. Arch Intern Med 1999; 159:2041–2050

27 Dawson DL, Cutler BS, Hiatt WR, et al. A comparison of cilostazol and pentoxifylline for treating intermittent claudi-cation. Am J Med 2000; 109:523–530

28 Angelkort B, Maurin N, Bouteng K. Influence of pentoxi-fylline on erythrocyte deformability in peripheral occlusivearterial disease. Curr Med Res Opin 1979; 6:255–258

29 Johnson WC, Sentissi JM, Baldwin D, et al. Treatment of claudication with pentoxifylline: are benefits related toimprovement in viscosity? J Vasc Surg 1987; 6:211–216

30 Angelkort B, Kiesewetter H. Influence of risk factors andcoagulation phenomena on the fluidity of blood in chronicarterial occlusive disease. Scand J Clin Lab Invest 1981;

156(suppl):185–18831 Hood SC, Moher D, Barber GG. Management of intermittent

claudication with pentoxifylline: meta-analysis of randomizedcontrolled trials. Can Med Assoc J 1996; 155:1053–1059

32 Bollinger A, Frei C. Double blind study of pentoxifyllineagainst placebo in patients with intermittent claudication.Pharmatherapeutica 1977; 1:557–562

33 DiPerri T, Guerrini M. Placebo controlled double blindstudy with pentoxifylline of walking performance in patients

with intermittent claudication. Angiology 1983; 34:40 –4534 Roekaerts F, Deleers L. Trental 400 in the treatment of

intermittent claudication: results of long-term, placebo-controlled administration. Angiology 1984; 35:396–406

35 Strano A, Davi G, Avellone G, et al. Double-blind, crossoverstudy of the clinical efficacy and the hemorheological effectsof pentoxifylline in patients with occlusive arterial disease of the lower limbs. Angiology 1984; 35:459 –466

36 Lindgarde F, Jelnes R, Bjorkman H, et al. Conservative drugtreatment in patients with moderately severe chronic occlusiveperipheral arterial disease. Circulation 1989; 80:1549–1556

37 Ciocon JO, Galindo-Ciocon D, Galindo DJ. A comparisonbetween aspirin and pentoxifylline in relieving claudicationdue to peripheral vascular disease in the elderly. Angiology 1997; 48:237–240

38 Porter JM, Cutler BS, Lee BY, et al. Pentoxifylline efficacy inthe treatment of intermittent claudication: multicenter con-trolled double-blind trial with objective assessment of chronicocclusive arterial disease patients. Am Heart J 1982; 104:66–72


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Antithrombotic Therapy in Peripheral Arterial Occlusive Disease

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