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Antithrombotic Therapy in
clamps (Grade 1A). In patients undergoing pros-
Peripheral Arterial Occlusive
thetic 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
The Seventh ACCP Conference on
2A). For routine patients undergoing infrainguinal
bypass without special risk factors for occlusion, we
Antithrombotic and Thrombolytic
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 rec-
G. Patrick Clagett, MD, Co-Chair;Michael Sobel, MD, Co-Chair; Mark R. Jackson, MD; ommend aspirin preoperatively and continued indef-
Gregory Y. H. Lip, MD; Marco Tangelder, MD; and initely (Grade 1A). In nonoperative patients with
asymptomatic or recurrent carotid stenosis, we rec-
ommend lifelong aspirin (Grade 1C؉). For all pa-
tients undergoing extremity balloon angioplasty, we
This chapter about antithrombotic therapy for pe-
recommend long-term aspirin (Grade 1C؉).
ripheral arterial occlusive disease is part of the
(CHEST 2004; 126:609S– 626S)
seventh ACCP Conference on Antithrombotic and
Thrombolytic Therapy: Evidence Based Guidelines.
Key words: anticoagulants; antithrombotic; occlusive artery dis-
Grade 1 recommendations are strong and indicate
that the benefits do, or do not, outweigh risks,
burden, and costs, and Grade 2 suggests that indi-
Abbreviations: ACD ϭ absolute claudication distance; BOA ϭ
vidual patients’ values may lead to different choices
Bypass, Oral Anticoagulants or Aspirin; CI ϭ confidence interval; (for a full understanding of the grading see Guyatt et
INR ϭ international normalized ratio; LMWH ϭ low molecular weight heparin; MI ϭ myocardial infarction; PAOD ϭ peripheral arterial oc- al, CHEST 2004;126:179S–187S). Among the key
recommendations in this chapter are the following:
RCT ϭ randomized controlled trial; rt-PA ϭ recombinant tissue- For patients with chronic limb ischemia, we recom-
type plasminogen activator; STILE ϭ Surgery vs Thrombolysis mend lifelong aspirin therapy in comparison to no
for Ischemia of the Lower Extremity; TIA ϭ transient ischemic attack; UFH ϭ unfractionated heparin; TOPAS ϭ Thrombolysis antiplatelet therapy in patients with clinically mani-
or Peripheral Arterial Surgery; VKA ϭ vitamin K antagonist fest coronary or cerebrovascular disease (Grade 1A)
and in those without clinically manifest coronary or
cerebrovascular disease (Grade 1C؉). We recom-
Patient populations with peripheral arterial occlusive
disease (PAOD) are summarized in Table 1.
mend clopidogrel over no antiplatelet therapy
(Grade 1C؉) but suggest that aspirin be used instead
1.0 Chronic Limb Ischemia
of clopidogrel (Grade 2A). For patients with dis-
abling intermittent claudication who do not respond
Atherosclerotic PAOD is symptomatic with intermittent to conservative measures and who are not candidates
claudication in 2 to 3% of men and 1 to 2% of women for surgical or catheter-based intervention, we sug-
Ͼ 60 years old.1–3 However, the prevalence of asymptom- gest cilostazol (Grade 2A). We suggest that clinicians
atic PAOD, generally proven by a reduced ankle/brachial not use cilostazol in patients with less-disabling clau-
systolic pressure index, is three to four times as great.4–5 dication (Grade 2A). In these patients, we recom-
After 5 to 10 years, 70 to 80% of patients remain mend against the use of pentoxifylline (Grade 1B).
unchanged or improved, 20 to 30% have progression of We suggest clinicians not use prostaglandins (Grade
symptoms and require intervention, and 10% require 2B). In patients with intermittent claudication, we
amputation.6,7 Progression of disease is greatest in patients recommend against the use of anticoagulants (Grade
with multilevel arterial involvement, low ankle-to-brachial 1A). In patients with acute arterial emboli or throm-
pressure indices, chronic renal insufficiency, diabetes bosis, we recommend treatment with immediate sys-
temic anticoagulation with unfractionated heparin
The prevalence of PAOD increases with age and is a (UFH) [Grade 1C]. We also recommend systemic
significant cause of hospital admission and an important anticoagulation with UFH followed by long-term
predicator of cardiovascular and stroke mortality, which is vitamin K antagonist (VKA) in patients with embol-
increased twofold to threefold.1,2,8,9 Rest pain and critical sim [Grade 1C]). For patients undergoing major
ischemia are usually the result of progression of athero- vascular reconstructive procedures, we recommend
sclerotic disease, leading to occlusion of the distal vessels UFH at the time of application of vascular cross-
such as the popliteal and tibial arteries. There is an inverserelationship between the ankle-to-brachial pressure index Reproduction of this article is prohibited without written permis- and clinically manifest cardiovascular disease.5 The lower sion from the American College of Chest Physicians (e-mail: the index, the greater the occurrence of adverse cardiac events, strokes, and cardiovascular deaths.
Correspondence to: G. Patrick Clagett, MD, UT SouthwesternMedical Center, 5323 Harry Hines Blvd, Dallas, TX 75235-9157; This chapter addresses antithrombotic therapy for pa- e-mail: [email protected] tients with PAOD. We note, however, that a systematic CHEST / 126 / 3 / SEPTEMBER, 2004 SUPPLEMENT review and metaanalysis10 of randomized trials of exercise artery disease and stroke. This applies to many patients therapy in patients with claudication suggests that exercise with chronic arterial insufficiency who also have clinically improves maximal walking time by 150%. One must judge manifest coronary or cerebrovascular disease. Almost all symptomatic antithrombotic therapy in this context. Fur- patients with PAOD who do not have clinically manifest thermore, while risk factor modification is not well studied disease have occult coronary or cerebrovascular disease.
in patients with PAOD, observational data and generali- Aspirin is less effective than ticlopidine and clopidogrel zation from trials11,12 in persons with other manifestations (see below). However, the marginal benefit of these other of cardiovascular disease support the importance of treat- drugs is small, and aspirin is much less expensive. These ing key risk factors such as smoking, diabetes, dyslipide- are the rationales for our recommendation for aspirin over 1.1 Antiplatelet therapy
Recommendation
Antiplatelet therapy may modify the natural history of 1.1.1. We recommend lifelong aspirin therapy (75 to chronic lower-extremity arterial insufficiency, as well as 325 mg/d) in comparison to no antiplatelet therapy in lower the incidence of associated cardiovascular events.
patients with clinically manifest coronary or cerebrovascu- No convincing data from properly designed large trials lar disease (Grade 1A) and in those without clinically
demonstrate that antithrombotic therapy will delay or manifest coronary or cerebrovascular disease (Grade
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 Anti-thrombotic Trialists’ Collaboration metaanalysis13 found One metaanalysis18 demonstrated that patients with that among 9,214 patients with PAOD in 42 trials, there intermittent claudication treated with ticlopidine had a was a 23% reduction in serious vascular events (p ϭ 0.004) significant reduction in fatal and nonfatal cardiovascular in patients treated with antiplatelet therapy. Patients with events in comparison with patients treated with placebo.
intermittent claudication, those having peripheral bypass, Ticlopidine has also shown a modest beneficial effect for endarterectomy, and those having peripheral angioplasty relieving symptoms, increasing walking distance, and im- all benefited to a similar degree. For all conditions, aspirin proving lower-extremity ankle pressure indices in patients at 80 to 325 mg/d was at least as effective as any other with intermittent claudication (see chapter by Patrono et regimen, including higher-dose aspirin therapy, which is al in this Supplement).19–20 In a multicenter, placebo- more prone to cause side effects and GI complications.
controlled RCT,21 ticlopidine, 250 mg/d, resulted in fewervascular surgery procedures (relative risk, 0.49; p Ͻ 0.001) among patients with intermittent claudication. However,ticlopidine is associated with a substantial risk of leukope- The antiplatelet trialists analysis13 showed that for all nia and thrombocytopenia, requiring close hematologic conditions, aspirin at 80 to 325 mg/d was at least as monitoring. Because of these side effects, clopidogrel has effective as any other regimen, including higher-dose replaced ticlopidine as the thienopyridine of choice.
aspirin therapy, which is more prone to cause side effectsand GI complications. Data from a single randomized Recommendation
controlled trial (RCT)14 suggest that aspirin, alone orcombined with dipyridamole, will delay the progression of 1.1.2. We recommend clopidogrel over ticlopidine established arterial occlusive disease as assessed by serial (Grade 1C؉).
angiography. This may have been an effect on inhibitingthrombotic occlusion of stenotic vessels rather than retard- In another study of 54 patients with intermittent clau- Clopidogrel is a thienopyridine, the chemical structure dication, the combination of aspirin and dipyridamole was of which is similar to ticlopidine, that exerts an irreversible found to increase the pain-free walking distance and antiplatelet effect primarily directed against adenosine resting limb blood flow.15 An RCT16 of 296 patients with diphosphate-induced stimulation of platelet function (see intermittent claudication found an improved coagulation chapter by Patrono et al in this Supplement). In a large, profile and ankle/brachial index with therapy, but did not multicenter RCT22 of 19,185 patients, investigators com- report if walking distance improved with combined ther- pared the relative efficacy of clopidogrel and aspirin in apy. The Physicians Health Study,17 a primary prevention reducing the risk of a composite end point of ischemic study, found that aspirin, 325 mg every other day, de- stroke, MI, or vascular death. The study population com- creased the need for peripheral arterial reconstructive prised patients with recent ischemic stroke, recent MI, or surgery; however, no difference was noted between the PAOD. The overall incidence of composite end points was aspirin and placebo groups in the development of inter- lower in the group treated with clopidogrel (5.32%/yr) than with aspirin (5.83%; p ϭ 0.043). A subgroup analysis Other chapters in these guidelines describe the com- suggested that a larger benefit of clopidogrel over aspirin pelling evidence for aspirin in patients with coronary in patients with symptomatic PAOD than those with Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Patients
PAOD
CHEST / 126 / 3 / SEPTEMBER, 2004 SUPPLEMENT cardiac or cerebrovascular disease. Subgroup analysis is produced a significant increase in walking distance for often misleading, and we are inclined to trust the overall onset of claudication (218 m for cilostazol vs 202 m for estimate of clopidogrel effectiveness in all patients with pentoxifylline, p ϭ 0.0001) and ACD (350 m for cilostazol vs 308 m for pentoxifylline, p ϭ 0.0005). In addition, therewere fewer patients who had no change or deterioration in Recommendation
walking distance (23% for cilostazol vs 34% with pentoxi-fylline).
1.1.3. We recommend clopidogrel in comparison to no Cilostazol thus appears to be an appropriate therapy for antiplatelet therapy (Grade 1C؉) but suggest that aspirin
be used instead of clopidogrel (Grade 2A).
patients with disabling claudication who are not candidatesfor revascularization. However, its high cost, modest effect Underlying values and preferences: This recommendation on walking distance, lack of demonstrated benefit in places a relatively high value on avoiding large expendi- improving health-related quality of life, and the salutary tures to achieve small reductions in vascular events.
effects of exercise therapy and risk factor modificationargue against its routine use in patients with less-disabling Cilostazol is a type III phosphodiesterase inhibitor that Cilostazol has weak platelet inhibitory effects, and there suppresses platelet aggregation and is a direct arterial are no data to support its use as an antiplatelet agent.
vasodilator. Its mechanism of action as a treatment for Antiplatelet therapy with aspirin or clopidogrel should be claudication is not fully understood. We found no system- continued in patients receiving cilostazol.
atic reviews on this drug for PAOD. Several publishedclinical trials that have evaluated the efficacy of cilostazol Recommendation
as a therapeutic agent for intermittent claudication.
In the first of these published trials,23 239 patients 1.1.4. For patients with disabling intermittent claudica- randomly assigned to receive a 16-week course of cilosta- tion who do not respond to conservative measures (risk zol or placebo, the cilostazol group showed an increase in factor modification and exercise therapy) and who are not absolute claudication distance (ACD) of 47%, while the candidates for surgical or catheter-based intervention, we control group improved by 13% (p Ͻ 0.001). Functional suggest cilostazol (Grade 2A). We suggest that clinicians
status assessment also showed improvement with cilosta- not use cilostazol in those with less-disabling claudication
zol compared with control subjects, although there were (Grade 2A).
significantly more side effects with cilostazol, most notablyheadache (30%) and diarrhea (12.6%).
Underlying values and preferences: The recommendation In a smaller trial24 of 12 weeks of cilostazol or placebo, against cilostazol for those with less-disabling claudication the ACD increased 31% with cilostazol, vs a drop of 9% places a relatively low value on small possible improve- with placebo (p Ͻ 0.01). In another study,25 45 patients ments in function in the absence of clear improvement in 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 allgroups, and follow-up was continued for 6 more weeks.
There was a more significant decrease in ACD after Pentoxifylline is a weak antithrombotic agent; its puta- cessation of cilostazol therapy than with either pentoxifyl- tive mechanisms of action include an increase in RBC line or placebo. The increase in ACD from baseline was deformity, and decreases in fibrinogen concentration, similar in both the cilostazol and pentoxifylline groups platelet adhesiveness, and whole-blood viscosity.28–30 One metaanalysis31 suggests that pentoxifylline improves walk- In a trial26 of 516 patients randomly assigned to cilosta- zol (100 mg bid or 50 mg bid) or placebo therapy for 24 ing distance by 29 m compared with placebo, although the weeks, those receiving 50 mg bid had a 38% and 48% improvement was approximately 50% in the placebo mean improvement in maximal and pain-free walking group, and use of pentoxifylline improved walking distance distance, respectively, while with a dose of 100 mg bid by an additional 30%. Moreover, clinical trials have shown showed a 51% and 59% improvement, respectively, com- conflicting results. Some32–37 have concluded that pentoxi- pared to placebo. Benefit was noted as early as 4 weeks, fylline was significantly more effective than placebo in with progressive improvement over the 24-week period of improving treadmill-walking distance, but others38–43 the trial. There was also a significant improvement in could not demonstrate consistent benefit. In many trials, functional outcomes with cilostazol, and no difference in patients treated with placebo also demonstrated signifi- the incidence of adverse events in the three groups. Side cant improvement. Thus, the actual improvement in walk- effects noted in each of the studies included headache, ing distance attributable to pentoxifylline is often unpre- loose and soft stools, diarrhea, dizziness, and palpitations.
dictable and may not be clinically important compared Cilostazol is more effective than pentoxifylline, as illus- with the effects of placebo.44 In summary, the evidence for trated in a study of 698 patients randomized to pentoxi- a beneficial effect of pentoxifylline is not strong enough to fylline (400 mg tid), cilostazol (100 mg bid), or placebo for suggest an important role in the treatment of patients with 24 weeks.27 In comparison to pentoxifylline, cilostazol Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Recommendation
walking distances (60% vs 35%). These benefits weremodest and probably not clinically significant. The inci- 1.1.5. We recommend against the use of pentoxifylline
dence of cardiac death, MI, coronary revascularization, (Grade 1B).
stroke, transient ischemic attack (TIA), or leg ischemia requiring intervention was similar in both groups.
Prostaglandins with antiplatelet and vasodilatory effects, Recommendation
such as prostaglandin E1 (PGE1) and prostaglandin I2(PGI 1.1.6. For limb ischemia, we suggest clinicians not use
2), have been administered IV or intra-arterially to patients with advanced chronic arterial insufficiency in prostaglandins (Grade 2B).
hopes of relieving rest pain and healing ischemic ulcers. In Underlying values and preferences: The recommendation a study47 of 80 patients with intermittent claudication, IV places a low value on achieving small gains in walking administration of a PGE1 produced a dose-related im- distance in the absence of demonstrated improvement in 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 three ischemic ulcers not healing for 3 weeks with standard carewho were randomized to receive either PGE1 or a placebo Other agents with putative antithrombotic activity that for 72 h through a central venous catheter, PGE1 was have been subjected to RCTs but were found to be found to be ineffective. In a small, randomized open ineffective in the treatment of intermittent claudication study,49 PGE1 administered IV and combined with an include the following: the antiserotonin agent ketanserin,56 intensive exercise regimen produced dramatic and sus- suloctidil,57 fish oil supplementation,58 and naftidrofu- tained improvement in symptom-free walking distance in ryl.59–60 Other ineffective drugs for intermittent claudica- comparison with exercise alone or exercise combined with tion (such as nifedipine, l-carnitine, etc) are not discussed, IV-administered pentoxifylline. The largest data set comes as there is little evidence for the role as antithrombotic from a multicenter RCT50 in which 1,560 patients with chronic critical ischemia of the leg were randomly as- Picotamide, an antiplatelet agent that inhibits throm- signed to receive either a daily IV infusion of PGE1 or boxane-A2 synthase and antagonizes thromboxane-A2 re- nothing (open-label study) during their hospital stay. At ceptors, has been evaluated in one, small, blinded RCT61 discharge, there was a greater reduction in composite in patients with PAOD. Treatment with picotamide sig- outcome events in the PGE1 group than in the control nificantly reduced the overall incidence of major and subjects (63.9% vs 73.6%; relative risk, 0.87; p Ͻ 0.001), minor cardiovascular events. In a blinded, placebo- but this difference was not statistically significant at 6 controlled RCT,62 patients treated with picotamide months (52.6% vs 57.5%; relative risk, 0.92; p ϭ 0.074).
showed no progression of carotid atherosclerosis (as mea- AS-013, a PGE1 prodrug, was evaluated in a small ran- sured by B-mode ultrasound) compared with placebo- domized trial51 of 80 patients with claudication, and was treated control subjects. There are no data on whether this associated with an increase of 35 m in maximal walking agent is superior or equivalent to aspirin or other agents.63 distance after 8 weeks of treatment, compared with a “Hemodilution therapy” for reducing the plasma viscosity slight decrease in placebo-treated control subjects. This involves the removal of blood and replacing it with a difference was statistically significant (p Ͻ 0.01), although colloidal solution such as hydroxyethyl starch or a low the clinical significance of the increase was marginal.
molecular weight dextran one or twice weekly for several A blinded trial that contained a high proportion of weeks, resulting in small improvement in pain-free walk- diabetics showed no beneficial effect of IV PGI2 on ulcer healing or rest pain.52 However, selective intra-arterial A Cochrane review66 assessed the effects of anticoagu- PGI2 was found to relieve rest pain and promote healing of lant drugs (unfractionated heparin [UFH], low molecular ulcers to a significantly greater degree than did placebo weight heparin [LMWH], and vitamin K antagonists treatment in 30 nondiabetic patients, half of whom had [VKAs]) in patients with PAOD. End points included thromboangiitis obliterans (Buerger disease).53 In another walking capacity (pain-free walking distance or absolute double-blind trial,54 PGI2 administered IV to nondiabetic walking distance), mortality, cardiovascular events, ankle/ patients with severe arterial insufficiency produced sig- brachial pressure index, progression to surgery, amputa- nificantly greater relief (lasting up to 1 month) of rest tion-free survival, and side effects. Thirteen trials were pain than did placebo, but there was no correlation initially considered eligible for inclusion in the review.
with changes in ankle-to-brachial pressure index, or ulcer Only three studies (two evaluating VKA, one evaluating UFH) met the high quality methodologic inclusion criteria Beraprost, an orally active PGI2 analog, was evaluated and were included in the primary analysis, while four other in the Beraprost et Claudication Intermittente-2 trial55 of studies were included in the sensitivity analysis. No signif- 549 patients with a pain-free walking distance of 50 to icant difference was observed between UFH treatment 300 m. After 6 months, more patients receiving beraprost and control groups for pain-free walking distance or (40 ␮g tid) compared to placebo had an increase in maximum walking distance at the end of treatment. The walking distance on a treadmill (44% vs 33%), and pain- review found no data to indicate that LMWHs benefit free walking distances (82% vs 53%), and maximum walking distance. No study reported a significant effect on CHEST / 126 / 3 / SEPTEMBER, 2004 SUPPLEMENT overall mortality or cardiovascular events, and the pooled with other degenerative or inflammatory diseases or with odds ratios were not significant for these outcomes. Major trauma. The upper extremity better tolerates arterial and minor bleeding events were significantly more fre- occlusion because of rich collateral blood supply: gangrene quent in patients treated with VKAs compared to control, or ischemic rest pain is rare in the absence of distal with a nonsignificant increase in fatal bleeding events. No embolization. Hypovolemia, hyperviscosity, and hyperco- major bleeding events were reported in the study evalu- agulability as observed in shock, thrombocytosis, polycy- ating UFH, while a nonsignificant increase in minor themia, and malignant disorders predispose to thrombotic bleeding events was reported. In conclusion, no benefit of arterial occlusion. Arterial thrombosis most frequently UFH, LMWH, or VKA has been established for intermit- tent claudication. An increased risk of major bleeding Therapeutic management will depend on whether the events has been observed especially with VKAs. The occlusion is caused by embolism in a healthy artery vs Cochrane review66 concluded that the use of anticoagu- thromboembolism in an atheromatous artery. Prompt lants for intermittent claudication cannot be recom- embolectomy through surgical intervention is the usual technique to remove emboli from healthy arteries. Theintroduction of the Fogarty balloon catheter 40 years ago Recommendation
dramatically decreased the mortality and the amputationrate from arterial embolism. Percutaneous thromboembo- 1.1.7. In patients with intermittent claudication, we lectomy with the aid of an aspiration catheter or of a recommend against the use of anticoagulants (Grade
thrombectomy device is a recent alternative. Literature on either of these new techniques is descriptive and wasrecently reviewed.69,70 No randomized comparison be- 2.0 Acute Limb Ischemia
tween the different options is available. Traditionally,thromboembolism in a severely diseased artery or in a The major causes of acute arterial insufficiency are vascular graft causing acute ischemia symptoms has been arterial thrombosis, embolus, and trauma. Extreme vaso- the domain of the vascular surgeon as well, but optimal spasm (eg, ergot induced) and arterial dissection are unusual causes. Most traumatic occlusive events are asso-ciated with transection, laceration, or occlusion from 2.1 Heparin
external compression such as a fracture or dislocation; butin some instances, thrombosis occurs from blunt trauma.
Patients presenting with acute limb ischemia secondary Iatrogenic vascular trauma, most often from diagnostic to thromboembolic arterial occlusion usually receive and therapeutic catheter placement, is a common cause of prompt anticoagulation with therapeutic dosages of UFH acute arterial occlusion. In most patients early surgery is in order to prevent clot propagation and to obviate further required, with appropriate repair of the injured vessel. If embolism. The logic of this common clinical practice is not thrombosis occurred, use of the Fogarty balloon catheter questioned, even though no formal studies have estab- to remove thrombi is often required and is usually effec- lished unequivocally a beneficial role of any antithrom- tive. Anticoagulation with UFH is variably used at the time botic agent in patients with acute embolic occlusion. The of operation, but may be contraindicated because of other expected adverse effect of perioperative anticoagulant injuries. Outcome is related to the seriousness of associ- therapy is an increased risk of wound complications, ated injuries and duration of ischemia; successful vascular particularly hematomas. The major role for continued repair can be achieved in most cases.
anticoagulant therapy (UFH followed by VKA) after em- Nontraumatic acute occlusion is mainly embolic or bolization is to prevent embolic recurrence if the source of thrombotic. The large majority of emboli arise from the embolism cannot be eradicated or corrected.
heart in patients with valvular disease and/or atrial fibril-lation, with prosthetic valves, or with mural thrombi in an Recommendation
infarcted or dilated left ventricle. Noncardiac sources ofembolism include arterial aneurysms, ulcerated athero- 2.1. In patients with acute arterial emboli or thrombosis, sclerotic plaque, recent (endo)vascular procedures, para- we recommend treatment with immediate systemic anti- doxic emboli from venous thrombi, and rarely arteritis or coagulation with UFH to prevent thrombotic propagation vascular trauma. Approximately two thirds of noncerebral (Grade 1C). We also recommend systemic anticoagula-
emboli enter vessels of the lower extremity and half of tion with UFH followed by long-term VKA to prevent these obstruct the iliofemoral segment, while the remain- recurrent embolism in patients undergoing embolectomy der involve the popliteal and tibial vessels. The upper- (Grade 1C).
extremity and renal plus visceral vessels each receiveapproximately 15% of emboli.67,68 2.2 Thrombolysis
Thrombotic occlusions of arteries are usually associated with advanced atherosclerosis, and arteries often have Initial intervention with thrombolysis with the aim of preexisting and developed collateral blood supply. For this eliminating all thrombotic and embolic material and re- reason, final occlusion may not be a dramatic event and is store perfusion is a potential alternative to surgical revas- sometimes silent; it is not an emergent process in many cularization in acute limb ischemia of thromboembolic patients. Thrombosis also occurs in vascular grafts and origin. Systemic thrombolysis with IV administration of a Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy thrombolytic agent was used in the 1960s and 1970s and no convincing scientific proof of superiority of any agent has been completely abandoned and replaced by catheter- for catheter-directed thrombolysis in terms of efficacy and directed thrombolysis. With this technique, a catheter is positioned intra-arterially and advanced into the thrombus Although the extensive literature on catheter-directed for local delivery of the thrombolytic agent. Several infu- thrombolysis is largely descriptive, five prospective ran- sion methods can be used. Initially, streptokinase was the domized studies compared this treatment method to most widely used agent, but later it was superseded in surgical intervention.77,80,81,84,85 Two meta-analyses86,87 are clinical use by urokinase and recombinant tissue-type available and conclude that there is a similar mortality and plasminogen activator (rt-PA). Dosages schemes vary con- amputation rate for thrombolysis and surgery; thromboly- siderably; an overview of reported dosages was published sis reduces the need for open major surgical procedures but causes more bleeding and distal embolization.
In a small trial,80 surgical thrombectomy was compared in Europe, but since the suspension of urokinase sales in to an intra-arterial continuous infusion of 30 mg of 1998, it has been administered in the United States as alteplase over 3 h in 20 patients with acute (Ͼ 24 h but well. In addition, new agents are being investigated. For Ͻ 14 days) arterial occlusion and severe leg ischemia. Only instance, reteplase, a nonglycosylated mutant of alteplase, patients with a need for intervention were included.
was tested in a few small series:72,73 doses of 0.5 up to 2 Considerable lysis was obtained in six of nine patients U/h produced thrombus dissolution rates and bleeding treated with alteplase, and half of them subsequently rates that appear comparable to published data with other underwent percutaneous transluminal angioplasty. Two thrombolytic agents, but a direct comparison is not avail- early reocclusions occurred. Thrombectomy also resulted in an immediate restitution of blood flow in six of nine A new approach is the use of the platelet glycoprotein IIb-IIIa antagonist abciximab as adjuvant therapy to Ouriel et al81 compared initial thrombolysis comple- thrombolysis with the hope of improving lytic efficacy and mented with percutaneous transluminal angioplasty or/ clinical outcome. A pilot trial74 randomized 70 patients to and surgery vs immediate surgery in 114 patients with urokinase plus abciximab or to urokinase plus placebo.
limb-threatening ischemia of Ͻ 7 days in duration, due to At 90 days, amputation-free survival was 96% in the native artery or graft occlusion. Thrombolysis resulted in urokinase-abciximab group vs 80% in the urokinase- dissolution of the occluding thrombus in 70% of the placebo group. Thrombolysis occurred faster in the former patients. Limb salvage rate was similar in the two groups group, but the rate of nonfatal major bleeding was also (82% at 1 year), but cumulative survival was significantly improved in patients randomized to thrombolysis due to Only a few randomized studies compared thrombolytic fewer cardiopulmonary complications in hospital (84% vs agents directly. An open trial75 compared intra-arterial streptokinase to intra-arterial and IV rt-PA in 60 patients The STILE trial77 randomized 393 patients with non- with recent onset or deterioration of limb ischemia; ini- embolic native artery or bypass graft occlusion in the lower tial angiographic success was superior with intra-arterial limbs within the past 6 months to either optimal surgical rt-PA (100%) than with intra-arterial streptokinase (80%; procedure or intra-arterial catheter-directed thrombolysis p Ͻ 0.04) or IV rt-PA (45%; p Ͻ 0.01), the 30-day limb with rt-PA or urokinase. The primary end point was a salvage rates being 80%, 60%, and 45%, respectively.
composite outcome of death, major amputation, ongoing Another randomized trial76 in 32 patients showed signifi- or recurrent ischemia, and major morbidity. At 1 month, cantly faster lysis with rt-PA than with urokinase, but the the primary end point was reached for 36.1% of surgical 24-h lysis rate and the 30-day clinical success rate were patients and 61.7% of thrombolysis patients (p Ͻ 0.0001).
similar. The Surgery vs Thrombolysis for Ischemia of the This difference was primarily due to ongoing/recurrent Lower Extremity (STILE) study77 included a comparison ischemia (25.7% vs 54.0%; p Ͻ 0.0001); lysis was unsuc- of rt-PA and urokinase; patients assigned to thrombolytic cessful in 28% of the patients assigned to thrombolysis treatment received at random one of the two drugs, and because of failure of proper catheter placement, an inex- the main report mentions similar efficacy and safety for plicably high rate. However, in a secondary analysis that stratified patients by duration of ischemia, thrombolysis A German study78 randomized 120 patients with throm- resulted in improved amputation-free survival at 6 months botic infrainguinal arterial occlusion to treatment with and shorter hospital stay in patients with acutely ischemic urokinase or rt-PA, and noted a slight improvement in limbs (Ͻ 14 days), whereas surgical revascularization was successful lysis in all segments treated with rt-PA more effective for more chronic ischemia (Ͼ 14 days).77 (p Ͻ 0.05), but local hematomas were more common. The Two additional publications82,83 analyzed the STILE Prourokinase Versus Urokinase for Recanalization of Pe- trial on an intention-to-treat basis for the 30-day, 6-month, ripheral Occlusions, Safety and Efficacy trial79 compared and 1-year results in patients with native artery and graft three doses of recombinant prourokinase to tissue culture occlusion separately. For 237 patients with native artery urokinase with complete lysis as a primary end point; the occlusion, the composite clinical outcome was in favor of highest lysis rate was obtained with the highest dose tested surgery because of a lower incidence of major amputation (8 mg/h for 8 h, then 0.5 mg/h), at the expense of a slightly (0% vs 10% at 1 year, p ϭ 0.0024) and recurrent ischemia increased frequency of bleeding and decrement in fibrin- (35% vs 64% at 1 year, p Ͻ 0.0001). Factors predictive of ogen level. In assessing all of these data, there is at present a poor outcome with lysis were femoropopliteal occlusion, CHEST / 126 / 3 / SEPTEMBER, 2004 SUPPLEMENT diabetes, and critical ischemia. Only 20% of those patients bypass grafts, the therapeutic options are either surgical had an onset or progression of ischemic symptoms of Ͻ 14 revision and thrombectomy, catheter-directed thromboly- days in duration; in these patients, the 1-year death/ sis, or insertion of a new graft. Factors to consider in amputation rate was similar for surgery and thrombolysis.
therapeutic decision making are the age and nature of the Overall, lysis failed to reestablish patency in 45% of graft, the duration and degree of ischemia, and the patients, but 22% did not receive a lytic agent because of availability of vein for a new distal bypass. In patients with problems with catheter positioning.82 For 124 patients a recent occlusion of a well-established graft, the working with bypass graft occlusion, there was also a better overall party proposed thrombolytic therapy as a primary treat- composite clinical outcome at 30 days and 1 year in the ment modality. Thrombolysis may eventually clear the surgical group compared to lysis, predominantly due to a thrombosed outflow vessels as well. However, the patency reduction in ongoing/recurrent ischemia. However, 39% rate 1 year after successful lysis of thrombosed grafts is low randomized to lysis failed catheter placement and re- (Ϯ 20%), and the question is whether the ultimate yield quired surgery. Following successful catheter placement, justifies the labor-intensive and expensive lytic proce- patency was reestablished by lysis in 84%. A poststudy analysis indicated that limb loss at 1 year was significantlylower in patients with ischemia for Ͻ 14 days if treated Recommendation
with thrombolysis compared with those treated surgically(20% vs 48%; p ϭ 0.026).83 2.2. In patients with short-term (Ͻ 14 days) thrombotic The Thrombolysis or Peripheral Arterial Surgery or embolic disease with low risk of myonecrosis and (TOPAS)84,85 investigators prospectively compared recom- ischemic nerve damage developing during the time to binant urokinase vs surgery in acute arterial occlusion achieve revascularization by this method, we suggest (Յ 14 days). In a first dose-ranging trial,84 they evaluated intra-arterial thrombolytic therapy (Grade 2B).
the safety and efficacy of three doses of recombinant Underlying values and preferences: This recommendation urokinase in comparison with surgery in 213 patients. The places relatively little value on small reductions in the amputation-free survival rate at 1 year was 75% in 52 need for surgical intervention and relatively high value on patients treated initially with recombinant urokinase at avoiding large expenditures and possible major hemor- 4,000 IU/min, and 65% in 58 surgically treated patients, a nonsignificant difference. The 4,000 IU/min dosage ap-peared the most appropriate thrombolytic regimen (com- 3.0 Vascular Grafts
pared with 2,000 IU/min and 6,000 IU/min) for the first4 h because it maximized lytic efficacy against the bleeding The superior patency of vein grafts is supported primar- risk. This optimal dosage regimen (4,000 IU/min for the ily by a single, multicenter, randomized trial published in initial 4 h followed by 2,000 IU/min for up to 48 h) was 1986,89 which compared saphenous vein grafts with ex- next tested in a large multicenter trial85 on 544 patients.
panded polytetrafluoroethylene prostheses for lower- Amputation-free survival rates in the urokinase group extremity arterial reconstructions. The primary patency were 71.8% at 6 months and 65.0% at 1 year, as compared rate at 4 years for infrapopliteal bypasses with saphenous with respective rates of 74.8% and 69.9% in the surgery vein was 49%, significantly better than the 12% patency group; these differences between the two groups were not rate with polytetrafluoroethylene bypasses (p Ͻ 0.001).
significant. Thrombolysis reduced the need for open Although demonstrating clear differences between vein surgical procedures (315 vs 551 at 6 months) without and prosthetic bypasses, this trial is also notable because it increased risk of amputation or death.
documented that even expert surgeons had failure rates Overall, the randomized trials provide no clear-cut that were alarmingly high. Other studies90,91 show im- answer to the dilemma which of the two treatments proved patency rates, with no major differences between (thrombolysis or surgical intervention) to prefer. They reversed and nonreversed in situ vein grafts in which the selected heterogeneous patient populations and studied valves are rendered incompetent. In the absence of venous complicated endpoints. The risk of intracranial bleeding conduits, placement of arterial prostheses may be neces- remains a major burden for thrombolytic treatment in sary, and most randomized trials evaluating available acute limb ischemia; in three American prospective ran- materials indicate that human umbilical vein grafts have domized studies that compared thrombolysis to surgery, slightly better patency than polytetrafluoroethylene.92–94 the intracranial bleeding rate with thrombolysis was 1.2% The variable patency of all lower-extremity arterial by- (STILE),77 2.1% (TOPAS-I),84 and 1.6% (TOPAS-II).85 passes, regardless of the type of bypass conduit, suggests A working party reached a consensus proposal on the the need for adjunctive antithrombotic therapy.
use of thrombolysis in the management of lower-limb There are similarities and differences in the pathophys- arterial occlusion.71 In native artery occlusion, a manage- iology of thrombotic occlusion of vein grafts and arterial ment strategy incorporating thrombolysis followed by prostheses.95 Both are subject to early occlusion from correction of the causative lesion was proposed as an technical problems that reduce or disturb blood flow.
appropriate strategy in patients with ischemia of Ͻ 14 days Antithrombotic therapy might prevent or delay some of in duration. Immediate surgical revascularization is to be these occlusions. Both are also vulnerable to intermediate preferred if thrombolysis would lead to an unacceptable and late occlusions from neointimal hyperplasia and pro- delay in effective reperfusion. In patients with irreversible gression of atherosclerosis in the native vascular beds.
ischemia, primary amputation is indicated. For occluded However, the sites of neointimal hyperplasia differ for vein Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy grafts and for vascular prostheses. In vein grafts, the Controversy also exists as to whether protamine is process can be either diffuse, leading to progressive beneficial or safe for restoring hemostatic competence luminal reduction of the entire graft, or focal, causing after routine peripheral vascular surgery. Protamine com- isolated stenoses at anastomoses or valve sites.95,96 Vascu- monly causes adverse hemodynamic effects; in diabetics lar prostheses, in contrast, are subject to the development receiving neutral protamine Hagedorn insulin, anaphylac- of neointimal hyperplasia at anastomoses in which the tic reactions may occur in 0.6 to 3.0% of patients.101–103 process stems from the adjacent artery. Patency of vein Reversal of UFH with protamine may not necessarily grafts and vascular prostheses is also adversely affected by reduce postoperative bleeding. In a single-center, ran- progressive inflow and outflow atherosclerosis that re- domized, double-blind study104 of 120 patients undergoing peripheral vascular surgery, protamine produced no dif- The principal difference between thrombotic occlusion ference in blood loss, bleeding complications, or transfu- of vein bypasses and that of prosthetic bypasses has to do sion requirement compared with those administered sa- with surface thrombogenicity. Because they are lined with line solution. One caveat is that the surgeons in this trial104 endothelium, vein grafts are inherently less thrombogenic used a dose of UFH (90 U/kg) that is lower than that than vascular prostheses that rarely develop a complete suggested above, albeit with satisfactory results. Also, endothelial lining. Vein grafts may lose variable amounts rapid reversal of UFH anticoagulation with protamine may of their endothelial lining during harvesting and implan- increase the risk of thrombosis, at least in carotid endar- tation, which may contribute to early occlusion. This terectomy. In a small trial105 of 64 patients randomized to suggests the rationale for early antithrombotic therapy that receive protamine or no reversal, the amount of wound could be discontinued after healing at anastomotic sites drainage was significantly less, and neck swelling was the and repavement of the graft with endothelium. Arterial same. Two patients receiving protamine suffered internal prostheses, however, are highly thrombogenic at the time carotid artery thrombosis compared with none in the of implantation and remain so. Studies97,98 with 111In- control group, although this difference was not statistically labeled platelets in humans demonstrate marked uptake of significant. UFH reversal with protamine sulfate is subject labeled platelets on femoropopliteal bypass prostheses of to wide practice variations among surgeons; the desirabil- Dacron or polytetrafluoroethylene, but little or no uptake ity of reversal or nonreversal has not been established.
on vein bypasses in the same position.
Recommendation
3.1 Intraoperative anticoagulation during vascular
3.1. For patients undergoing major vascular reconstruc- reconstructions
tive procedures, we recommend UFH at the time of IV UFH is traditionally administered prior to clamping application of vascular cross-clamps (Grade 1A).
arteries and interrupting flow. The goals are to preventstasis thrombosis in the often-diseased proximal and distal 3.2 Prolonging the patency of grafts
vessels, and to avoid the accumulation of thrombi at anastomoses and other sites of vascular injury. Random-ized trials of this therapy are probably not justified, and In 1975, the first RCT106 showed the protective action the primary question remains what should be the optimal of aspirin on thromboembolic events in patients after intensity of anticoagulation during the procedure. Follow- peripheral bypass surgery. Six trials of antiplatelet therapy ing the guidelines developed by cardiologists and inter- in patients with peripheral bypass grafts were described in ventional radiologists, some surgeons will monitor UFH the Sixth ACCP Consensus Conference on Antithrombotic dosage and responses using a point-of-care coagulation Therapy.107 These trials and others were pooled in the testing device such as the activated clotting time.99 In the second part of the metaanalysis by the 1994 Antiplatelet absence of direct monitoring, a fairly intense level of Trialists’ Collaboration.108 All unconfounded randomized anticoagulation is generally recommended during surgery, trials of antiplatelet therapy available before March 1990, because of the wide variability in responses to UFH. A in which vascular graft or native arterial patency was rational UFH regimen is to administer 100 to 150 U/kg IV studied systematically, were included. In a metaanalysis of before application of cross-clamps, and to supplement this those 11 studies, a significant risk reduction of graft every 45 to 50 min with 50 U/kg until cross-clamps are occlusion of 32% in patients who received platelet inhib- removed and circulation is reestablished. The timing of the supplemental doses is based on the half-life of UFH A metaanalysis109 performed in 1999 of trials in infrain- guinal bypass surgery found five trials110–114 comparing Even in aortic surgery, in which some surgeons do not aspirin (alone or combined with other antiplatelet therapy) consider UFH essential, anticoagulation may prevent re- against placebo. In 423 patients treated with antiplatelet mote thromboses. In an RCT100 of 284 patients undergo- drugs, 120 bypasses occluded (28.4%), compared with 144 ing elective abdominal aortic aneurysm repair, there was occlusions in 393 randomized control subjects (36.6%).109 no difference in the incidence of blood loss, transfusion The relative risk was 0.78 (95% confidence interval [CI], requirement, or arterial thrombosis in either group. How- 0.64 to 0.95), with a proportional risk reduction of 22%.
ever, those treated with UFH sustained fewer fatal (1.4% This corresponds with an absolute risk reduction of 8.2%.
vs 5.7%; p Ͻ 0.05) and nonfatal MIs (2.0% vs 8.5%; Antiplatelet therapy affects prosthetic and vein grafts p Ͻ 0.02) than those who did not receive UFH.
differently. A favorable effect of antiplatelet therapy was CHEST / 126 / 3 / SEPTEMBER, 2004 SUPPLEMENT demonstrated in the trials111–113 studying patients with angiography when indicated. In 66 treated patients, 13 prosthetic grafts, whereas trials110,114 in which at least 70% grafts occluded (19.7%), compared with 23 occlusions in had venous grafts were inconclusive. This stronger bene- 64 control subjects (35.9%), a relative risk of 0.55 (95% CI, ficial effect of aspirin on prosthetic grafts was also sup- 0.30 to 0.99), with a proportional risk reduction of 45%.
ported in a short-term (6 weeks) trial by Clyne et al,115 The corresponding absolute risk reduction by VKA was who demonstrated a benefit of aspirin and dipyridamole 16.2%. Limb loss was also significantly less common in the treatment in patients with prosthetic grafts, whereas no anticoagulated group (6.1%) than in the control group benefit was seen in the vein graft bypass group. The (20.3%). Among the anticoagulated patients, 27 patients beneficial effect of antiplatelet therapy on prosthetic graft (40.9%) died during 10 years of follow-up, compared with patency was confirmed in a recent overview analysis.116 In 37 subjects (57.8%) in the control group (relative risk, the Antiplatelet Trialists’ Collaboration overview108 of all 0.71; 95% CI, 0.49 to 1.01), with an absolute risk reduction antiplatelet studies, neither direct nor indirect compari- of 16.9%. The study reported one fatal GI hemorrhage in sons of the effects of different regimens (aspirin, dipyrid- amole, sulfinpyrazone, ticlopidine and suloctidil) on vas- A second trial124 included a more heterogeneous group cular patency provided convincing evidence that one of 116 patients undergoing various vascular reconstruc- antiplatelet regimen was more effective than another. In tions (ie, vein or prosthetic bypass and endarterectomy).
the Dutch Bypass, Oral Anticoagulants or Aspirin (BOA) Intention-to-treat analysis showed no difference in pa- study117 (see below), which randomized a large number of tency rate, limb salvage, and survival at the first, second, patients undergoing lower-extremity bypass (vein and and third year of follow-up between the anticoagulated prosthetic) to VKA vs aspirin, aspirin was found to signif- group and the control group. These conflicting results with icantly improve patency of prosthetic grafts.
the trial by Kretschmer et al123 may have been due to the Ticlopidine, an inhibitor of adenosine diphosphate- lower level of anticoagulation (target INR, 1.8 to 2.8) in induced platelet activation, has also been shown to be the latter trial, and by the differences in graft materials: effective in improving the patency of femoropopliteal vein in the first trial, and prosthetic grafts or endarterec- and femorotibial bypasses. In a randomized, multicenter, tomy in more than half of the patients in the second trial.
placebo-controlled trial118 of 243 patients, primary patency Four trials117,125–127 comparing VKA with aspirin in at 24 months was 82% in the ticlopidine group and 63% in patients after infrainguinal bypass surgery or thromboen- the placebo group (p ϭ 0.002). In clinical use, ticlopidine darterectomy have been reported. In 1979, Schneider et has now been superceded by the chemically related drug al125 reported a trial of 91 patients with a vein femoropop- clopidogrel, for which new trials are underway. At present, liteal bypass and 122 patients after thromboendarterec- there are no definitive data to recommend clopidogrel to tomy. They were randomized to treatment with either aspirin (1,000 mg/d) or aspirin plus dipyridamole (225 Controversy still remains as to whether antiplatelet mg/d) or VKA (target range not reported). The overall therapy is best started preoperatively or postoperatively, 2-year patency rate did not differ significantly in the although the weight of evidence suggests inhibition of groups. However, subgroup analysis of patients after vein platelet function is best established prior to the vascular bypass surgery demonstrated a better patency rate in the injury. Two of three trials112,113 of aspirin showed a benefit group treated with VKAs compared with both antiplatelet in graft patency when the drug was started preoperatively, groups, 87% vs 65% (p Ͻ 0.005). In the subgroup of and the third trial114 showed no benefit when antiplatelet patients undergoing thromboendarterectomy, antiplatelet therapy was begun postoperatively. This third trial114 had therapy proved to be favorable compared to VKA; patency the largest percentage of vein grafts, which are thought to rates were 80% and 51%, respectively (p Ͻ 0.002).
be less thrombogenic. Data from the literature119–122 on The Dutch BOA study randomized a total of 2,690 the patency of aortocoronary saphenous vein grafts sup- patients from 80 centers to VKA therapy (target INR, 3 to ports the concept of beginning antiplatelet therapy prior to 4.5) 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 mean Recommendation
follow-up was 21 months. The VKA group had 308 graftocclusions, compared to 322 occlusions in the aspirin 3.2.1. In patients undergoing prosthetic infrainguinal group (hazard ratio, 0.95; 95 CI, 0.82 to 1.11), suggesting bypass, we recommend aspirin (Grade 1A).
no overall benefit of one treatment over the other. Thehazard ratios of VKA vs aspirin were essentially the same in patients with femoropopliteal (hazard ratio, 0.97; 95%CI, 0.81 to 1.16), and femorocrural bypass grafts (hazard Two randomized trials123,124 have compared the efficacy ratio, 0.95; 95% CI 0.70 to 1.30). However, analysis of VKAs to no antithrombotic therapy in patients after stratified for graft material showed a lower risk of vein infrainguinal bypass surgery. Kretschmer and col- graft occlusion in anticoagulated patients than in those leagues123 studied the effect of long-term treatment with receiving aspirin (hazard ratio, 0.69; 95% CI, 0.54 to 0.88).
VKA (target international normalized ratio [INR], 2.4 to Seventeen patients would require treatment to prevent 4.8) on vein graft patency, limb salvage, and survival in one occlusion. Conversely, the risk of prosthetic graft patients operated on for claudication or critical ischemia.
occlusion was lower in patients treated with aspirin (haz- Patency was determined by Doppler ultrasonography, and ard ratio, 1.26; 95% CI, 1.03 to 1.55). Fifteen patients Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy would require treatment to prevent one occlusion. The aspirin group (risk ratio, 1.04; 95% CI, 0.72 to 1.51).
composite outcome event of vascular death, myocardial Subgroup analysis according to length of bypass did not infarction, stroke, or amputation occurred 248 times in the show any difference either, although there was a trend in VKA group and 275 times in the aspirin group (hazard favor of VKA plus aspirin in patients who received a pedal ratio, 0.89; 95% CI, 0.75 to 1.06). Patients treated with bypass. In patients with prosthetic bypasses, 44 occlusions VKA had significantly more major bleeding episodes than (23.5%) occurred in 187 patients with VKA plus aspirin, vs patients treated with aspirin: 108 episodes vs 56 episodes 64 occlusions (34.4%) in patients treated with aspirin (risk (hazard ratio, 1.96; 95% CI, 1.42 to 2.71). The optimal ratio, 0.62; 95% CI, 0.42 to 0.92), resulting in a 38% intensity of VKA therapy, ie, that intensity with the lowest proportional risk reduction with combination treatment.
incidence of both ischemic and hemorrhagic events, ap- This effect was due to the difference found in the 212 patients with 6-mm bypasses (mainly femoropopliteal Only one trial129 has directly compared a LMWH with above knee). Total mortality was higher in the VKA-plus- platelet inhibitors to prevent graft thrombosis. Two hun- aspirin group (31.8%) than in the aspirin group (23%; risk dred patients with prosthetic and vein infrainguinal bypass ratio, 1.41; 95% CI, 1.09 to 1.84), which was surprisingly grafts were treated for 3 months with dalteparine com- caused by an excess of malignancies in the group treated pared to aspirin plus dipyridamole. Randomization was with combination therapy. There were no clear differences stratified according to indication for surgery. Graft pa- in vascular mortality and nonfatal ischemic events between tency after 1 year of follow-up was better in the dalte- the treatment groups. There were significantly more parine group (79.5%) than in the antiplatelet group bleeding complications in the group with combination (64.1%). The subgroup operated on for limb salvage therapy than in the aspirin-alone group.
accounted for most of this benefit. Unfortunately, theproportion of patients in this subgroup with prosthetic or Recommendation
3.2.3. For routine patients undergoing infrainguinal Recommendation
bypass without special risk factors for occlusion, we rec-
ommend against VKA plus aspirin (Grade 1A). For those
3.2.2. We suggest that VKA not be used routinely in
at high risk of bypass occlusion and limb loss, we suggest patients undergoing infrainguinal femoropopliteal or distal VKA plus aspirin (Grade 2B).
vein bypass (Grade 2A).
Underlying values and preferences: These recommenda- Underlying values and preferences: This recommendation tions place a high value on the avoidance of bleeding attributes relatively little value to small increases in long- complications but recognize that there are circumstances term patency and relatively high value to avoiding hemor- in which the threat of limb loss and major disability may 4.0 Carotid Endarterectomy
In a small trial, Sarac et al126 studied 56 patients with 4.1 Aspirin
vein bypasses considered to be at high risk for thrombosisdue to suboptimal venous conduit, poor runoff, or reop- In patients undergoing carotid endarterectomy, aspirin erative grafting. All patients received preoperative aspirin.
therapy is an important adjunct. The goal of antithrom- One group was treated with IV UFH immediately post- botic therapy in this setting is to prevent immediate, operatively (target activated partial thromboplastin time, perioperative, and long-term neurologic complications 1.5 times control), until long-term treatment with VKA stemming from thrombus formation at the endarterec- (target INR, 2 to 3) and aspirin were instituted. The other tomy site. Scintigraphic studies with 111In-labeled platelets group received aspirin, 325 mg/d. The cumulative 3-year document marked deposition of platelets at the endarter- primary rates were significantly greater in the UFH, VKA, ectomy site immediately after operation.130,131 The inten- and aspirin group vs the aspirin group (74% vs 51%). The sity of platelet accumulation decreases over time, possibly primary-assisted and secondary patency rates were simi- because of re-endothelialization of the endarterectomy larly favorable for the VKA group. However, these bene- site. In one study131 of 22 patients, treatment of patients fits came at the expense of a significantly higher rate of undergoing carotid endarterectomy with aspirin plus di- wound hematomas and reoperations for bleeding (32% vs pyridamole significantly decreased 111In platelet deposi- tion, and appeared to decrease the incidence of perioper- In the Veterans Affairs trial,127 831 patients with vein ative stroke. A study132 of 125 patients assessing the and prosthetic bypasses were stratified for vein and pros- benefit of aspirin therapy for longer periods after carotid thetic grafts and randomized to treatment with low- endarterectomy has been reported. Patients receiving intensity VKA (INR, 1.4 to 2.8) plus aspirin, 325 mg/d, or aspirin, 650 mg bid, started on the fifth postoperative day aspirin alone. The average follow-up was 39.3 months in had a slight but significant reduction in unfavorable end the vein bypass group and 36.6 months in the group points when considered together (continuing TIAs, stroke, receiving prosthetic grafts. Fifty-seven of 231 venous retinal infarction, and death from stroke) during a 2-year grafts (24.7%) occluded in the group with combination follow-up period in comparison with control subjects therapy, compared with 57 of 227 grafts (25.1%) in the receiving placebo. This experience contrasts with that of a CHEST / 126 / 3 / SEPTEMBER, 2004 SUPPLEMENT randomized trial of 301 patients comparing very-low-dose from the Veterans Administration asymptomatic carotid aspirin therapy, 50 –100 mg/d, with placebo after carotid stenosis study138,139 suggests that aspirin may be beneficial endarterectomy.133 Therapy was started 1 week to 3 in patients with advanced stenosis who do not undergo months after operation, and no significant benefit of carotid endarterectomy. A surprising 16% of patients very-low-dose aspirin therapy was detectable. However, randomized to medical therapy were intolerant and had to the timing of perioperative aspirin therapy may be critical, discontinue aspirin. The incidence of neurologic events with late postoperative initiation of therapy being too late was significantly higher among patients who stopped to be beneficial. This is suggested by a randomized, double-blind trial134 of aspirin, 75 mg/d, vs placebo in 232 The long-term protective effects of aspirin on stroke patients; therapy was started preoperatively and was asso- rate for asymptomatic patients with Ն 50% carotid steno-sis is unclear. In a blinded, placebo-controlled trial in ciated with a marked reduction in intraoperative and which 372 asymptomatic patients with Ն 50% carotid stenosis were randomized to either aspirin (325 mg/d) or The ASA and Carotid Endarterectomy Trial135 was a placebo, no difference in stroke rate or incidence of a multicenter, randomized, double-blind clinical trial in composite end point of ischemic events was observed at a which 2849 patients scheduled for carotid endarterectomy mean follow-up of 2.3 years.140 The clinical application of were randomly assigned to one of four aspirin doses (81 these findings, particularly concerning the use of aspirin in mg, 325 mg, 650 mg, and 1,300 mg). Aspirin was started these patients as a means of preventing cardiac events, is before surgery and continued for 3 months. The combined tempered by the relatively short follow-up period and by rate of stroke, MI, and death was lower in the low-dose the exclusion of patients with symptomatic cerebrovascu- groups (81 mg and 325 mg) than in the high-dose groups lar disease, recent MI, and unstable angina.
at 30 days (5.4% vs 7.0%, p ϭ 0.07) and at 3 months (6.2% Significant stenoses recurring at the site of endarterec- vs 8.4%, p ϭ 0.03). Since many patients would be receiv- tomy are found in as many as 10 to 19% of patients after ing higher doses of aspirin prior to randomization into the carotid endarterectomy.141 Data from retrospective stud- study, and surgery would be performed prior to washout of ies142,143 suggest that antiplatelet therapy does not reduce the previous dose platelet effect, a separate efficacy the incidence of recurrent carotid artery stenosis. A analysis was performed of patients previously receiving randomized trial144 confirmed that treatment with aspirin 650 mg of aspirin and who were randomized Ն 2 days and dipyridamole does not prevent symptomatic or asymp- before surgery. In the efficacy analysis, there were 566 tomatic recurrent stenosis after carotid endarterectomy.
patients in the low-dose group, and 550 patients in the Although there are no data to recommend aspirin treat- high-dose group. The combined rate of stroke, MI, and ment for patients with asymptomatic or recurrent carotid death occurred less frequently in the low-dose group than stenosis in order to prevent progression or symptom in the high-dose group at both 30 days and 3 months (3.7% development, these patients have a high prevalence of vs 8.2%, p ϭ 0.002; 4.2% vs 10.0%, p ϭ 0.0002).135 associated coronary and PAOD. Therefore, antiplatelet Based on these considerations, perioperative aspirin therapy may improve long-term cardiovascular outcomes.
therapy, 75 to 325 mg/d, is appropriate therapy in patientsundergoing carotid endarterectomy. Therapy should bestarted at the time of clinical presentation and continued Recommendation
through the perioperative period. Bleeding complications, 5.0. In nonoperative patients with asymptomatic or particularly wound hematomas, occur in 1.4 to 3.0% of recurrent carotid stenosis, we recommend lifelong aspirin, patients undergoing carotid endarterectomy, and are as- 75 to 162 mg/d (Grade 1C؉).
sociated with incomplete reversal with protamine of intra-operative UFH, hypertension, and perioperative antiplate-let therapy.136,137 If intraoperative UFH is not fully 6.0 Lower-Extremity Endovascular Procedures
reversed or continuous UFH anticoagulation is adminis- Recommendations for optimal antithrombotic therapy tered postoperatively, perioperative aspirin therapy would for lower-extremity arterial balloon angioplasty are ham- potentially increase the incidence of hematomas and other 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- Recommendation
nal angioplasty is appropriate for focal stenotic lesions ofthe iliac and femoropopliteal arteries, particularly when 4.1. We recommend that aspirin, 75 to 325 mg, be given the indication for limb revascularization is intermittent preoperatively and continued indefinitely in patients un- claudication rather than critical ischemia, and in nondia- dergoing carotid endarterectomy (Grade 1A).
betic patients with relatively preserved tibial artery run-off.145 There is less agreement regarding the suitability of 5.0 Asymptomatic and Recurrent Carotid
transluminal angioplasty for more diffuse and extensive Stenosis
Complicating the matter even further is the technologic It is unknown whether aspirin therapy will prevent or “moving target” of catheter-based interventions. The use delay the onset of TIAs and strokes in patients with of self-expanding metallic stents can salvage what other- asymptomatic cerebrovascular disease. Indirect evidence wise might be an unacceptable technical outcome from Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy balloon angioplasty alone. The routine use of stents, not been studied in RCTs. Interest in the use of aspirin however, has not been shown to improve the results of with either ticlopidine or clopidogrel has undoubtedly lower extremity balloon angioplasty.145,146 Newer devices been stimulated by the favorable results reported with such as medication-coated stents are being tested in the aspirin and ticlopidine in comparison with aspirin alone lower-extremity arterial circulation.147 Based on the prom- and aspirin with warfarin after coronary artery stenting.154 ising early results seen with coronary stenting,148 such There are important differences between lower-extremity devices might find a role in the peripheral arterial vascular arterial interventions and those in the coronary circulation bed. It cannot be assumed then, that results from clinical to call into question the validity of such an extrapolation.
trials evaluating antithrombotic therapy for balloon angio- Nonetheless, given the relatively high rate of failure of plasty alone will necessarily extrapolate to its use with lower-extremity intervention and the increasing use of stents in these interventions, investigation aimed at study- Life-long antiplatelet therapy is recommended for all ing such combinations of antiplatelet therapy in this patients with PAOD on the basis of their increased risk of coronary and cerebrovascular events. Given this, the pri- In summary, antiplatelet therapy with aspirin is indi- mary issue governing the proper use of antithrombotic cated for all patients undergoing lower-extremity balloon therapy in conjunction with lower-extremity balloon an- angioplasty (with or without stenting), as it is currently gioplasty and stenting is that of agent and dosage.
recommended for all patients with PAOD. There are Whether antiplatelet therapy improves patency of insufficient data to recommend any additional antiplatelet lower-extremity angioplasty is a separate question, and has or antithrombotic agents for iliac artery angioplasty and been addressed in two RCTs149,150 comparing combina- stenting. Similarly, insufficient data exist to recommend tions of aspirin and dipyridamole with placebo. In a additional antithrombotic agents in the setting of femoro- single-center trial149 of 199 patients undergoing lower- popliteal or tibial arterial angioplasty and stenting. Specif- extremity angioplasty, patients were randomized to a ically, the addition of anticoagulation to antiplatelet ther- combination of dipyridamole (225 mg) plus high-dose apy does not appear to convey any advantage, and likely aspirin (990 mg), dipyridamole with low-dose aspirin (300 increases the risk of bleeding complications. Based on the mg), or placebo Only patients undergoing successful data from the coronary circulation, it is reasonable to balloon angioplasty of femoropopliteal arterial segment consider combinations of aspirin and thienopyridines in atherosclerotic obstructive lesions were randomized. Clin- high-risk, small-diameter tibial artery angioplasty.
ical and angiographic follow-up showed an improvementin both treatment groups in comparison with placebo; Recommendation
however, only the high-dose aspirin group achieved astatistically significant improvement.
6.0. For all patients undergoing lower-extremity balloon In another RCT150 from 12 centers, 223 patients under- angioplasty (with or without stenting), we recommend going balloon angioplasty of iliac and femoropopliteal long-term aspirin, 75 to 162 mg/d (Grade 1C؉).
segments 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 1.0 Chronic Limb Ischemia
patients undergoing treatment of more favorable iliaclesions in the placebo group (65% vs 51%); adjunctive use 1.1 Antiplatelet therapy
of metallic stents was not performed, as is commonly done now in clinical practice with the advent of low-profile,self-expanding, flexible stents.
1.1.1. We recommend lifelong aspirin therapy, 75 to It is not uncommon for combinations of anticoagulation 325 mg/d, in comparison to no antiplatelet therapy in and antiplatelet therapy to be used in patients undergoing patients with clinically manifest coronary or cerebrovascu- femoropopliteal, and tibial artery balloon angioplasty. This lar disease (Grade 1A) and in those without clinically
does not appear to be supported by the results of the three manifest coronary or cerebrovascular disease (Grade
RCTs151–153 published regarding this issue; a total of 438 patients were randomized in the three studies. In all threestudies,151–153 the arterial patency rates were slightly lower in the anticoagulation groups, but this was not statisticallysignificant in any of the studies. Also, there tended to be 1.1.2. We recommend clopidogrel over ticlopidine more bleeding complications in the anticoagulation (Grade 1C؉).
groups, 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- 1.1.3. We recommend clopidogrel in comparison to no plasty and stenting, particularly when the treated arteries antiplatelet therapy (Grade 1C؉), but suggest that aspi-
are in the femoropopliteal segments, and in the smaller- rin be used instead of clopidogrel (Grade 2A).
diameter tibial arteries. As yet, such combinations have Underlying values and preferences: This recommendation CHEST / 126 / 3 / SEPTEMBER, 2004 SUPPLEMENT places a relatively high value on avoiding large expendi- Underlying values and preferences: This recommendation tures to achieve small reductions in vascular events.
places relatively little value on small reductions in theneed for surgical intervention and relatively high value on avoiding large expenditures and possible major hemor-rhagic complications.
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 3.0 Vascular Grafts
candidates for surgical or catheter-based intervention, we 3.1 Intraoperative anticoagulation during vascular
suggest cilostazol (Grade 2A). We suggest that clinicians
reconstructions
not use cilostazol in those with less-disabling claudication
(Grade 2A).
3.1 For patients undergoing major vascular reconstruc- tive procedures, we recommend UFH at the time of
application of vascular cross-clamps (Grade 1A).
Underlying values and preferences: The recommendationagainst cilostazol for those with less-disabling claudication 3.2 Prolonging the patency of grafts
places a relatively low value on small possible improve-ments in function in the absence of clear improvement in 3.2.1. In patients undergoing prosthetic infrainguinal by- pass, we recommend aspirin (Grade 1A).
1.1.5. We recommend against the use of pentoxifylline
(Grade 1B).
3.2.2. We suggest that VKA not be used routinely in
patients undergoing infrainguinal femoropopliteal or distal vein bypass (Grade 2A).
1.1.6. For limb ischemia, we suggest clinicians not use
Underlying values and preferences: This recommendation prostaglandins (Grade 2B).
attributes relatively little value to small increases in long-term patency and relatively high value to avoiding hemor- Underlying values and preferences: The recommendation places a low value on achieving small gains in walkingdistance in the absence of demonstrated improvement in 3.2.3. For routine patients undergoing infrainguinal bypass without special risk factors for occlusion, we rec- ommend against VKA plus aspirin (Grade 1A). For those
at high risk of bypass occlusion and limb loss, we suggest
1.1.7. In patients with intermittent claudication, we VKA plus aspirin (Grade 2B).
recommend against the use of anticoagulants (Grade
1A).
Underlying values and preferences: These recommenda-tions place high value on the avoidance of bleeding 2.0 Acute Limb Ischemia
complications but recognize that there are circumstanceswhere the threat of limb loss and major disability may 2.1 Heparin
2.1. In patients with acute arterial emboli or thrombosis, we recommend treatment with immediate systemic anti- 4.0 Carotid Endarterectomy
coagulation with UFH to prevent thrombotic propagation
(Grade 1C). We also recommend systemic anticoagula-
4.1 Aspirin
tion with UFH followed by long-term VKA to preventrecurrent embolism in patients undergoing embolectomy 4.1. We recommend that aspirin, 75 to 325 mg/d, be (Grade 1C).
given preoperatively and continued indefinitely in patients
undergoing carotid endarterectomy (Grade 1A).
2.2 Thrombolysis
5.0 Asymptomatic and Recurrent Carotid
2.2. In patients with short-term (Ͻ 14 days) thrombotic Stenosis
or embolic disease with low risk of myonecrosis andischemic nerve damage developing during the time to 5.0. In nonoperative patients with asymptomatic or achieve revascularization by this method, we suggest recurrent carotid stenosis, we recommend lifelong aspirin, intra-arterial thrombolytic therapy (Grade 2B).
75 to 162 mg/d (Grade 1C؉).
Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy 6.0 Lower Extremity Endovascular Procedures
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