Treatment of acute occlusion of peripheral arteries

Thrombosis Research 106 (2002) V285 – V294

Treatment of acute occlusion of peripheral arteries Vincenzo Costantini a,*, Massimo Lenti b a

Dipartimento di Medicina Interna, Sezione di Medicina Interna e Cardiovascolare, Universita` degli Studi di Perugia, Via E. dal Pozzo, I-06126, Perugia, Italy b Dipartimento di Scienze Chirurgiche, Unita` Operativa di Chirurgia Vascolare, Universita` degli Studi di Perugia, Perugia, Italy

Abstract Acute lower-extremity peripheral arterial occlusion is responsible for a wide variety of complications culminating in limb loss or death. The real incidence of acute limb ischemia (ALI) in the general population is not well known even though recent epidemiological data estimated that it occurs in 14 out of a population of 100,000 and that it accounts for 10 – 16% of the vascular workload. The two main causes of acute occlusion of peripheral arteries are: (i) embolism and (ii) thrombosis, which usually occurs in cases of severe atherosclerotic stenoses. Arterial flow can be restored through operative revascularization or pharmacological dissolution of thrombus. Immediate surgical revascularization is indicated in the profoundly ischemic limb. Catheter embolectomy is also usually preferred for emboli to a nonatherosclerotic limb. Catheter-directed thrombolysis has become a commonly employed technique in the treatment of ALI. It may offer definitive treatment without the need of major surgery in a significant subset of patients with acute occlusion of a native leg artery or a bypass graft. A number or reports from individual centers and three large prospective studies, which compared intra-arterial thrombolysis to surgical intervention, suggest that thrombolytic therapy may be an appropriate initial treatment of ALI, provided that the limb is not immediately or irreversibly threatened. Using this approach, the underlying lesions can be further defined by angiography, and the percutaneous or surgical revascularization procedure can be performed. However, severe bleeding is still a non-rare complication of intra-arterial thrombolysis and the risk of intracranial hemorrhage is 1 – 2%. D 2002 Elsevier Science Ltd. All rights reserved. Keywords: Acute limb ischemia; Acute arterial occlusion; Catheter-direct thrombolysis; Thrombolytic therapy; Embolectomy; Vascular surgery

1. Introduction Acute peripheral arterial occlusion (APAO) can be associated with a spectrum of presenting signs and symptoms. In an extreme case, a patient without underlying arterial occlusive disease who suffers from an acute embolic occlusion at the femoral bifurcation may present with a profoundly ischemic lower extremity, requiring urgent intervention. At the other end of the scale, an acute embolic or thrombotic occlusion of a chronically diseased but only partially patent artery may be associated with only mild progression of chronic symptoms and modest deterioration in hemodynamics. Despite progress in many areas of the procedures in Abbreviations: APAO, acute peripheral arterial occlusion; ALI, acute critical limb ischemia; PAOD, peripheral arterial occlusive disease; PTFE, poly-tetrafluoroethylene; rt-PA, recombinant tissue-type plasminogen activators; UK, urokinase; SK, streptokinase; FDP, fibrinogen degradation product; SVS/ISCVS, The Society for Vascular Surgery/The International Society for Cardiovascular Surgery. * Corresponding author. Tel.: +39-075-5722905; fax: +39-0755722011. E-mail address: [email protected] (V. Costantini).

revascolarization, APAO continues to account for a wide variety of complications, culminating very often in limb loss or death. Very little published epidemiological data are available to establish the real incidence of APAO in the general population. An audit carried out in Gloucestershine have found an 14/100,000 incidence of acute limb ischemia (ALI) in the general population, which increases to 17 per 100,000 if bypass graft occlusions were included [1]. The Swedish Vascular Registry [2] confirms the above data, reporting an average regional incidence of 13/100,000. Native artery occlusions usually occur in the setting of severe atherosclerotic stenoses; alternatively, an artery may become occluded when an embolus becomes dislodged from a proximal source and is trapped at the site of a peripheral arterial bifurcation. Bypass graft occlusions generally occur following reduction in graft flow from a stenotic lesion within the conduit, compromised outflow, or reduced inflow. The exception to this caveat is the prosthetic graft; thrombosis may develop in the absence of a causative anatomic lesion. The conditions that cause APAO are numerous and are listed in Table 1. In addition, it is important to consider other

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Table 1 The pathogenesis of acute occlusion of peripheral arteries

2. Clinical classification and outcome of acute peripheral arterial occlusion

Causes of acute occlusions of peripheral arteries, in atherosclerotic patients . Thrombosis of a native artery with atherosclerotic stenoses . Thrombosis of an arterial bypass graft . Embolism from heart, aneurysm, atherosclerotic plaque, or critical

stenosis upstream (including cholesterol or atherothrombotic emboli during endovascular procedures) . Thrombosed aneurysm (with particular regard to popliteal aneurysm) Causes of acute critical limb ischemia in non-atherosclerotic patients . Arterial trauma (especially iatrogenic) . Aortic/arterial dissection . Arteritis with thrombosis (e.g., giant cell arteritis, thromboangiitis . . . .

obliterans) Spontaneous thrombosis associated with hypercoagulable state) Popliteal cyst with thrombosis Poplitean entrapment with thrombosis Vasospasm with thrombosis (e.g., ergotism)

pathological conditions that may mimic arterial occlusion, such as the low cardiac output, due to heart failure, especially if associated with peripheral arterial occlusive disease (PAOD). However, the two main causes of APAO are embolism and thrombosis. Differentiation between these two can be difficult, and is clinically impossible in 10– 15% of cases [3]. In a study [4] that compared the pre-operative diagnosis of ALI with the operative diagnosis, the authors found that 70% of pre-operative diagnosis of embolism but only 47% of thrombosis were correct. With the decline of the incidence of cardiac valvular diseases due to the rheumatic fever, and with the growing use of oral anticoagulant in patients with atrial fibrillation, the proportion of ALI due to cardiac embolism has also declined. In the meantime, increase in the elderly population—and therefore the prevalence of patients with PAOD—increases the number of APAO attributable to thrombosis. The analysis of the occlusion characteristics of patients enrolled in the recent randomized multicenter Thrombolysis or Peripheral Arterial Surgery trial (TOPAS) demonstrated indeed that the cause of APAO was thrombosis in 85% and embolism in 15% of patients [5,6].

The severity of APAO depends primarily on the location and the extent of luminal obstruction by new thrombus or embolus and the capability of the existing collateral bed of carrying blood around this obstruction. For instances, an embolus characteristically lodges in an apparent normal vascular bed where there has been no previous stimulus for collateral development, whereas the atheromatous narrowing that ultimately leads to thrombosis also stimulates collateral development, in direct relationship to the pressure gradient across the lesion. When thrombosis ultimately occurs, the pre-existing collateral circulation often lessens the resulting ischemia. Because of this, and the abrupt impact of embolism, an arterial embolus is more likely than arterial thrombosis to produce sudden symptoms and severe, limb-threatening ischemia. These characteristics represent the common or usual incidents, but they are not invariable. Thrombosis can be dramatically sudden and emboli can be occur silently, particularly in obtunded or sleeping patients. A clinical classification of the different stages of ALI was proposed in the Society for Vascular Surgery/The International Society for Cardiovascular Surgery (SVS/ ISCVS) report [7] in 1986, which had undergone a revision more recently [8]. The main objective of this classification is to stratify limbs into defined groups for decision-making purposes; however, the original classification has been widely used in clinical trials and has been shown to correlate with the outcome. The clinical categories of ALI are summarized in the Table 2. However, the search for some definitive markers of tissue viability and reversibility of ischemia is a very important objective of the ongoing research because it is still difficult to accurately distinguish between categories IIa and IIb and between IIb and III. The risks and the outcomes in a APAO patient are proportional to the degree of ischemia. Patients who present with severity level I should be treated in a manner not dissimilar to patients with chronic, severe lower extremity

Table 2 Clinical classification of acute limb ischemia (from Rutherford et al. [8]) Category

I. Viable II. Threatened a. Marginally b. Immediately

III. Irreversiblea

a

Description/prognosis

Findings

Doppler signals

Sensory loss

Muscle weakness

Arterial

Venous

Not immediately threatened

None

None

Audible

Audible

Salvageable if promptly treated Salvageable with immediate revascularization Major tissue loss or permanent nerve damage inevitable

Minimal (toes) or none More than toes, associated with rest pain Profound, anesthetic

None

(Often) inaudible

Audible

Mild, moderate

(Usually) inaudible

Audible

Profound, paralysis (rigor)

Inaudible

Inaudible

The differentiation between class IIb and III can be difficult at the onset of the leg ischemia.

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ischemia. In contrast, patients with more severe levels of APAO (IIa, IIb and III categories) share similar risks and outcomes, showing an immediate life-threatening and limbthreatening problem. Patients with class III ischemia can be subdivided into early and late presentation. Those with early presentations may benefit from an attempt at restoration of distal perfusion, even if the patient may have some minor amputations from the forefoot and prolonged nerve dysfunction, while those with late presentations will require major amputation because of advanced extensive tissue ischemia and necrosis. In this case, the risk is not only for salvaging a limb because patients with late stage ALI are also facing serious risk of death [9]. The sudden onset of hypoperfusion of the leg leads rapidly to systemic acid –base and electrolyte disorders that impair cardiopulmonary function [10]. Elevated myoglobin levels are associated with irreversible renal failure. Successful revascularization may induce a severe reperfusion injury, causing further neuromuscular damage within the extremity. Despite many progresses in the fields of the immediate management of ALI and in the area of the revascularization procedures, APAO continues to be associated with substantial limb loss and considerable mortality. Indeed, most recent large series report that 30-day mortality still accounts for approximately 15%, while the amputation rate varies much more, from approximately 10% to 30% [3]. Risk factors determining the outcome of patients with APAO have been extensively evaluated in numerous recent epidemiological studies but the results were often conflicting. However, it is generally believed that prompt treatment is the most important factor in terms of saving a viable leg. In one study [2], the amputation rate was found to be proportional to the interval between onset of ALI and exploration (6% if within 12 h, 12% within 13 –24 h, and 20% after 24 h). Another widely accepted concept is that the rate of limb savage, but not acute mortality, is lower when ischemia is due to thrombosis compared with embolism [11]. In contrast, a patient with an embolic cause for an ischemic leg is at a higher risk of death because of the associated underlying cardiac disease. Finally, there is wide agreement that immediate anticoagulation on diagnosis, with therapeutic levels of heparin, reduces morbidity and mortality [2].

3. Thrombolysis for acute peripheral arterial occlusion Thrombolytic agents have been clinically employed since 1955 [12], providing an attractive alternative to surgical therapy. Thrombolysis offers several potential advantages when compared with the surgical alternatives. It may relieve the arterial obstruction through a less invasive treatment modality. It may help dissolve platelet-fibrin aggregates in the microcirculation and thrombi in collateral vessels. More gradual reperfusion may avert the sudden release of anaerobic metabolites into the systemic circulation and thus reduce the risk of reperfusion or compartment syndrome.

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At the beginning of 1970s, thrombolytic agents were administered by the intravenous route and some clinical studies demonstrated that streptokinase or urokinase are effective in restoring the patency of acute occluded arteries in about 75% of the cases [13], while the efficacy was lower or absent in longer-lasting occlusion [14]. However, the risk of serious bleeding complications was very high so that the procedure of systemic infusion of thrombolytic agents in the treatment of APAO was largely neglected in favor of catheter-direct thrombolytic therapy. The objective of this procedure is to concentrate lytic agents directly into the thrombus so that the systemic drug concentration and the total dose required for therapy are reduced, thereby decreasing bleeding complications. With the procedure it is possible to obtain a quick restoration of the arterial blood flow to the ischemic limb, unless a posttreatment contrast study reveals fixed obstructing lesions, which can be treated by surgical and/or percutaneous angioplasty [15,16]. 3.1. Indications for thrombolytic therapy Candidates for intra-arterial thrombolytic therapy should include those with: (1) acute (of less than 14 days’ duration) thrombosis of a previously patent bypass graft or native artery; (2) acute arterial embolus not accessible to embolectomy; (3) acute thrombosis of a popliteal artery aneurysm resulting in severe ischemia, provided that all run-off vessels are also thrombosed; and (4) acute thromboembolic occlusion in situation in which surgery carries a high potential mortality. Setting, in which thrombolytic therapy is unlikely to be effective, includes irreversible limb ischemia, mild to moderate ischemia with tolerable claudication, early postoperative bypass graft thrombosis, and large vessel thrombi easily accessible to surgery. 3.2. Contraindications to thrombolytic therapy A series of absolute, relative and minor contraindications to thrombolysis are listed in the Table 3 [17]. In addition, demonstration of intracardiac thrombi on echocardiography is predictive of a higher risk for embolization during lytic therapy [18]. Such patients should be excluded from consideration for thrombolysis. When these findings are absent, the rate of embolic stroke from thrombolysis is less than 1% [18]. However, since the risk of subsequent reembolization from the heart is thought to be low, a routine pre-lysis echocardiogram is considered unnecessary—unless in conditions with high risk of cardiac embolism (mitral valve disease, chronic atrial fibrillation). In addition, the risk of distal embolization from thrombosed popliteal aneurysms also poses a relative contraindication, except when the clinical setting is similar to that described in item (3) of the previous paragraph. Patients with an acute, severe, irreversible limb ischemia and no evidence of collateral circulation are not candidates for thrombolysis. Indeed, the rapid restoration of blood flow in

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Table 3 Controindication to thrombolysis Absolute contraindications . Active bleeding diathesis . Acute gastroduodenal ulcers and/or recent gastrointestinal bleeding

(within previous 10 days) . History of stroke (excluding TIA) within previous 2 months . Neurosurgery (intracranial, spinal) within previous 3 months . Intracranial trauma within previous 3 months

Relative contraindications . Major non-vascular surgery or trauma within previous 10 days . Cardiopulmonary resuscitation within previous 10 days . Uncontrolled hypertension (systolic > 180 mm Hg or diastolic>110 mm . . . . .

Hg) Puncture of uncompressible vessel Intracranial neoplasm Mitral valve disease Recent eye surgery Aneurysm, with particular regard to known, silent intracerebral vascular malformations

Minor contraindications . Renal or hepatic insufficiency (particularly if associated with coagulop. . . .

athy Bacterial endocarditis Pregnancy Diabetic hemorrhagic retinopathy Antiplatelet therapy

these cases increases the risk of the rare (less than 1%) but serious reperfusion syndrome [10]. 3.3. Techniques for intra-arterial thrombolysis Since the duration of infusion increases morbidity and expense [19], more fibrin-specific and rapid-acting plasminogen activators and new infusion methods have been developed over the past few years with the objective of accelerating thrombolysis. The technique most often practiced today is still the procedure described by McNamara and Fischer in 1985 [20]. In patients with femoral and iliac occlusion, the preferred access site is the controlateral femoral artery. Access through the ipsilateral femoral is favored for thrombi in the superficial femoral, popliteal, or tibial arteries. By using the ipsilateral limb, potential catheter-related complications in the intact limb are avoided. If neither femoral artery can be used, a low brachial artery access may be considered. Once the access site is identified, a small Teflon (poly-tetrafluoroethylene [PTFE])-coated guidewire is inserted after direct puncture and is manipulated into the thrombus. A widely used procedure is the so-called regional thrombolysis in which the catheter tip is collocated on the upper edge of the thrombus or within the proximal part of the thrombus. The thrombolytic agent can be infused with a constant infusion pump or alternatively with periodic tapering of the infusion rate with the highest dose given within the first few hours.

However, numerous experimental and clinical trials have documented that forceful infusion of the thrombolytic into the entire length of the thrombus accelerates thrombolysis [21,22]. Indeed, a recent review [23] suggests that successful passage of the guidewire through the thrombus predicts >95% likelihood of successful lysis, whereas inability to pass the thrombus reduces the chance of success. Successful outcome was more frequent in prosthetic grafts (78%) and native arterial occlusions (72%) than in vein graft thromboses (53%). Patients without diabetes had higher success rates than persons with diabetes (80% and 52%, respectively). Thus, an efficacious procedure is based on the aggressive initial lacing of the entire length of the thrombus with a high-dose bolus of lytic agents, while withdrawing the catheter from the distal to the proximal end of occlusion, followed by a continuous infusion of low dose thrombolytic agent [19]. Alternatively, it is largely utilized a pulse-spray infusion of forceful periodic injection of thrombolytic agent into the thrombus in order to fragment it and increase the surface area available for the action of the lytic agents [24]. A partial modification of this technique is the so-called ‘‘pulse spray pharmacomechanical thrombolysis’’ that combines mechanical thrombus disruption with brief high pressure pulsed injections of a concentrated thrombolytic agent throughout the thrombus [25]. The repeated forceful intrathrombotic injection of small volumes of thrombolytic agent macerates the clot by mixing the drug within the fibrin mass and thus augmenting the interactive surface area. A small, randomized prospective clinical trial [26] have compared slow continuous infusion with forced periodic infusion of urokinase with the pulse spray pharmacomechanical system after that both groups of patients initially forced periodic intrathrombotic bolus of concentrate urokinase. The conclusion of the study was that pulse-spray infusion was as safe and efficacious as continuous infusion; however, the aggressive initial spray lacing of the thrombus was fundamental to reduce the total treatment time. Infusion should be continued as necessary to eliminate all of the thrombus since residual thrombus is highly thrombogenic. 3.4. Choice of lytic agent A variety of plasminogen activators have been used to recanalize APAO, including streptokinase, urokinase, tissuetype plasminogen activators (rt-PA) and more recently recombinant glycosylated pro-urokinase and recombinant staphylokinase. Currently, urokinase is preferred over streptokinase for peripheral arterial thrombolysis because it achieves a higher initial clinical success rate (90% for UK vs. 60% for SK) with a lower incidence of bleeding complications [27,28]. Streptokinase was widely used at the dosage of 5000 IU/kg at a continuous infusion, while for urokinase the initial lowdose concept [29] was gradually abandoned in favor of higher doses with progressive tapering [20,30]. For instances, a popular scheme is 240,000 IU/h for 2 h or until

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restoration of antegrade flow, reduced to 120,000 IU/h for another 2 h and 60,000/h until lysis is complete. Analysis of non-randomized and of few randomized controlled trials suggests that t-PA is also effective in occluded peripheral arteries, and its use is associated with bleeding rates similar to those observed with streptokinase [31,32]. With rt-PA (alteplase), the dosage schemes utilized vary from 0.025 to 0.1 mg/kg/h and from 0.25 to 10 mg/h, without any obvious benefit when the higher dosages were used. A small open-label, prospective, randomized trial [33] in 32 patients compared rt-PA with urokinase for treating acute peripheral arterial and graft occlusions (of mean duration less than 12 days). rt-PA tended to induce more rapid thrombolysis than urokinase but there was no statistically significant difference in either the number of patients achieving complete lysis at 24 h or in the clinical outcomes at 30 days. However, there was a statistically significant decrease in fibrinogen levels with rt-Pa and bleeding complications tended to be more frequent with rt-PA. The analysis of the two thrombolytic arms of the STILES trial (surgery vs. thrombolysis in the Lower Extremity study) confirmed that the safety and efficacy of rt-PA and urokinase are similar [34]. A nonrandomized, retrospective analysis [35] compared the efficacy and safety of local infusion of streptokinase, urokinase and rt-PA in about 500 patients with peripheral arterial occlusions. Complete thrombolysis was obtained in 60%, 91%, and 95% of patients treated with SK, rt-PA, and UK, respectively. The incidence of major hemorrhage were 28%, 12%, and 6%, respectively, with SK, rt-PA, and UK, while there was a 2% incidence of intracranial hemorrhage with SK and rt-PA, and none were reported for patients given UK. The incidence of death was 4% for SK, 2% for rt-PA, and none for UK. In conclusion, although randomized, controlled studies comparing different agents directly are few, it is possible to state that there are minimal differences in the efficacy between rt-PA and UK (although urokinase seems to cause fewer and less severe hemorrhages). Cost-effectiveness studies comparing UK to rt-PA are not available. In conclusion, no absolute recommendations can be made about the preferred agents and doses at present because of the limited comparative data. New thrombolytic agents with a superior fibrin-specificity are currently subject to an extensive investigation for recanalization of APAO, with the main objective of significantly decreasing the bleeding complication rate of intraarterial thrombolysis. The PURPOSE trial [36] is a randomized, double-blind, parallel, phase II, prospective multicenter study that compared three doses of intra-arterial recombinant prourokinase (2, 4 or 8 mg/h for 8 h, then 0.5 mg/h) vs. a standard dose of urokinase for the treatment of APAO (of duration less than14 days). The results of the study demonstrated that the highest dose of recombinant prourokinase was associated with an increased rate of thrombolysis relative to the other treatment groups, associated with a slightly increased frequency of bleeding complications and decrements in fibrinogen con-

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centration. Conversely, the lowest dose of recombinant prourokinase induced a slightly slower rate of thrombolysis, but bleeding complications and fibrinogenolysis were diminished. The urokinase group displayed a thrombolysis rate and bleeding complications similar to those observed with the intermediate dose (4 mg/h) of recombinant prourokinase but with a relatively low rate of major bleeding events and no episodes of intracranial hemorrhage. Recombinant staphylokinase is another promising thrombolytic agent, with a unique fibrin specificity [37], which has been recently used for intra-arterial infusion in patients with both acute and more chronic peripheral arterial occlusion. The results of this single-center, uncontrolled study [38] demonstrated that complete lysis was obtained in 83% and partial lysis in 13% of patients. Interestingly, no significant difference in lysis rate could be observed between patients with recent occlusion (<14 days) and those with older occlusions. These results seem to be in sharp contrast to those obtained in the STILE study [34], in which less response to lytic therapy and a higher amputation rate were observed in patients who exhibited symptoms for longer periods (>14 days). This unique efficacy of recombinant staphylokinase towards older thrombi is very promising and deserves further confirmation in randomized, controlled clinical studies. The 1-year amputation-free survival rate was 84%, including a 1-year mortality of 6.9% and an amputation rate of 9.8% in survivors. However, although recombinant staphylokinase is a highly fibrin-selective thrombolytic agent, major bleeding was observed in 12% of patients and intracranial bleeding occurred in 2.1% of patients who died within 2 months. Thus, recombinant staphylokinase seems to be a very effective thrombolytic agent for patients with peripheral arterial occlusion since lysis rate and long-term outcome compare favorably with those observed in recent controlled clinical studies. However, the incidence of major bleeding and of intracerebral hemorrhage seems to occur at rates comparable to those with less fibrin-selective agents, urokinase and rt-PA. 3.5. Adjunctive therapy and laboratory monitoring To reduce the problem of concurrent rethrombosis during thrombolytic therapy, full systemic anticoagulation with intravenous heparin have to be applied as soon as the catheter has been introduced into the thrombus [39]. Since response to heparin is highly variable among individual patients—because fibrinogenolysis and the products of fibrinogen degradation increase the individual’s sensitivity to heparin—the adequacy of anticoagulation must be accurately monitored by means of the activate partial thromboplastine time (aPTT). Post-lysis anticoagulation is recommended until the underling lesion is corrected, since a significantly reduction of the amputation rate was observed [2]. However, these results were not confirmed by a randomized study that did not shown any benefit of anticoagulation on amputation or mortality [40]. Long-term

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anticoagulation is recommended for cases of arterial embolism, particularly when cardiac diseases and/or chronic atrial fibrillation are the putative source of embolism [41]. Antiplatelet agents, mainly aspirin if not contraindicated, is used to prevent re-thrombosis and to reduce the global cardiovascular risk [42]. Laboratory monitoring of hemostatic parameters that may reflect the systemic lytic state (e.g., fibrinogen, FDP, clotting times, platelet count) has limited predictive capacity of hemorrhagic complications or of successful outcome [18,43]. However, bleeding complications are well correlated with a low fibrinogen level [43]. Additional laboratory evaluation is necessary to detect occult hemorrhage and to follow renal function. Thus, baseline hemoglobin and hematocrit levels, blood urea nitrogen and creatinine levels are obtained. 3.6. Complications The complications of this approach can be related to intra-arterial catheter insertion or can be a result of thrombolytic therapy. Catheter-related complications include pericatheter thrombosis, which occurs in about 3% of adequately anticoagulated patients to 16.7% of patients in different series [30,44]. Rethrombosis is due to poor flow and occlusive catheter [45]. A procoagulant state may be induced by the catheter material and by the thrombolyitic agents themselves [46]. Therefore, to minimize the risk of pericatheter thrombosis, it is necessary to maintain a therapeutic anticoagulation and to avoid any unnecessary prolongation of infusion. Catheter-related trauma, resulting in mural dissection or a puncture site pseudo-aneurysm, is observed in 1.2 –1.4% of patients [47]. However, the major complication of thrombolytic therapy is bleeding. The frequency of complications varies widely depending on the definition and reporting of hemorrhagic complications. In a review of clinical studies [48], published between 1974 and 1988, on patients undergoing intra-arterial thrombolysis for peripheral arterial thrombosis, the incidence of hemorrhagic stroke was 1%, major hemorrhage (causing hypotension or requiring transfusion or other specific treatment) was 5.1% and minor hemorrhage (mainly, puncture site hematomas or oozing) was 14.8% of patients. More recently, a collected series of patients of the British Thrombolysis Study Group showed an incidence of 2.3% for stroke [49]. In three prospective randomized clinical trials [34,5,6], which compared thrombolysis to surgery, the intracranial bleeding time was 1.2% (STILE), 2.1% (TOPAS-1) and 1.6% (TOPAS-II). As demonstrated in the first phase of the latter study, the concomitant infusion of therapeutic dosage of heparin is crucial for the occurrence of intracranial hemorrhage (4.8% and 0.5% of patients, with or without concurrent infusion of heparin, respectively). Distal embolization of thrombus fragments during treatment, causing a sudden onset of pain or loss of distal pulse, occurs in about 5% of cases [1]. Most such emboli are

resolved with continued lytic therapy. Excessive clot fragmentation should be avoided so as to reduce the risk of such embolization. Acute deterioration of the limb due to increasing ischemia is observed in 25% of these patients and may require thrombus aspiration or operative intervention if thrombolysis does not improve the clinical condition within a few hours. Compartment syndrome, a complication of rapid reperfusion of the limb, is noted in about 2% of patients [18]. It is clinically manifested by pain, tenseness over the anterior muscle compartment and progressive loss of muscle and nerve function. Fasciotomy successfully relieves the high compartment pressures. More rare complications (less than 0.5% of patients) of intra-arterial thrombolysis include acute renal failure, allergic reaction to the lytic agents, particularly with streptokinase and myocardial infarction [18]. Death is a rare complication of intra-arterial thrombolytic therapy, occurring in less than 1% of patients and it is due to intracranial or intraperitoneal hemorrhage or to complications related to the reperfusion syndrome [18,50]. In general, the risk of serious complications during intraarterial thrombolysis can be decreased by an accurate selection of patients and by reducing the duration of the thrombolysis. Indeed, it has been determined that the risk of major complications increases with the duration of the thrombolytic infusion from 4% at 8 h to 34% at 40 h [19].

4. Surgery for acute peripheral arterial occlusion Immediate surgical revascularization is indicated in the profoundly ischemic limb—that is, classes IIb and early III. Embolectomy is generally indicated in the presence of severe acute ischemia, usually indicated by loss of sensitivity, discolouration of the skin, decreased skin temperature and moderate rigor of the muscles. Although early diagnosis and treatment is important, the time factor does not contraindicate the surgical treatment itself. When ischemia becomes irreversible, there is blotchy cyanotic discolouration not influenced by digital pressure, the calf muscle has a firm consistency and there is anesthesia and paralysis of the extremity. In these cases, the treatment of choice is primary amputation. If there is a clear history of previous embolization, it is not useful to perform pre-operative angiography— which will be required in case of any doubt about the diagnosis or when acute arterial thrombosis is suspected. It is very important to correct severe risk factors like cardiac insufficiency and dehydration without causing delay of the treatment. As soon possible, heparin is given intravenously as a bolus of 100 –150 UI per kg of weight, taking into consideration the factors that may influence the selection of anesthesia. Blood is typed and cross-matched. The patient is prepared from the nipples to the toes of both feet because more extensive surgery may be necessary; anyway, in case of isolated femoro-popliteal occlusion with palpable femoral pulse, only the ipsilateral groin is often prepared.

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4.1. Anesthesia Local anesthesia with lidocaine 0.5 – 1% is recommended when embolectomy can be completed via the common femoral artery. If any additional surgical procedure seems reasonably doubtful, local anesthesia may be a disadvantage. Epidural anesthesia is contraindicated if the patient is already heparinized and only spinal anesthesia with a fine needle can avert intraspinal bleeding. Often, many surgeons in these particular cases prefer to perform the operation with general anesthesia. Close monitoring during the operation is mandatory because of the high incidence of cardiovascular disease. 4.2. Surgical procedure Usually, most embolectomies can be performed via local arteriotomy on the common femoral artery. A longitudinal or transversal incision is made in order to obtain control of the common, superficial and profunda femoral arteries. Embolectomy is performed trough the Fogarty catheter and the procedure must be repeated until no residual embolic material is found, keeping in mind that several withdrawals with a high shear force can induce intimal hyperplasia. Completion angiography is mandatory because in femoro-popliteal embolectomy residual material has been found in 25– 40% [51] of all cases. Intra-operative thrombolysis appears to be effective in removing the residual material of embolization. In case of delayed embolectomy, a cleavage plane between embolus and arterial wall may be difficult to identify and in these cases, ring-stripper can be used after the balloon catheter or a bypass graft is applied for revascularization. When arterial thrombosis is the cause of acute ischemia, it is mandatory to perform an arterial reconstruction following angiographic investigation. Thrombosis of a popliteal aneurysm may also be the cause of ischemia and the correct procedure is to exclude the aneurysm and to perform the vascular reconstruction.

5. Surgical vs. intra-arterial thrombolysis procedures for acute peripheral arterial occlusion In the last few years, three large prospective randomized trials have directly compared intra-arterial thrombolysis with surgical intervention for treatment of APAO. Comparison of the studies is limited by certain differences in protocol and inclusion criteria of patients (for instance, acute vs. sub-acute or chronic limb ischemia; thrombotic vs. embolic occlusion; native vs. bypass graft occlusion; proximal vs. distal occlusion). In addition, end points in each of the studies also vary: the Rochester study [52] used ‘‘event-free survival’’; the STILE trial [34] used ‘‘composite clinical outcome’’ and the TOPAS study [5,6] used ‘‘arterial recanalization and extent of lysis’’. However, these trials

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demonstrated the advantages, the limits and the complementary nature of the two options and served to clarify which is the correct management of patients with APAO. In the Rochester study [51], 114 patients with class II limb-threatening ischemia of less than 7 days’ duration (majority of the patients presented arterial occlusion of less than 24 h) were randomly assigned to intra-arterial thrombolysis with urokinase or to immediate surgery. The study included patients with both thrombotic and embolic occlusions of native arteries and bypass grafts. Thrombolysis was always followed by an elective balloon angioplastic or surgical procedure to correct lesions unmasked after successful clot dissolution, which was obtained in 70% of patients. At the 12-month follow-up, the cumulative limbsalvage rates were similar for both groups at 82%. However, mortality rates were high, approximating 14% in the urokinase group and 18% in the surgical group during the initial hospitalization. The 12-month mortality were markedly higher in the surgical group (42% vs. 16%, p=0.01) primarily due to the increased frequency of in-hospital cardiopulmonary complications in the operative group (49% for surgery vs. 16% for thrombolysis, p=0.001). This study indicated a clear survival advantage of thrombolytic therapy among high-risk patients treated acutely during an episode of truly limb-threatening ischemia. The STILE trial [34] compared surgery with thrombolytic therapy for non-embolic, native artery or bypass graft occlusion in the lower limbs. Patients in this trial presented progressive lower-limb ischemia of 6 months or of shorter duration and were randomized to one of three groups: surgery, intra-arterial thrombolysis with urokinase or with rt-PA. The primary endpoint was a composite outcome of death, major amputation, major morbidity, hemorrhage, ongoing or recurrent ischemia and other procedural complications. The results for urokinase and rt-PA were similar and, therefore, these data were combined for purposes of comparison with surgery. Initially, the study was designed to include 1000 patients but it terminated after the first interim analysis of 393 patients as a result of the detection of significant differences in the primary endpoint between the surgical and thrombolytic groups. It is noteworthy to underline that the angiographer was unable to place the infusion catheter into the thrombus in 41% of patients with occluded bypass grafts and in 22% of patients with occluded native arteries. On an intent-to-treat basis, the primary outcome variable occurred with greater frequency in the thrombolytic group, 61.7% vs. 36.1% ( p<0.001). Further analysis revealed that the major differences did not involve the endpoints of death, limb loss, or major morbidity. Rather, the difference in the composite outcome occurred primarily as a result of an increase in the frequency of ongoing or recurrent ischemia in thrombolytic patients (54% vs. 26%; p<0.001), of life-threatening hemorrhage (5.6% vs. 0.7%; p=0.014) and vascular complications (9.7% vs. 3.5%; p=0.032). However, in a secondary analysis [52], which stratified patients by duration of ischemia, thrombolysis resulted in a clear benefit for patients with

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acutely ischemic limb (less than 14 days) whereas surgical revascularization was more effective for rather chronic ischemia (more than 14 days). Indeed, at 30 days, patients with acute ischemia treated with thrombolysis had lower amputation rate (6% vs. 18% for surgery, ( p=0.05) and shorter hospital stay (9.7 vs. 14 days for surgery, p<0.04), compared with the surgical group. For patients with chronic ischemia, surgery was more beneficial and patients suffered significantly less ongoing or recurrent ischemia (21% vs. 58% for thrombolysis, p<0.001). Assessed at 6 months of follow-up, patients presenting within 14 days of the occlusive event and treated with thrombolytic maintained a lower risk of amputation (11% vs. 30% for surgery, p=0.02). In contrast, patients with more chronic symptoms had a lower amputation rate with surgical treatment (3% vs. 12%, p=0.01). Finally, a post-study analysis [53] indicated that limb loss at 1 year was significantly lower in patients with acute limb-ischemia treated with thrombolytic compared with those treated surgically (20% vs. 48% for surgery, p=0.026). These results suggest that intra-arterial thrombolytic therapy may be appropriate for patients with acutely ischemic extremities, while surgery may be the best for patients with sub-acute or chronic symptoms. The TOPAS trial investigated patients with limb ischemia of less than 14 days’ duration caused by embolic and thrombotic native artery and bypass graft occlusions. The phase I was a dose-ranging trial [5] devoted to compare three different dosages (2000, 4000 and 6,000 IU/min) of recombinant urokinase. The results of the study demonstrated that a regimen of 4000 IU urokinase/min for 4 h, followed by an infusion of 2000 IU/min for up to 44 additional h, produced complete clot lysis in 71% of patients. Mortality rates and amputation-free survival rates in this group were similar to those in the surgical control group, but patients treated with thrombolysis required significantly fewer major surgical procedures. The incidence of intracranial bleeding was 2.1%. This dosage regimen was next tested in a large multicenter study [6] on 544 patients (TOPAS-II). Amputation-free survival rates in the urokinase group were 71.8% at 6 months and 65% at 1 year, as compared with respective rates of 74.8% and 69.9% in the surgery group; these differences between the two groups are not significant. The thrombolytic therapy reduces the need for an invasive procedure over the first 6 months and averted an open surgical procedure in about 30% patients without increased risk of amputation or death. Based on these data, a Working Party proposed that thrombolytic therapy should be considered as an appropriate initial management in patients with acute occlusion of leg arteries or bypass grafts [54]. However, several vascular surgeons still disagree with this recommendation. Dr. Porter, concluded his comment [55] to the publication of the TOPAS trial [6] in the same issue of the Journal with the following sentence: ‘‘For the time being I not regard thrombolytic therapy as first-line treatment for acute arterial thromboembolism of the legs’’.

More recently, a retrospective study [56] analyzed the clinical outcome and the cost of 100 consecutive cases in which intra-arterial urokinase was used as the initial treatment for native lower extremity occlusive disease. The primary outcome used to judge the success of thrombolysis was relief of ischemia, defined as a sustained improvement of the patient’s ischemic symptoms after thrombolysis, without the need for subsequent surgical intervention. With this outcome, thrombolysis was successful in only 70%, 53%, and 43% of the patients at 30 days, 1 year and 2 years, respectively. A very similar poor outcome was observed in patients with acute native artery occlusion in the STILE trial [34]. Thus, the analysis of these data suggests that initial thrombolysis is a reasonable approach only for the small subset of patients who present with isolated aortoiliac occlusion. In addition, the average cost of thrombolysis per patients was $18,490, in the range of what has been reported [57] for infrainquinal surgical revascularization ($22,096 for femoro-politeal bypass graft). Ouriel et al. [58] found total treatment costs of $22,171 for the thrombolytic group and $19,775 for the operative group. However, the consideration that a substantial proportion of patients treated with initial thrombolysis will eventually require surgery (two-thirds at 6 months in the TOPAS trial.) raises the possibility that a strategy of initial lysis may be significantly more costly than a strategy of initial surgery. The hypothesis that initial surgery could be more costeffective than thrombolysis was recently confirmed in a cost-effectiveness analysis [59] based on TOPAS trial data.

6. Conclusions Immediate surgical revascularization is indicated in the profoundly ischemic limb. Catheter-directed thrombolysis may be an appropriate initial treatment of acute (less than 14 days’ duration) limb ischemia, provided that the limb is not immediately or irreversibly threatened. Using this approach, the underlying lesions can be further defined by angiography, and the percutaneous or surgical revascularization procedure can be performed. However, severe bleeding is a non-rare complication of intra-arterial thrombolysis and the risk of intracranial hemorrhage is still 1 –2%. In addition, recent cost-effectiveness analysis raises the possibility that a strategy of initial thrombolysis may be significantly more costly than a strategy of initial surgery.

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