Thrombolytic Therapy with Use ofAlteplase (rt-PA) in PeripheralArterial Occlusive Disease: Review ofthe Clinical Literature1

Charles P. Semba, MDTimothy P. Murphy, MDCurtis W. Bakal, MD, MPHKarim A. Calis, PharmD, MPHTerence A. S. Matalon, MDand the Advisory Panel*

Index terms: Alteplase ● Arteries, pe-ripheral ● Arteries, stenosis or obstruction● Thrombolysis ● Tissue plasminogen acti-vator

JVIR 2000; 11:149–161

Abbreviations: PAO � peripheral arte-rial occlusive, PGE � prostaglandin E,PST � pulse spray thrombolysis, rt-PA �recombinant tissue plasminogen activa-tor, t-PA � tissue plasminogen activator

PURPOSE: The clinical literature describing the use of alteplase inthe treatment of peripheral arterial occlusive (PAO) disease is re-viewed.

MATERIALS AND METHODS: The literature database was ac-quired by a MEDLINE search using the Boolean keyword string:tissue plasminogen activator and/or rt-PA and peripheral not ani-mal. A review was performed to identify the dose range of alte-plase, technique of infusion, use of anticoagulation, clinical suc-cess rates, and risk of complications.

RESULTS: Forty-six clinical studies were identified. There are fewprospective, randomized clinical trials and a lack of standardizedprotocols and endpoints. Use of catheter-directed infusions of re-combinant tissue plasminogen activator (rt-PA) may be beneficialversus surgery in the initial management of acute limb ischemia(< 14 days) and in reducing the magnitude of subsequent surgicalor percutaneous revascularization. For patients with chronic limbischemia (> 14 days), irreversible acute limb ischemia, or ad-vanced diabetic arteriopathy, catheter-directed infusion of rt-PAor other plasminogen activators may be unsuitable. The risk of ad-verse bleeding appears related to the overall dose and duration ofinfusion. These risks appear similar to those of urokinase. The roleof heparin in increasing adverse bleeding during rt-PA therapy isunclear.

CONCLUSIONS: There is no generally accepted dose or techniquefor administering catheter-directed thrombolysis using alteplase;however, several studies have demonstrated its clinical safety andefficacy. Formal studies will be required to determine the optimaldose, technique of infusion, the role of anticoagulation, and com-plication rates when alteplase is used for PAO disease.

PERIPHERAL arterial occlusive(PAO) disease is the most commoncause of limb ischemia (1). Althoughsurgical intervention has been thehistorical standard of care for re-storing limb perfusion, catheter-directed thrombolysis has beenshown to be useful in rapid clot dis-solution, unmasking underlying ste-noses, and simplifying subsequenttreatment decisions (2–4). In many

patients, thrombolysis can reducethe scope of or even eliminate theneed for surgery (4). For the past 20years, urokinase has been the drugof choice for catheter-directedthrombolysis; however, in late 1998the Food and Drug Administration(FDA) suspended sales of urokinasein the United States (5,6). Theshortage of urokinase has led to adilemma in clinical practice since

1 Received October 27, 1999 accepted No-vember 1. This study was supported inpart by an unrestricted grant from Ge-nentech, Inc., South San Francisco, Calif.Address correspondence to C.P.S., In-terventional Radiology, H-3646, StanfordUniversity Medical Center, Stanford, CA94305; E-mail: csemba@stanford.edu*Program co-chairs: Terence A. S. Mata-lon, MD, Chicago, IL; Curtis W. Bakal,MD, MPH, New York, NY; Karim A. Ca-lis, PharmD, MPH, Bethesda, MD;Paramjit Chopra, MD, Chicago, IL; Patri-cia E. Cole, PhD, MD, New Haven, Conn;Anthony J. Comerota, MD, Philadelphia,PA; Buddy Connors, MD, Fairfax, VA;Jacob Cynamon, MD, New York, NY;Gerald E. Grubbs, MD, Naples, FL; ZivHaskal, MD, New York, NY; Suzanne La-Vere Herbst, RN, MA, Syracuse, NY;David W. Hunter, MD, Minneapolis, MN;Timothy P. Murphy, MD, Providence, RI;Kathy Phelps, PharmD, Winston-Salem,NC; Charles P. Semba, MD, Stanford,CA; David Stump, MD, San Francisco,CA; Steven Thomas, MBBS, MRCP,FRCR, Sheffield, England; David L.Warner, MD, Chicago, IL; and Gerald Ze-mel, MD, Miami, FL.

© SCVIR, 2000

State of the Art

149

few U.S. interventionalists haveany prior experience using alterna-tive agents in treating PAO disease.Potential alternatives to urokinaseinclude streptokinase, anistreplase,reteplase, and recombinant tissueplasminogen activator (rt-PA). Be-cause of significant published expe-rience with rt-PA in the coronaryand peripheral circulation and unfa-vorable experience with streptoki-nase-based thrombolytic agents,this review focuses on rt-PA.

This clinical review of the cathe-ter-directed use of alteplase ana-lyzes the dose range, technique ofinfusion, use of anticoagulation,clinical success rates, and risk ofcomplications when treating PAOdisease. Although reteplase is an-other FDA-approved formulation oft-PA, the published literature onthis drug in PAO disease is insuffi-cient to make recommendations re-garding its performance comparedwith alteplase at this time.

MATERIALS AND METHODS

● Literature Review

Because of the unavailability ofurokinase in the United States, anadvisory panel to the Society ofCardiovascular & InterventionalRadiology (SCVIR) was organized inJuly 1999 to provide to the Societymembership a review of alternativeplasminogen activators in clinicalpractice. The multidisciplinary Ad-visory Panel on Catheter-DirectedThrombolytic Therapy comprisesinterventional radiologists, vascularsurgeons, neuroradiologists, re-search scientists, pharmacists, andallied health personnel. There areno published clinical series describ-ing catheter-directed thrombolysisusing the alternative tissue plas-minogen activators reteplase (7) oranistreplase (8); thus, the reviewfocused exclusively on alteplase.Streptokinase, a first-generationplasminogen activator, was not con-sidered.

The database of clinical litera-ture was gathered using a MED-LINE search consisting of the Bool-ean keyword string: tissue plasmin-

ogen activator and/or rt-PA and pe-ripheral not animal. Clinical studiesselected required publication in apeer-reviewed journal with an ab-stract written in English; non-En-glish reports were translated forreview by the panel. Single case re-ports or applications in deep veinthrombosis, dialysis graft thrombol-ysis, or catheter clearance were notreviewed. The project was sup-ported by an unrestricted grantfrom Genentech, Inc. (South SanFrancisco, Calif.) with the sponsor-ship of the SCVIR.

Forty-six clinical studies inwhich alteplase was used to treatPAO disease were identified. Thereare few randomized, prospective,and controlled studies comparingrt-PA and urokinase. The review islimited by lack of uniform reportingstandards, variability in clinicalendpoints, diverse definitions of ma-jor and minor complications, andvariability in thrombolytic tech-niques. Studies describe the use ofboth single- and double-chain re-combinantly derived tissue plasmin-ogen activator.

Summarizing a single uniformprotocol from the numerous clinicalstudies is not possible because ofthe wide variability in reporting (9).Several independent variables areidentified, including: (i) study popu-lations, ie, acute versus chroniclimb ischemia; (ii) target sitetreated, ie, native vessel or graft;(iii) dosing regimen, ie, dose ofrt-PA and duration of rt-PA ther-apy; (iv) method of infusion, ie, con-tinuous infusion versus bolus infu-sion or other method; (v) anticoagu-lation therapy, ie, heparin or aspi-rin; and (vi) clinical endpoints, ie,successful lysis versus clinicallyuseful lysis versus amputation-freesurvival.

● Definitions

Because of the confusion in ter-minology and inability to cross-ref-erence clinical results, an interna-tional group of vascular specialistsproduced a consensus document in1998 to establish uniform reportingstandards for thrombolytic therapy(10). Unfortunately, the majority of

reports reviewed here were not pub-lished using these guidelines. TheWorking Party on Thrombolysis inthe Management of Limb Ischemiadefines initial technical thrombo-lytic success as the “restoration ofanterograde flow with complete ornear complete lysis of thrombus”(10). The British ThrombolysisStudy Group further distinguishes“complete lysis” from “clinically use-ful lysis,” “lysis but no runoff,” and“failure of lysis” (11). A brief sum-mary of common terminology in theliterature is provided below.

Complete lysis.—Clearance of anoccluded vessel by thrombolytictherapy with restoration of flow torunoff and reestablishment of pe-ripheral pulses (11) or clearance ofan occluded vessel by thrombolytictherapy as determined by serial an-giograms (12–18).

Clinically useful lysis.—Partialclearance of a thrombus that re-lieves rest pain or improves the an-kle-to-brachial index (ABI) by 0.2;or partial clearance of a thrombusthat results in a smaller surgicalprocedure than was possible beforethrombolysis; or partial clearanceenabling a procedure to be per-formed when none was possible be-fore lysis (11).

Successful thrombolysis.—Radio-graphic evidence of recanalizationwith or without clinical evidence ofreperfusion (12-22).

Time to lysis.—Time from onsetof thrombolytic infusion to completerecanalization or maximal radio-logic lysis (23).

Lysis with no runoff.—Lysis ofthe acute thrombus without estab-lishing runoff flow into major distalvessels (11).

Lysis failure.—No improvementor deterioration in limb perfusion(11).

DISCUSSION

Regimens for using rt-PA forcatheter-directed therapy for PAOdisease are still evolving. Patientselection, optimal doses, modes ofdelivery, management of side ef-fects, and other factors related to itsclinical use are not yet standard-

150 ● Thrombolytic Therapy with Use of Alteplase

February 2000 JVIR

ized. However, there are many clini-cal series describing the safety andefficacy of rt-PA for the treatmentof PAO disease. In an attempt tosummarize the state of the scienceof rt-PA and provide a reference forimmediate clinical application andfuture research direction, this arti-cle reviews patient, drug, and drug-delivery characteristics based onpublished data from randomizedand nonrandomized trials usingrt-PA in the management of PAOdisease.

● Tissue Plasminogen Activator

The final common pathway inclot formation is the enzymaticcleavage of fibrinogen into fibrin bythrombin. The proteinaceous fibrinstrands enmesh aggregated plate-lets and red blood cells to form athrombus. Enzymatic breakdown ofcross-linked fibrin strands withinthe thrombus is accomplished bythe generation of plasmin by tissueplasminogen activator (t-PA) (Fig1). A naturally occurring single-chain polypeptide secreted by vas-cular endothelial cells, t-PA plays acentral role in the endogenous fi-brinolytic process (24). In additionto cleaving apart fibrin, plasmincan convert the single-chain mole-cule of t-PA to a double-chain mole-

cule (25,26). Both the single- anddouble-chain forms of t-PA havesimilar enzymatic activity in thepresence of fibrin (27,28). From aclinical standpoint, both single-chain and double-chain t-PA areconsidered equally effective for clotlysis.

Alteplase (Activase; Genentech,South San Francisco, Calif.) is asingle-chain serine protease pro-duced by recombinant DNA meth-ods. The gene sequence that ex-presses t-PA is isolated from thehuman melanoma cell line and in-serted into the ovarian cell of theChinese hamster. The recombi-nantly derived t-PA (rt-PA) is iso-lated, purified, and packaged as asterile, lyophilized powder in 50- or100-mg vials (29).

The recombinant form of t-PA(rt-PA) was first approved in 1987by the FDA and is indicated fortreating acute myocardial infarc-tion, acute pulmonary embolism,and acute ischemic stroke.

There are currently three othertissue plasminogen activators avail-able in the United States: streptoki-nase (Streptase; Astra Pharmaceu-ticals, Wayne, Pa); anistreplase(Eminase; Roberts PharmaceuticalCorporation, Eatontown, NJ); andreteplase (Retavase; Centocor, Inc.,Malvern, Pa). Urokinase (Abboki-

nase; Abbott Laboratories, AbbottPark, Ill) availability has been lim-ited since late 1998. Streptokinaseis a proteolytic enzyme produced by�-hemolytic streptococci and wasthe first thrombolytic agent used forthe treatment of PAO disease byCharles Dotter in 1974 (30). Thougheffective in clot lysis, it has the dis-advantage of being antigenic; circu-lating antibodies generated after astreptococcal infection or prior ad-ministration of streptokinase cancause allergic reactions and de-crease the bioavailability of thedrug (31). Comparative studies haveshown that streptokinase is inferiorto urokinase and rt-PA in its abilityto lyse peripheral arterial thrombi,and rt-PA shows faster fibrin degra-dation than either streptokinase orurokinase (32).

Urokinase is produced by humanneonatal kidney cells in culture. Itsprimary advantage was its consis-tency in performance, predictability,lack of immunogenicity, and de-creased bleeding complications com-pared with streptokinase (33). Be-cause of superior efficacy and lessadverse bleeding, urokinase becamethe standard of care in interven-tional practices in the UnitedStates. In late 1998, the U.S. FDAissued warnings regarding the po-tential risk for infectious diseasesfrom urokinase and subsequentlysuspended sales in 1999 (5,6).

Anistreplase is a stabilized inter-mediate complex of human plasmin-ogen and streptokinase and is ap-proved for the treatment of acutemyocardial ischemia (8). Since it isderived from �-hemolytic strepto-cocci, it carries the inherent antige-nicity problem as seen with strep-tokinase. There are no reports ofcatheter-directed applications ofanistreplase.

Reteplase is a recombinantly de-rived mutein of t-PA. It is com-prised of 355 of the 527 amino acidsthat form rt-PA and is approved forbolus infusion treatment of acutemyocardial ischemia (7). Reteplaseis currently undergoing clinical in-vestigation for PAO disease, butthere have been no published re-ports thus far.

Figure 1. Biochemical pathway showing the effect of tissue plasminogen activa-tors in plasma and at the surface of fibrin clots. Printed with permission fromStump DC, Mann KG (80).

Semba et al ● 151

Volume 11 Number 2

● Patient Selection Criteria

The success of thrombolytic ther-apy with rt-PA depends on optimalpatient selection. Table 1 presentsan overview of exclusion criteria. Ingeneral, these criteria are related tothe potential complications of treat-ment, particularly hemorrhage, andpatients at risk for adverse bleedingshould not receive tissue plasmino-gen activators (34,35). Contraindica-tions for thrombolytic therapy in-clude patients with active internalhemorrhage, recent major surgeryor trauma, known bleeding diathe-sis, uncontrolled hypertension, andcerebrovascular infarction or bleed-ing during the preceding 2 months.Pregnant women and those in theimmediate postpartum period alsoshould not receive thrombolytictherapy (10,36). Because catheter-directed thrombolysis may requireseveral hours before successful lysisis achieved, patients with acute

limb ischemia progressing to sen-sory and motor deficit and irrevers-ible ischemic injury are not candi-dates for rt-PA therapy.

● Dosing Regimens

Despite descriptions of variousdosing regimens, there is no consen-sus or standardized definition of“high-dose” or “low-dose” rt-PAtherapy. The dosing of rt-PA can bedivided into two categories-weight-based versus non-weight-based regi-mens-and nearly all studies reporteffective rates of recanalization andsafety with both. In general, thelowest effective dose has yet to bedetermined. With weight-based reg-imens, rt-PA doses ranged from0.02 to 0.1 mg/kg/h (14,22,37). Innon-weight-based regimens, dosesranged from 0.25 to 10 mg/h(17,19). Only a single randomizedstudy was identified that directlycompared the efficacy of two dosesof rt-PA, 0.05 versus 0.025 mg/kg/h,using catheter-directed methods(38). Although both doses were sim-ilarly successful in achieving recan-alization, the lower dose required alonger time to reach lysis (3.1 hoursand 12.0 hours for the higher andlower doses, respectively). The totalinfused doses have ranged from 5 toapproximately 50 mg (17,22). Themaximum total dose of rt-PA shouldnot exceed 100 mg; this is based onintravenous therapy for acute myo-cardial ischemia (29). In summary,rt-PA has been shown to be effec-tive over a wide range of doses, andthe appropriate dose must be basedon patient characteristics and riskfor complications, particularly hem-orrhage. Until further data becomeavailable, it appears prudent to be-gin with lower doses (eg, 0.25–1 mg/h).

● Method of Infusion

Several different methods havebeen used to deliver alteplase inmanaging PAO disease. These in-clude intravenous infusions, in-traarterial continuous infusions,bolus infusions, and pulse-spraytechniques.

Intraarterial versus intravenousinfusion.—Since the enzymatic po-tential of rt-PA is markedly en-hanced on the fibrin surface of clot,it theoretically should be equallyactive when given systemically by aperipheral intravenous line or bydirect intraarterial methods (39).Systemic (intravenous) administra-tion of rt-PA has been proven bene-ficial in coronary, pulmonary, andcerebral artery thrombosis; how-ever, the clot volume— especially inacute myocardial ischemia andstroke—is significantly smaller com-pared with thrombosis seen in PAOdisease. Because of the length andvolume of thrombus present in PAOdisease, Berridge reasoned that it isunlikely that a rapid-onset, short-duration thrombolytic agent cancause adequate clot lysis and thatfor thrombolytic treatments to besuccessful in PAO disease, a fibrin-specific agent must be given overseveral hours without causing un-due systemic lytic effect (34).

The safety and efficacy parame-ters of intravenous versus intraarte-rial routes of rt-PA administrationwere evaluated in a randomized,parallel-group study (34). An analy-sis of data on 40 patients revealedthat intravenous delivery of rt-PAwas not as successful as direct in-traarterial administration and car-ried a significantly higher risk ofhemorrhagic complications. Intraar-terial infusion of rt-PA producedconsistent and more completethrombolysis, with no hemorrhagiccomplications in a group of 20 pa-tients with lower limb ischemiaover a 3-month study period. Thus,in spite of the availability of therelatively fibrin-specific rt-PA, di-rect intraarterial administrationremains the method of choice forthrombolysis in PAO disease.

Continuous endhole infusions.—Catheter-directed thrombolysis us-ing continuous infusion of rt-PArepresents the most commonly de-scribed technique in treating PAOdisease. An endhole catheter isplaced at the leading edge of thethrombus and the catheter tip isperiodically repositioned from theproximal to distal regions of thethrombus. Ongoing angiography is

Table 1Overview of Exclusion Criteriafor Recombinant TissuePlasminogen Activator Therapyin Patients With PeripheralArterial Occlusion

Active internal hemorrhage*Proximal arterial emboli (�2 days

duration)†

Known bleeding diathesis† or addedrisk of bleeding (eg, active pepticulcer)

Cerebrovascular accident withinpreceding 2 months*†

Recent major surgery/trauma (�10days,† �2 weeks*)

Infected bypass grafts*Infective endocarditis*Inability to traverse the occlusion

with a guide-wire*Inability to withstand further

ischemia up to 24 hours* (totalischemia with rapidly progressingsensory and motor deficit)

Presence of irreversible ischemicinjury*

Arterial thrombosis causing severeischemia with good runoff†

Pregnancy*/childbearing potential†

Inability to provide consent*†

* Yusuf et al, 1995 (35).† Berridge et al, 1991 (34).

152 ● Thrombolytic Therapy with Use of Alteplase

February 2000 JVIR

used to determine when sufficientlysis in one area has been accom-plished and advancing the cathetertip is warranted. The dose of rt-PAselected is given through the end-hole of a single-lumen catheter us-ing a constant (steady flow) infusionpump. (Arguably, the current stateof the art advocates the placementof an infusion wire and/or multisi-dehole delivery catheter completelywithin and spanning the entirelength of the thrombus [intrathrom-bus infusion]) (40).

Anticoagulation with systemicheparin is commonly used immedi-ately following successful thrombol-ysis and subsequent intervention toprevent acute rethrombosis. How-ever, during continuous thrombo-lytic infusion, the use of concomi-tant heparin varied widely. Thiswas due to observations that hepa-rin does not increase the efficacy oflysis (41) and the increased inci-dence of bleeding complicationsseen with prolongation of the par-tial thromboplastin time (PTT) (42).A summary of various randomized(18) and nonrandomized (15–23,32,37,43,44). trials utilizing continu-ous infusion rt-PA therapy withheparin and without heparin is pre-sented in Tables 2 and 3, respec-tively.

Of the 444 patients tested in thestudies using heparin, successfulthrombolysis has been reported inan average of 91% of patients, withmajor complications ranging from 0to 17.4%. Heparin use ranged froma continuously infused subtherapeu-tic dose of 250 IU/h to a one-timebolus of 10,000 IU. Of the 233 pa-tients treated without concomitantheparin, the overall incidence ofsuccessful thrombolysis was 85%,with major bleeding occurring in0–14% of patients. The efficacy ofheparin versus no heparin duringrt-PA therapy was assessed in onlyone small study involving 30 pa-tients (41). The study compared out-comes between an equal number ofcases treated either with rt-PA only(0.5 mg/h; mean duration, 26 hours)or rt-PA plus heparin (rt-PA 0.5mg/h plus heparin 250 U/h; meanduration, 32 hours). It concludedthat the addition of heparin had no

significant benefit (41). Based onthe overall clinical experience withcontinuous infusion therapy, no con-clusions can be drawn regarding thesafety or efficacy of rt-PA with orwithout heparin.

The long-term clinical outcomesafter lower extremity thrombolytictherapy have been reported in 288patients with up to 4 years of fol-low-up (13). Continuous intraarte-rial infusion rt-PA therapy (2.5mg/h for a maximum of 5 hours)can result in primary clot lysis andsuccessful recanalization (defined asthat persisting at a 2-week clinicalexamination) with long-term benefitdependent on the nature of thetreatment site. By using Kaplan-Meier survival curves, cumulativepatency at 4 years was determinedto be 100%, 95%, 78%, and 62% formacroemboli arising from primaryangioplasty, emboli, in situ throm-boses, and bypass graft thromboses,respectively (Fig 2).

In a single study of 120 patientswith “acute” or “subacute” limbischemia randomized to eitherurokinase or rt-PA, the rt-PA grouphad faster lysis with lower amputa-tion rates at 6 months, with no ma-jor bleeding complications in eithertreatment group (45). Long-termpatency was independent of patientage and gender and equally success-ful in popliteal arteries with oc-cluded tibial runoff and in femoralor popliteal segments with normaltibial runoff. However, other inves-tigators have shown that long-termoutcome is inferior for patients withchronic femoropopliteal occlusivedisease, advanced diabetic arteri-opathy, or critical limb ischemia(46).

Intrathrombus bolusing.—Al-though continuous infusion therapyof rt-PA 0.5–1.0 mg/h has been suc-cessful, the long durations of infu-sion make it less desirable in casesof more severe acute limb ischemia(stage IIa or IIb), when time is criti-cal (47). Therefore, a regimen con-sisting of an initial high-dose bolusof rt-PA has been proposed toshorten the duration of thrombo-lytic therapy. The term “bolusing,”often used interchangeably with“lacing,” refers to the intrathrombic

delivery of a concentrated lyticagent to saturate the thrombuswith plasminogen activator with theintent to increase the rate of fibri-nolysis (10). Bolusing may providebiochemical benefits, since the riskof bleeding has been correlated withdecreased levels of fibrinogen andincreased fibrin degradation prod-ucts seen in prolonged continuousinfusions. It has been postulatedthat a short infusion at a higherdose may have fewer adverse bleed-ing complications since there is lessfibrinogen depletion and less sys-temic circulation of plasmin (48). Asingle prospective, randomizedstudy has compared a high-dose bo-lus infusion of rt-PA (3 � 5 mggiven over 30 minutes; then 3.5mg/h for up to 4 hours; then 0.5–1.0mg/h) with low-dose continuous in-fusion (rt-PA 0.5–1.0 mg/h) (11).The study data suggest that a high-dose bolus infusion can reduce sig-nificantly the median duration ofinfusion without altering efficacy orincreasing complications (P �.0001). The median duration of infu-sion was decreased by 80%, from 20hours to 4 hours, with almost 50%of the patients showing complete orclinically useful lysis by 4 hours(P � .0001). The incidence of majorhemorrhage in patients receivingbolus therapy was comparable tothe incidence in those receiving con-tinuous infusion (6.1% vs 6.8%, re-spectively).

Other studies have shown an in-creased risk for hemorrhage whenbolusing was done at higher doses(49,50). In a small, noncomparativetrial of 23 patients receiving an ini-tial bolus of rt-PA 20 mg followedby 1 mg/h, the rate of major bleed-ing was 35%, with two intracranialhemorrhages; one episode was fatal(50). This was later compared withcontinuous infusion techniques (1mg/h) and demonstrated a 46% de-crease in infusion time (14.4 vs26.7 h; P � .005) compared withcontinuous infusion, but with agreater incidence of major hemor-rhage in patients receiving bolustherapy (35% vs 3.7%; P � .0022)(51). However, this high rate ofadverse bleeding has not beenuniformly seen. The British

Semba et al ● 153

Volume 11 Number 2

Tab

le2

Su

mm

ary

ofR

and

omiz

ed(n

�1)

and

Non

ran

dom

ized

(n�

6)T

rial

sA

dm

inis

teri

ng

t-P

Ab

yE

nd

hol

eS

low

Intr

aart

eria

lIn

fusi

onA

lon

gw

ith

Intr

aven

ous

Hep

arin

Tri

alT

ype

ofT

rial

Nu

mbe

rof

Pat

ien

tsM

ean

Age

(y)

Mea

nD

ura

tion

ofO

cclu

sion

/Sym

ptom

s

t-P

AH

epar

inB

leed

ing

Dos

eD

ura

tion

ofIn

fusi

onD

ose

Du

rati

onof

Infu

sion

Maj

orM

inor

Ber

oet

al,

1995

N20

64.6

(39–

79)

27.2

d(1

–117

d)18

.3d

(1–9

0d

amon

gsu

cces

ses)

Rat

e:2

mg/

hM

ean

tota

ldo

se:

38.9

mg

(8–8

4m

gam

ong

succ

esse

s)

Mea

n:

19.7

h(r

ange

,4–

42h

amon

gsu

cces

ses)

500–

1,00

0U

/hN

otst

ated

14%

(n�

3,w

ith

1fa

tal

intr

acra

nia

lh

emor

rhag

e)

19%

Hes

set

al,

1996

N28

871

(24–

88)

Not

stat

edR

ate:

2.5,

5,10

mg/

hM

ean

:78

,92

,10

7m

inre

spec

tive

ly

Hep

arin

5,00

0IU

(in

trap

roce

dure

;th

enIV

orS

Cfo

rad

diti

onal

2–3

d;do

sen

otst

ated

)

Not

stat

ed0%

2%

Kop

pen

stei

ner

etal

,19

88N

9N

otst

ated

28d

(10

min

–75

d)R

ate:

0.02

mg/

kg/h

Tot

aldo

se:

5m

g(r

ange

,2–

14m

g)

Med

ian

:15

0m

in(r

ange

,90

–420

min

)

Tot

alof

3,00

0–5,

000

UIn

term

itte

ntl

yu

sin

gpr

oced

ure

tofl

ush

con

tras

tm

ediu

mca

thet

er

0%0%

Daw

son

etal

,19

91N

a10

69.3

(40–

95)*

18.5

d(1

2h–8

4d)

Rat

e:0.

5–1.

0m

g/h

Mea

nto

tal

dose

:n

otst

ated

Mea

n:

32.7

h(n

ora

nge

stat

ed)

250

U/h

Not

stat

ed0%

Not

stat

ed

Kra

use

and

En

dsin

,19

93N

b28

63(4

6–83

)U

pto

4m

oT

otal

:2.

5–7.

5m

gM

ean

tota

ldo

se:

not

stat

ed

Mea

n:

2h

(ran

ge,

1–5

h)

10,0

00IU

hep

arin

in50

mL

NaC

l24

h0%

7%

Ver

stra

ete

etal

,19

88N

50(1

0m

g/h

)11

(5m

g/h

)5

(3m

g/h

)

64.8

(37–

86)†

56d

(1–3

65d)

†R

ate:

3,5,

or10

mg/

hT

otal

mea

ndo

ses:

42,

39,

47m

g,re

spec

tive

ly

Not

stat

edV

ario

us:

2,50

0–5,

000

IUbo

lus;

400

IU/h

IA;

1,00

0IU

/hIV

Not

stat

ed10

mg/

h;

4%3

and

5m

g/h

:0%

10m

g/h

:16

%3

and

5m

g/h

:37

%

Gra

oret

al,

1993

Ra

2369

.6 (not

stat

ed)

Nat

ive:

68d

Gra

fts:

4d

(not

stat

ed)

0.05

mg/

kg/h

Mea

n:

5.8

h(n

ora

nge

stat

ed)

1,00

0IU

/hIV

Not

stat

ed17

.4%

4.3%

Not

e.—

Nu

mbe

rsin

pare

nth

eses

are

ran

ges.

IA�

Intr

aart

eria

l,N

�N

onra

ndo

miz

ed,

R�

Ran

dom

ized

.a

Tri

alin

clu

ded

ast

rept

okin

ase

trea

tmen

tar

m.

bT

rial

incl

ude

da

uro

kin

ase

trea

tmen

tar

m.

*T

otal

thro

mbo

lysi

spo

pula

tion

incl

ude

s18

pati

ents

rece

ivin

gst

rept

okin

ase.

†C

har

acte

rist

ics

are

for

50pa

tien

tsat

a10

mg/

ht-

PA

dose

only

;ot

her

pati

ents

(3an

d5

mg/

hdo

ses)

had

sim

ilar

char

acte

rist

ics.

154 ● Thrombolytic Therapy with Use of Alteplase

February 2000 JVIR

Tab

le3

Su

mm

ary

ofN

onra

nd

omiz

edT

rial

s(n

�8)

Ad

min

iste

rin

gt-

PA

by

En

dh

ole

Slo

wIn

traa

rter

ial

Infu

sion

wit

hou

tIn

trav

enou

sH

epar

in

Tri

alN

o.of

Pat

ien

tsM

ean

Age

(y)

Du

rati

onof

Occ

lusi

on/

Sym

ptom

s

Med

ian

Len

gth

ofO

cclu

sion

(cm

)

t-P

AM

ean

Tim

eto

Lys

isO

vera

llL

imb

Sal

vage

Ble

edin

g

Dos

eD

ura

tion

ofIn

fusi

onM

ajor

Min

or

Ear

nsh

awet

al,

1988

*28

Med

ian

:65

.5(4

2–83

)M

edia

n:

7.5

d(r

ange

,1–

28d)

22(5

–30)

Rat

e:0.

25,

0.5,

1.0,

or2.

5m

g/h

Mea

nto

tal

dose

:n

otst

ated

Med

ian

:22

h(r

ange

not

stat

ed)

Med

ian

:22

h(r

ange

not

stat

ed)

68%

(30

d)14

%14

%

Gra

oret

al,

1986

1859

(38–

76)

Mea

n:

6.8

d(r

ange

,1–

21d)

Not

stat

edR

ate:

0.1

mg/

kg/h

Mea

nto

tal

dose

:29

.2m

g/dL

(ran

ge,

9–58

mg/

dL)

Mea

n:

202

min

(ran

ge,

60–3

90m

in)

202

min

(ran

ge,

60–3

90m

in)

Not

stat

ed6%

(n�

1de

ath

at48

hw

hil

eon

hep

arin

)

17%

Ber

ridg

eet

al,

1989

1375

.3�

12.2

Med

ian

:18

d(r

ange

,1–

60d)

18�

13.7

Rat

e:0.

5m

g/h

Mea

nto

tal

dose

:n

otst

ated

Not

stat

ed26

.2�

12.6

87%

(30

d)0%

30% (2

2%h

adP

TA

)G

raor

etal

,19

8822

63(n

otst

ated

)M

ean

graf

tag

e:28

8d

Not

stat

edR

ate:

0.05

or0.

1m

g/kg

/hT

otal

dose

not

stat

ed

�8

hN

otst

ated

73%

(30

d)4%

36%

Ris

ius

etal

,19

8625

Mea

nn

otst

ated

(38–

76)

Mea

n:

6.5

d(1

h–2

1d)

Not

stat

edR

ate:

0.1

mg/

kg/h

Mea

nto

tal

dose

:29

.5m

g(r

ange

,4.

5–58

mg)

Not

stat

ed3.

6h

(ran

ge,

1–6.

5h

)92

%4%

(n�

1de

ath

at48

hw

hil

eon

hep

arin

)

12%

Lon

sdal

eet

al,

1992

*69

Med

ian

:67

.5(4

2–93

)M

edia

n:

10.5

d(r

ange

,1–

49)

15(r

ange

,2–

70)

Rat

e:0.

25–2

.5m

g/h

in18

pati

ents

;0.

5m

g/h

in51

pati

ents

Not

stat

edM

edia

n:

22h

(ran

gen

otst

ated

)94

%(3

0d)

7%10

%

Spe

nge

let

al,

1993

4670

.6�

11.7

(37–

92)

Med

ian

:25

d(r

ange

,1–

179

d)14

.4�

9.2

(ran

ge,

2–44

)R

ate:

1–9.

4m

g/h

(mea

nn

otst

ated

)M

ean

tota

ldo

se:

5.8

�

3.8

mg

(ran

ge,

1–17

.8m

g)

Up

to4

h(7

3%�

2h

)N

otst

ated

100%

0%0%

Wei

dau

er&

Tim

mer

man

n,

1990

12M

ean

not

stat

ed(4

9–72

)3–

40w

ks(m

edia

nn

otst

ated

)

2–15 (m

edia

nn

otst

ated

)

Rat

e:2.

5m

g/h

Tot

aldo

se:

6.5–

20m

g(m

ean

not

stat

ed)

2.5–

8h

(mea

nn

otst

ated

)N

otst

ated

Not

stat

ed0%

17%

Not

e.—

Nu

mbe

rsin

pare

nth

eses

are

ran

ges.

PT

A�

perc

uta

neo

us

tran

slu

min

alan

giop

last

y.*

Tri

alin

clu

ded

ast

rept

okin

ase/

hep

arin

trea

tmen

tar

m.

Semba et al ● 155

Volume 11 Number 2

Thrombolysis Study Group databaseof 73 patients (52) shows majorhemorrhage occurring in 11% of pa-tients with comparable demographicparameters and receiving similarbolus therapy as the Ward study(50).

In summary, bolus rt-PA therapyappears to provide an advantage inreducing the duration of treatmentand may be of particular benefit inthe management of acutely ischemiclimbs. However, it must be weighedagainst the possible increased riskof hemorrhage and associatedevents.

Pulse-spray thrombolysis.—Be-cause the time to reperfusion is crit-ical in the long-term viability of theseverely ischemic limb, pulse-spraytechniques have been proposed toreduce the lysis time to a few hoursin a single setting (53,54). Pulse-spray thrombolysis (PST) refers tothe technique of forcefully injectingthe thrombolytic agent into thethrombus. The intent is to fragmentthe thrombus, increase the surfacearea available for enzymatic actionby the plasminogen activator, andshorten the treatment time (10,55).In a pilot study, thrombolysis couldbe achieved within 2 hours usingPST, compared with 25 hours in

historical controls receiving continu-ous infusions (56). In a small, ran-domized, prospective trial, PST wassuperior to continuous infusiontherapy when comparing rt-PA0.066 mg injected every 30 secondsto low-dose, continuous infusion(P � .002). However, there weresignificant discrepancies in the totaldose of rt-PA infused per hour (7.92mg/h for PST vs 0.5 mg/h continu-ous infusion) (35). Thus, it is notclear whether the advantages weredue to a higher rt-PA dose, pulse-spray techniques, or both. Greaterimprovements in the ABI werefound in patients undergoing PSTthan in those given continuous infu-sion therapy (53). The complicationrate in small trials is low and mor-tality is not increased, comparedwith conventional infusions (57).

Though rapid recanalization hasbeen achieved with PST, not all pa-tients will be successfully treatedusing PST alone; many will requireadditional continuous rt-PA infu-sions to ensure more completethrombolysis. In a study of 28 oc-cluded arteries treated with PST,reperfusion was established in amean time of 110 minutes, but com-plete lysis required additional infu-sion of rt-PA in 89% of patients,

thereby extending the overall lysisprocedure to an average of 17 hours(57).

While PST has been shown todecrease lysis times, its widespreaduse in PAO disease remains contro-versial. It is not uniformly em-braced because of the risk of down-stream emboli, the need to use anautomated injection device or fre-quent manual injections, and ques-tionable advantages when treatingPAO disease (58).

Alternative infusion techniques.—Novel methods have been used todeliver rt-PA, including the use ofballoon infusion catheters and syn-ergistic delivery of prostaglandins.Isolating the region to be treatedusing a balloon infusion catheterhas been referred to as segmentallyenclosed thrombolysis (SET). Fol-lowing angioplasty of an occludedfemoropopliteal segment (withoutantecedent lysis), the double-ballooninfusion catheter is inserted intothe target segment to temporarilyisolate the vessel segment from thesystemic circulation. After the bal-loons on the proximal and distalportions of the infusion catheter areinflated, blood is evacuated fromthe vessel and replaced with a solu-tion containing rt-PA (eg, 5 mg) andheparin (eg, 1,000 IU), which is leftin place for a short period (eg, 30minutes). Standard anticoagulanttherapy is instituted at the comple-tion of the procedure. The potentialvalue of this combination is thatboth physical dilatation and phar-macologic thrombolysis can act to-gether to bring about recanalizationthrough independent mechanisms.This has been demonstrated inthree nonrandomized studies inwhich patients underwent success-ful percutaneous transluminal an-gioplasty, followed by SET withrt-PA (59-61). Patency rates of100% at 1 month (61) and 80% at 1year (59) have been reported. Anearly rethrombosis rate of 9% withSET compared favorably with a41% rethrombosis rate in a series ofsimilar patients who had angio-plasty alone (P � .001) (60).

Combination therapy using rt-PAand prostaglandin E1 (PGE1) hasbeen reported in one study treating

Figure 2. Cumulative patency (%) within 4 years after recanalization with locallow-dose thrombolytic therapy with rt-PA for almost 2 weeks as a function of thetype of occlusion. The four different lines indicate this in sequence from top to bot-tom in the eight macroembolic occlusions occurring as a complication of primaryangioplasty, in the 34 embolic occlusions, in the 166 thrombolytic occlusions, and inthe 15 occlusions of femoropopliteal/crural bypasses.

156 ● Thrombolytic Therapy with Use of Alteplase

February 2000 JVIR

chronic femoral artery occlusionspersistent after a 3-hour infusion ofrt-PA 2–10 mg and/or angioplasty(62). An infusion of PGE1 (2.1 mL/h,0.4 �g/mL) followed by rt-PA (1mg/h) with heparin in an alternat-ing 3-hour schedule resulted in a55% recanalization rate after 1–7days. This data suggest that PGE1may provide a benefit in openingocclusions that fail a short course ofcontinuous rt-PA thrombolysis, al-though nearly half of these occlu-sions did not respond to the pro-posed therapy.

Platelet glycoprotein receptor IIb/IIIa antagonists, in combinationwith lytic agents, are currently thefocus of a clinical trial exploringtheir use in managing acute coro-nary ischemia and their potentialfor achieving faster lysis than thatachieved with antiplatelet or lytictherapy alone (63). While this typeof combination therapy appearspromising, there are no publishedstudies evaluating catheter-directedtreatment of PAO disease, and clini-cal investigations are under way.

● Thrombolytic Results:Treatment SiteCharacteristics

Native versus graft arterial seg-ments.—Thrombolysis with rt-PAappears to be equally effective intreating acutely thrombosed nativearteries and vascular grafts, bothsynthetic and autologous vein by-pass grafts (12,18,64,65). A singlerandomized trial, including a uroki-nase treatment arm, showed equalthrombolytic outcomes when pa-tients received rt-PA or urokinasefor either peripheral arterial or by-pass graft occlusions (18).

Duration of infusion and lengthof occlusion.—No correlation be-tween total length of occlusion (incentimeters) and time required toachieve complete lysis has beenfound with either bolus infusion us-ing rt-PA (64) or PST (53).

Duration of limb ischemia.—Ran-domized, prospective trials showevidence that patients with acutelimb ischemia (� 14 days) have im-proved survival and long-term bene-fits when thrombolysis is used as

the initial therapeutic option(40,46,65,66), or require a decreasedmagnitude of surgery following lytictherapy compared with chronicallyischemic limbs (46,67,68). Based onthese findings, thrombolysis shouldbe considered primarily for acutelimb ischemia. The Working Partyon Thrombolysis in the Manage-ment of Limb Ischemia recommendsthat surgical or endovascular ther-apy (excluding thrombolysis) shouldbe the initial therapeutic option forchronic arterial occlusions (�14days) causing limb-threatening isch-emia (10).

Thrombotic versus embolic occlu-sions.—Many clinical studies do notdistinguish in situ thrombosis ver-sus embolic occlusions when de-scribing native artery occlusions.Most studies simply describe thetarget vessel treated (eg, poplitealartery) but fail to describe whetherthe lesion represented an embolusor native thrombosis. Only onestudy was identified that directlycompared the efficacy of thrombo-lytic therapy using rt-PA in throm-botic versus embolic occlusions ofthe superficial femoral and/or popli-teal arteries (42). Treatment in-volved an infusion of rt-PA 10 mgwith heparin 3,000 IU over 6 hours,up to a maximum of four cycles. Re-sults indicated that a significantlybetter patency rate was achievablein embolic occlusions versus throm-botic occlusions initially (88% vs56%; P � .001) and throughout a2-year follow-up (82% vs 49%; P �.001). Clinical improvements at dis-charge (92% vs 67%) also werefound to be superior in patientswith emboli.

● Thrombolysis VersusSurgery/Angioplasty

Catheter-directed rt-PA therapyas a stand-alone procedure in treat-ing limb-threatening ischemia hasshown equal (65) or decreased bene-fit in long-term clinical outcomescompared with surgical revascular-ization alone (46,69,70). Because ofthe controversy surrounding themerits of thrombolysis versus sur-gery (71), only recently have ran-domized, prospective studies been

performed to evaluate the role ofthrombolysis and surgery in manag-ing limb ischemia. Unfortunately,the design of these studies gives theimpression that thrombolysis andsurgery are competing instead ofcomplementary modalities. The ma-jority of these clinical trials usedurokinase but may provide insightinto anticipated outcomes usingrt-PA (40,65-68).

One single-center prospectivetrial (the Rochester study) of pa-tients with acute limb ischemia(�14 days) compared surgical inter-vention alone with urokinase ther-apy prior to surgical revasculariza-tion (40,66). At 1 year, the cumula-tive limb salvage rate was similar(82%), but overall survival rateswere higher in the thrombolysisgroup (84% vs 58%; P � .01), sug-gesting that thrombolysis may be asafer alternative to surgery in theinitial treatment of acute limb isch-emia.

The STILE (Surgery VersusThrombolysis for Ischemia of theLower Extremity) trial was a pro-spective, randomized trial compar-ing surgery and thrombolysis(urokinase or rt-PA) and showed nodifference in mortality, amputation,or major morbidity between the twotreatment groups based on the in-tent to treat (65). However, evaluat-ing outcomes based on the durationof limb ischemia, patients withacute (�14 days) limb ischemiatreated with lytic therapy had bet-ter amputation-free survival ratesat 6 months (85% vs 62% for sur-gery; P � .01) and a major reduc-tion in the magnitude of surgery.Patients with chronic limb ischemiahad lower amputation rates whensurgery was the initial revascular-ization technique (4% vs 14% forlytic therapy; P � .01). Analysis ofthe thrombolysis arm showed nodifference in safety and efficacy inpatients treated with urokinase orrt-PA, although more rapid lysiswas seen with rt-PA.

The STILE trial concluded thattreatment of patients with acutelimb ischemia is safer with shorterhospitalization using initial throm-bolytic therapy and that surgery ismore effective and safer for patients

Semba et al ● 157

Volume 11 Number 2

with chronic limb ischemia. Resultsof the Thrombolysis or PeripheralArterial Surgery (TOPAS) I and IIstudies evaluating the use of recom-binantly derived urokinase and sur-gery in treating acute limb ischemiashowed no difference in mortality oramputation rates, but the magni-tude of surgery was reduced in thethrombolysis group (67,68).

Catheter-directed rt-PA therapyalso is a complementary modality topercutaneous angioplasty (72–74).Results from a randomized trial in-dicate that thrombolytic therapyfollowed by angioplasty may be bet-ter than angioplasty alone in pa-tients with claudication but not se-vere or limb-threatening ischemia(72). Thrombolytic therapy con-sisted of an initial 8-mg bolus ofrt-PA by PST followed by continu-ous infusion of rt-PA 4 mg/h for upto 4 hours. Nonrandomized trialshave demonstrated that thrombo-lytic therapy followed by balloonangioplasty may obviate prostheticbypass grafting in more than 50%of patients with chronic aortoiliacocclusion (73) and that lytic therapyfollowed by laser angioplasty has a100% recanalization rate and a 75%patency rate for up to 24 months(74). However, the merits of laser-assisted angioplasty have neverbeen proven (75).

● Effects of rt-PA Therapy onSystemic CoagulationParameters

The effects of catheter-directedthrombolysis with rt-PA and alter-ations in systemic coagulation pa-rameters are not well understood.During rt-PA infusion, it has beenobserved that the thrombin timeincreases with concomitant de-creases in fibrinogen, plasminogen,�2-antiplasmin, and euglobulin clotlysis time (Table 4) (56). Thesefindings are consistent with in-creased systemic fibrinolysis anddecreased hemostasis, although at-tempts to correlate these biochemi-cal parameters with adverse bleed-ing have not been consistent [Yusuf(1994), Rauber (1997)] (56,76). Al-though maintaining the fibrinogenvalue above 100 mg/dL typically has

been used to monitor urokinase in-fusions, there have been no clinicaltrials to support such laboratorymonitoring in predicting adversebleeding during thrombolytic ther-apy with urokinase or rt-PA. Cur-rently, there is no consensus onwhich coagulation parametersshould be monitored when usingrt-PA to reduce hemorrhagic com-plications.

● The Risk of Adverse Bleedingwith rt-PA

The risk of major adverse bleed-ing, including intracranial hemor-rhage, appears similar to urokinase;however, this analysis is limitedbecause of the imprecision in defini-tions and lack of uniform standardsin reporting complications. The rateof major hemorrhage with rt-PAwas estimated by surveying clinicaltrials involving at least 45 patients.Thirteen different dosing regimensin 12 studies involving 1,291 pa-tients were identified, and the over-all incidence of major adverse bleed-ing was estimated to be 5.1%(range, 0–17%) using rt-PA(11,13,17,18,23,42,45,54,65,77–79).This is similar to the reported expe-rience in using urokinase and re-combinant urokinase (40,65,66,68).In regards to the risk of intracra-nial hemorrhage, there were seven

reported cases (0.54%; range, 0 to2.2%), with a wider range in thereported confidence intervals; thisprobably was due to the small sam-ple size of individual studies (Fig3). In comparison, the range of inci-dence of intracranial hemorrhagewith recombinant urokinase andurokinase is reported to be 1.6%and 1.8%, respectively, in 329 pa-tients receiving catheter-directedlytic therapy for acute limb isch-emia (40,66,68).

The use of systemic anticoagula-tion with heparin may increase therisk of adverse bleeding duringrt-PA infusion therapy (42); how-ever, this evidence has not beenconclusively proven in randomized,controlled trials.

CONCLUSION

Numerous clinical trials involv-ing the catheter-directed use ofrt-PA have demonstrated clinicalsafety and efficacy with complica-tion rates similar to those of uroki-nase when treating PAO disease.There is no generally accepted dos-ing regimen, preferred method ofinfusion, or consensus regarding theuse of concomitant anticoagulation.Catheter-directed delivery of rt-PAis a complementary and not acompeting technology with surgical

Table 4Changes in Systemic Fibrinolytic Parameters After 1-Hour Intra-ArterialPulse-Spray Thrombolysis With Recombinant Tissue PlasminogenActivator (rt-PA) in 20 Patients With Lower Extremity Occlusion

ParameterBaseline Median

(range)

After 1 Hour(10 mg rt-PA)

Median (range) P Value*

Thrombinclotting time(sec)

16.2 (13.8–60.0) 24.15 (17.70–60.00) .003

Fibrinogen (g/L) 4.28 (1.16–8.19) 2.86 (0.40–9.40) .001Euglobulin clot

lysis time(min)

225 (120–290) 5 (5–40) .0001

�2-Antiplasmin(nmol/L)

117 (52–168) 44.5 (23.0–86.0) .001

Plasminogen (%) 115 (80–182) 68.5 (44.0–119.0) .001

* Wilcoxon matched pairs signed rank test.Yusuf et al, 1994 (35).

158 ● Thrombolytic Therapy with Use of Alteplase

February 2000 JVIR

or percutaneous revascularization;in appropriately selected patients, itcan reduce or obviate subsequentsurgery for acute limb ischemia(�14 days). It appears equally effi-cacious with native arteries andvascular grafts and effective intreating both in situ thrombi andemboli with bleeding risks similarto urokinase.

This review is limited by thedearth of prospective, randomizedtrials and the lack of uniformity inreporting standards. Because of nu-merous unanswered questions-suchas the optimal rt-PA dose, tech-

nique of intrathrombic rt-PA deliv-ery, concomitant use of heparin,and the parameters associated withadverse bleeding-further controlled,prospective, and randomized studiesare essential.

References1. Mills JL, Porter JM. Basic data

related to clinical decision makingin acute limb ischaemia. Ann VascSurg 1991; 5:96–98.

2. Moran KT, Jewell ER, Persson AV.The role of thrombolytic therapy insurgical practice. Br J Surg 1989;76:298–304.

3. Miller BV, Sharp WJ, Hoballah JJ,

et al. Management of infrainguinaloccluded vein bypasses with a com-bined approach of thrombolysis andsurveillance. Arch Surg 1992; 127:986–989.

4. Ouriel K. Surgery versus thrombo-lytic therapy in the management ofperipheral arterial occlusions. JVIR1995;6:48S–54S.

5. Difficulties in obtaining sufficientamounts of urokinase (letter).Rockville: Center for Biologics Eval-uation and Research, Public HealthService, Food and Drug Administra-tion; December 11, 1998.

6. Important drug warning: dearhealthcare provider (letter). Rock-ville: Center for Biologics Evalua-tion and Research, Public HealthService, Food and Drug Administra-tion; January 25, 1999.

7. Wooster MB, Luzier AB. Rete-plase: a new thrombolytic for thetreatment of acute myocardial in-farction. Ann Pharmacother 1999;33:318–324.

8. Anderson JL, Sorensen SG, MorenoFL, et al. Multicenter patency trialof intravenous anistreplase com-pared with streptokinase in acutemyocardial infarction: the TEAM-2Study Investigators. Circulation1991; 83:126–140.

9. Andaz S, Shields DA, Scurr JH,Smith PD. Thrombolysis in acutelower limb ischemia. Eur J VascSurg 1993; 7:595–603.

10. Working Party on Thrombolysis inthe Management of Limb Ischemia.Thrombolysis in the management oflower limb peripheral arterial occlu-sion: a consensus document. Am JCardiol 1998; 81:207–218.

11. Braithwaite BD, Buckenham TM,Galland RB, et al on Behalf of theThrombolysis Study Group. Pro-spective randomized trial of high-dose versus low-dose tissue plasmin-ogen activator infusion in the man-agement of acute limb ischaemia.Br J Surg 1997; 84:646–650.

12. Bero CJ, Cardella JF, Reddy K, etal. Recombinant tissue plasmino-gen activator for the treatment oflower extremity peripheral vascularocclusive disease. JVIR 1995;6:571–577.

13. Hess H, Mietaschk A, von BilderlingP, Neller P. Peripheral arterial oc-clusions: local low-dose thrombolytictherapy with recombinant tissue-type plasminogen activator (rt-PA).Eur J Endovasc Surg 1996; 12:97–104.

14. Koppensteiner R, Minar E, AhmadiR, Jung M, Ehringer H. Low-doses

Figure 3. Intracranial hemorrhage selected tissue plasminogen activator (t-PA)rates in studies.

Semba et al ● 159

Volume 11 Number 2

of recombinant human tissue-typeplasminogen activator for localthrombolysis in peripheral arteries.Radiology 1988; 168:877–878.

15. Dawson KJ, Reddy K, Platts AD,Hamilton G. Results of a recentlyinstituted programme of thrombo-lytic therapy in acute lower limbischaemia. Br J Surg 1991; 78:409–411.

16. Krause FJ, Endsin O. Lokale kath-eterlyse der femoralarterie: rt-PAversus urokinase. Fortscjr Rontgen-str 1993; 158:46–48.

17. Verstraete M, Hess H, Mahler F, etal. Femoro-popliteal artery throm-bolysis with intra-arterial infusionof recombinant tissue-type activator:report of a pilot trial. Eur J VascSurg 1988; 2:155–159.

18. Graor RA, Olin JW, Bacharach M.Comparison of t-PA and urokinasefor peripheral arterial thrombolysis.J Vasc Med Biol 1993; 4:311–314.

19. Earnshaw JJ, Westby JC, GregsonRHS, et al. Local thrombolytictherapy of acute peripheral arterialischaemia with tissue plasminogenactivator: a dose-ranging study.Br J Surg 1988; 75:1196–1200.

20. Graor RA, Risius B, Young JR, etal. Peripheral artery and bypassgraft thrombolysis with recombinanthuman tissue-type plasminogen ac-tivator. J Vasc Surg 1986; 3:115–124.

21. Berridge DC, Gregson RHS, Hop-kinson BR, Makin GS. Intra-arte-rial thrombolysis using recombinanttissue plasminogen activator (r-TPA): the optimal agent, at the opti-mal dose? Eur J Vasc Surg 1989;3:327–332.

22. Risius B, Graor RA, Geisinger MA,et al. Recombinant human tissue-type plasminogen activator forthrombolysis in peripheral arteriesand bypass grafts. Radiology 1986;160:183–188.

23. Lonsdale RJ, Berridge DC, Earn-shaw JJ, et al. Recombinant tis-sue-type plasminogen activator issuperior to streptokinase for localintra-arterial thrombolysis. Br JSurg 1992; 79:272–275.

24. Levine EG, Loskutoff DJ. Culturedbovine endothelial cells produceboth urokinase and tissue-type plas-minogen activators. J Cell Biol1982; 94:631–636.

25. Wallen P, Pohl G, Bergsdorf N, etal. Purification and characteriza-tion of a melanoma cell plasminogenactivator. Eur J Biochem 1983; 132:681–686.

26. Vehar GA, Spellman MW, Keyt BA,

et al. Characterization studies ofhuman tissue-type plasminogen ac-tivator produced by recombinantDNA technology. Cold Spring Har-bor Symp Quant Biol 1986; 51:551–562.

27. Tate KM, Higgins DL, Holmes WE,et al. Functional role of proteolyticcleavage at arginine-275 of humantissue plasminogen activator as as-sessed by site-directed mutagenesis.Biochemistry 1987; 26:338–343.

28. Lijnen HR, Van Hoef B, De Cock F,Collen D. Effect of fibrin-like stim-ulators on the activation of plasmin-ogen by tissue-type plasminogen ac-tivator (t-PA): studies with activesite mutagenized plasminogen andplasmin resistant t-PA. ThrombHaemost 1990; 64:61–68.

29. Activase (Alteplase recombinant)package insert. Genentech, Inc,South San Francisco, CA, 1999.

30. Dotter CT, Rosch J, Seaman AJ.Selective clot-lysis using streptoki-nase. Radiology 1974; 111:31–37.

31. Riggs P, Ouriel K. Thrombolysis inthe treatment of lower extremityocclusive disease. Surg Clin NorthAm 1995; 75:633–645.

32. Graor RA, Olin J, Bartholomew JR,et al. Efficacy and safety of intra-arterial local infusion of streptoki-nase, urokinase, or tissue plasmino-gen activator for peripheral arterialocclusion: a retrospective review. JVasc Med Biol 1990; 2:310–315.

33. Van Breda A, Katzen BT, DeutschAS. Urokinase versus streptoki-nase in local thrombolysis. Radiol-ogy 1987; 165:109–111.

34. Berridge DC, Gregson RHS, MakinGS, Hopkinson BR, Makin GS.Randomized trial of intra-arterialrecombinant tissue plasminogen ac-tivator, intravenous recombinanttissue plasminogen activator andintra-arterial streptokinase in pe-ripheral arterial thrombolysis. Br JSurg 1991; 78:978–995.

35. Yusuf SW, Whitaker SC, GregsonRHS, et al. Prospective random-ized comparative study of pulsespray and conventional local throm-bolysis. Eur J Endovasc Surg 1995;10:136–141.

36. NIH Consensus Development Con-ference. Thrombolytic therapy inthrombosis. Br Med J 1980; 280:1585–1587.

37. Graor RA, Risius B, Young JR, etal. Thrombolysis of peripheral ar-terial bypass grafts: surgical throm-bectomy compared with thromboly-sis. J Vasc Surg 1988; 7:347–355.

38. Krupski WC, Feldman RK, Rapp

JH. Recombinant human tissue-type plasminogen activator is aneffective agent for thrombolysis ofperipheral arteries and bypassgrafts: preliminary report. J VascSurg 1989; 10:491–500.

39. Holvaert P, Cleemput H, Collen D.Assay of human tissue-type plas-minogen activator with an enzyme-linked immunosorbent assay(ELISA) based on three murinemonoclonal antibodies to t-PA.Thromb Haemost 1985; 54:684–687.

40. Ouriel K, Shortell CK, Azodo MW,Guitterrez OH, Marder VJ. Acuteperipheral arterial occlusion: predic-tors of success in catheter-directedthrombolytic therapy. Radiology1994; 93:561–566.

41. Berridge DC, Gregson RHS, MakinGS, Hopkinson BR. Tissue plas-minogen activator in peripheral ar-terial thrombolysis. Br J Surg 1990;77:179–182.

42. Decrinis M, Pilger E, Stark G, LaferM, Obernosterer A, Lammer J. Asimplified procedure for intra-arte-rial thrombolysis with tissue-typeplasminogen activator in peripheralarterial occlusive disease: primaryand long-term results. Eur Heart J1993; 14:297–305.

43. Spengel FA, Kuffer G, Stiegler H.Efficacy and tolerance of recombi-nant tissue-type plasminogen acti-vator in patients with thrombotic orembolic occlusions of leg arteries.Clin Invest 1993; 71:323–326.

44. Weidauer TH, Timmermann J. Lo-cal intra-arterial thrombolysis withlow-dose rt-PA. Fortschr Med 1990;108:700–702.

45. Schweizer J, Altmann E, StossleinF, Florek HJ, Kaulen R. Compari-son of tissue plasminogen activatorand urokinase in the local infiltra-tion thrombolysis of peripheral arte-rial occlusions. Eur J Radiol 1996;22:129–132.

46. Weaver FA, Comerota AJ, Young-blood M, et al. Surgical revascular-ization versus thrombolysis for non-embolic lower extremity native ar-tery occlusions: results of a prospec-tive randomized trial. J Vasc Surg1996; 24:513–523.

47. Rutherford RB, Baker JD, Ernst C,et al. Recommended standards forreports dealing with lower extrem-ity ischemia: revised version. J VascSurg 1997; 26:517–538.

48. Agnelli G. Rationale for bolus t-PAtherapy to improve efficacy andsafety. Chest 1990; 97:161S–167S.

160 ● Thrombolytic Therapy with Use of Alteplase

February 2000 JVIR

49. Braithwaite BD, Birch PA, PoskittKR, Heather BP, Earnshaw JJ.Accelerated thrombolysis with highdose bolus t-PA extends the role ofperipheral thrombolysis but mayincrease the risks. Clin Radiol 1995;50:747–750.

50. Ward AS, Andaz SK, Bygrave S.Peripheral thrombolysis with tissueplasminogen activator: results oftwo treatment regimens. Arch Surg1994; 129:861–865.

51. Ward AS, Andaz SK, Bygrave S.Thromoblysis with tissue-plasmino-gen activator: results with a high-dose transthrombus technique. JVasc Surg 1994; 19:503–508.

52. Braithwaite BD. Thrombolysiswith tissue-plasminogen activator:results with a high-dose tran-sthrombus technique (letter). J VascSurg 1995; 21:540.

53. Yusuf SW, Whitaker SC, GregsonRHS, et al. Immediate and earlyfollow-up results of pulse spraythrombolysis in patients with pe-ripheral ischaemia. Br J Surg 1995;82:338–340.

54. Armon MP, Yusuf SW, WhitakerSC, Gregson RH, Wenham PW,Hopkinson BR. Results of 100cases of pulse-spray thrombolysisfor acute and subacute leg ischemia.Br J Surg 1997; 84:47–50.

55. Bookstein JJ, Fellmeth B, RobertsA, Valji K, Davis G, Machado T.Pulse-spray pharmacomechanicalthrombolysis: preliminary clinicalresults. Am J Radiol 1989;152:1097–1100.

56. Yusuf SW, Westby J, Wenham PW,et al. Systemic fibrinolytic effect ofpulse-spray thrombolysis with tis-sue-type plasminogen activator (rt-PA). Fibrinolysis 1994; 8:108–110.

57. Roeren T, Lachenicht B, Dux M, etal. Therapeutic efficacy of pulsedspray lysis in peripheral arterialocclusions. Fortschr Rontgenstrasse1996; 164:489–495.

58. Kandarpa K, Goldhaber SZ, Meyero-vitz MF. Pulse-spray thrombolysis:the “careful analysis.” Radiology1994; 193:320–324.

59. J�rgensen B, Tonnesen KH, BulowJ, et al. Femoral artery recanaliza-tion with percutaneous angioplastyand segmentally enclosed plasmino-gen activator. Lancet 1989; 1:1106–1108.

60. J�rgenson B, Tonnenson KH,Nielsen JD, et al. Segmentally en-closed thrombolysis in percutaneoustransluminal angioplasty for femo-ropopliteal occlusions: a report froma pilot study. Cardiovasc InterventRadiol 1991; 14:293–298.

61. Tonnesen KH, Holstein P, AndersenE. Femoro-popliteal artery occlu-sions treated by percutaneous trans-luminal angioplasty and enclosedthrombolysis: results in 53 patients.Eur J Vasc Surg 1991; 5:429–434.

62. Kroger K, Hwang I, Rudofsky G.Recanalization of chronic peripheralarterial occlusions by alternatingintra-arterial rt-PA and PGE1.VASA 1998; 27:20–23.

63. Antman EM, Giugliano RP, GibsonCM, et al. Abciximab facilitatesthe rate and extent of thrombolysis:results of the Thrombolysis in Myo-cardial Infarction (TIMI) 14 trial.The TIMI 14 investigators. Circula-tion 1999; 99:2720–2732.

64. Buckenham TM, George CD, Ches-ter JF, et al. Accelerated thrombol-ysis using pulsed intra-thrombusrecombinant human tissue plasmin-ogen activator (rt-PA). Eur J VascSurg 1992; 6:237–240.

65. STILE Investigators. Results of aprospective randomized trial evalu-ating surgery versus thrombolysisfor ischemia of the lower extremity:STILE trial. Ann Surg 1994; 220:251–268.

66. Ouriel K, Shortell CK, deWeese JA,et al. A comparison of thrombolytictherapy with operative revascular-ization in the initial treatment ofacute peripheral arterial ischemia .J Vasc Surg 1994; 19:1021–1030.

67. Ouriel K, Veith FJ, Sasahara AA.Thrombolysis or peripheral arterialsurgery (TOPAS): Phase I results. JVasc Surg 1996; 23:64–73.

68. Ouriel K, Veith FJ, Sasahara AA.A comparison of recombinant uroki-nase with vascular surgery as ini-tial treatment for acute arterial oc-clusion of the legs. N Engl J Med1998; 338:1105–1111.

69. Nilsson L, Albrechtsson U, JonungT, et al. Surgical treatment versusthrombolysis in acute arterial occlu-sion: a randomized controlled study.Eur J Vasc Surg 1992; 6:189–193.

70. Hoch JR, Tullis MJ, Archer CW, etal. Thrombolysis versus surgery as

the initial management for nativeartery occlusion: efficacy, safety,and cost. Surgery 1994; 116:649–657.

71. Palfreyman SJ, Michaels JA. Sys-tematic review of intra-arterialthrombolytic therapy for peripheralvascular occlusions (abstract). Br JSurg 1999; 86:704.

72. Meyerovitz MF, Didier D, Vogel J,Soulier-Parmeggiani L, Bou-nameaux H. Thrombolytic therapycompared with mechanical recanali-zation in non-acute peripheral arte-rial occlusions: a randomized trial.JVIR 1995;6:775–781.

73. Pilger E, Decrinis M, Stark G, et al.Thrombolytic treatment and balloonangioplasty in chronic occlusion ofthe aortic bifurcation. Ann InternMed 1994; 120:40–44.

74. Otto W, Rowinski O, Malkowski P,Paczkowski P, Pruszynksi B, Kar-wowski A. Laser angioplasty andthrombolytic treatment for femoralartery occlusion. Radiol Oncol 1995;29:185–189.

75. Lammer J. Laser angioplasty ofperipheral arteries: an epilogue?Cardiovasc Intervent Radiol 1995;18:1–8.

76. Rauber K, Heidinger KS, Kemkes-Matthes B. Coagulation alterationsdue to local fibrinolytic therapy withrecombinant tissue-type plasmino-gen activator (rt-PA) in patientswith peripheral arterial occlusivedisease. Cardiovasc Intervent Radiol1997; 20:169–173.

77. Ellis PK, Kelly BE, McIlrath EM.The use of recombinant human tis-sue type plasminogen activator (rt-PA) in both graft and native arter-ies in the lower limb: results over a2-year period. J Intervent Radiol1996; 11:145–147.

78. Lambert AW, Trkulja D, Fox AD,Budd JS, Chalmers AH, HorrocksM. Age-related outcome for periph-eral thrombolysis. Eur J Vasc Endo-vasc Surg 1999; 17:144–148.

79. Von Knorring S, Perakyla T, EdgrenJ, et al. Thrombolytic treatment ofacute or chronic leg ischemia. AnnChir Gynaecol 1995; 84:369–371.

80. Stump DC, Mann KG. Mechanismsof thrombus formation and lysis.Ann Emerg Med 1988;17:1138–1147.

Semba et al ● 161

Volume 11 Number 2