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Thrombolysis therapy in patients with femoropopliteal synthetic graft occlusions
Thrombolysis Femoropopliteal
Therapy in Patients With Synthetic Graft Occlusions
Yasuharu Ikeda, MD, Mark C. Rummel, MD, Pankaj K. Bhatnagar, MD, Charles K. Field, MD, Paul A. Khoury, MD, Audrey R. Wilson, MD, Morris D. Kerstein, MD, FACS, Teruo Matsumoto, MD, PhD, FACS, Philadelphia, Pennsylvania
BACKGROUND: The aim of this study was to evaluate the efficiency of thrombolysis in the presence of an occluded femoropopliteal synthetic graft. PATIENTS AND METHODS: Over a 3-year period, 46 occluded femoropopliteal grafts were treated with urokinase and reconstruction. The cases were divided into three groups: group 1 (n = 25), complete thrombolysis followed by reconstruction or angioplasty or both; group 2 (n = 5), complete thrombolysis alone; and group 3 (n = 16), failure of thrombolysis requiring reconstruction or leading to amputation. Patients were closely observed after the treatment for more than 1 year. RESULTS: There are no fatal complications among patients with thrombolytic therapy. In group 1, the 3-year patency rates were 12% and the 3-year limb salvage rates were 77%. In group 2, the 3-year patency rates and the limb salvage rates were 20% and 80%, respectively. The group 3 patency rates and the limb salvage rates were 8% and 40%, respectively. The best results were achieved in patients who had thrombolysis followed by reconstruction (group 1) and in those who had thrombolysis alone (group 2). Limb salvage was poor in patients with failure of lytic therapy regardless of the reconstruction (P
D
etection of impending graft failure is a difficult but important aspect of vascular surgery.’ Thrombosis of a bypass graft often results in limb-threatening ischemia.* Standard surgical therapy, such as thrombectomy or angioplasty, has relative poor results in this setting.’ Intra-arterial thrombolysis with high-dose urokinase is now a recognized treatment of occluded arteries.+” Although the durability of thrombolytic therapy alone in failed synthetic grafts is discouraging, 4.5 lysis of an occluding thrombus allows better visualization of inflow and outflow vessels and often discloses the cause of the thrombosis.6 Successful lysis results in an immediate improvement in circulation and allows for a less extensive reconstructive procedure to address the inciting lesion.; Compared with surgical thrombectomy, thrombolytic therapy effectively recanalizes additional small-diameter, branching, or collateral vessels” and reduces outflow resistance.’ Percutaneous thrombolysis is a less invasive procedure in a situation in which multiple previous surgeries make a further surgical approach less desirable.‘” Additionally, better short-term patency and limb salvage rates can be obtained with thrombolysis and an adjunctive surgical revision compared with surgical revision alone.’ At our institution, patients with acutely or subacutely occluded prosthetic grafts were treated with a combination of urokinase therapy and a vascular reconstructive procedure. Over a 3-year period, we reviewed our experience with patients who underwent urokinase therapy followed by a vascular reconstructive procedure for acutely or subacutely occluded prosthetic grafts. All patients had suffered a sudden recent onset or deterioration of symptoms of lower-limb ischemia within the preceding 30 days. The goal of this study was to evaluate the efficacy of thromholysis and multiple secondary vascular reconstructive procedures in patients who have had an occlusion of a previously placed peripheral arterial synthetic bypass graft.
PATIENTS
From the Department of Surgery (YI, MCR, PKB, CKF, MDK, TM) and the Department of Radiology (PAK, ARW), Hahnemann University Hospital, Philadelphia, Pennsylvania. Requests for reprints should be addressed to Yasuharu Ikeda, MD, Department of Surgery, Kameyama Eiko Hospital, 58 Befu Shime-machi Kasuya-Gun, Fukuoka 81 i-22, Japan. Manuscript submitted June 14, 1994 and accepted in revised form November 21, 1994.
THE AMERICAN
AND METHODS
From February 1989 through June 1992, 30 patients had 46 episodes of acute or subacute thrombosis of synthetic vascular grafts treated with percutaneously delivered intra-arterial urokinase. Patients who had acute onset of limb-threatening ischemia or disabling claudication in a limb previously reconstructed with a synthetic bypass were considered for thrombolytic therapy. Patients with imminent tissue loss, defined as an inability to tolerate an additional 24 hours of ischemia,“,” were taken directly to surgery. Absolute contraindications to thrombolysis using urokinase included recent stroke or active gastrointestinal bleeding; abdominal, chest, JOURNAL
OF SURGERYa
VOLUME
171
FEBRUARY
1996
251
THROMBOLC TABLE
cause of thrombolysis
I Influence of Various Patient Factors With Thrombolytic Therapy in 46 Cases
Factor
Group 1 (n = 25)
Sex (M:F) 12:13 Mean age (y) 64 Mean laboratory values Hemoglobin (mg/dL) 12 Prothrombin time (s) 13 Partial thromboplastin time (s) 36 Fibrinogen (mg/dL) 283 Diabetes 13 Hypertension 15 Coronary disease 10 Current smoking 22 Mean initial ankle brachial index 0.18 Indication Claudication 7 Limb salvage 18 Mean duration of occlusion (h) 143 Mean duration of urokinase 27 infusron (h) Total dose of urokinase (IU) 3,118,OOO Complications (%) 7 (28)
Group 2 (n = 5)
Group 3 (n = 16)
4:l 67
13:3 63
12 13 33 336 3 3 1 4 0.19
13 12 38 315 2 10 4 14 0.11
2 3 132 22
6 10 185 33
4,643,OOO 3,498,OOO 1
(20)
7 (44)
A compares of vauous factors ln patients with thrombolylic therapy was done. No factors were assooated wth a s/gnbcant difference !n outcome (P ~3 05)
or neurologic surgery within 3 weeks; cc,agulopathy; or a central nervous system tumor.ss’ All patients in this study had undergone from one to four previous vascular reconstructive procedures and had at least 1 synthetic arterial graft in place. Occlusion occurred in 46 femoropopliteal grafts terminated in suprageniculate popliteal artery. An arteriogram was obtained before treatment to demonstrate the area of proximal occlusion, the inflow and the runoff vessels. The urokinase infusion catheter was inserted by way of the contralateral common femoral artery in 39 (85%) of the cases. Other sites for insertion of the infusion catheter included the brachial artery, direct puncture of the graft, and the contralateral limb of an aortobifemoral graft. A loading dose of 250,000 to 1,OOO,OOO 1U (4,000 IU/mL in sterile saline solution) of urokinase was laced throughout the thrombus by way of a tract made with a guidewire. The initial infusion took place over a 20- to 60-minute period. Urokinase was then infused at 4,000 lU/min until antegrade blood flow was reestablished and subsequently at 1,000 to 2,000 IU/min until clot lysis was complete. Intravenous heparin (600 to 1,000 N/h) was administered concurrently and for at least 24 hours after termination of urokinase infusion. Fluoroscopic angiography or arteriography was performed every 6 to 24 hours to evaluate the graft and run-off vessels. Patients were admitted to the intensive care unit after the urokinase infusion and were prescribed bed rest. The prothromhin time, partial thromboplastin time, platelet count, and fibrinogen, creatinine, and hemoglobin levels were measured hefore Infusion of urokinase. These tests, as well as fibrin degradation products, were monitored at 4- to 6-hour intervals during urokinase infusion and for 24 hours thereafter. Therapy was continued until complete lysis occurred, or, be252
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failure, other therapy was chosen by the angiographer and vascular surgeon. Complete or successful thrombolysis was defined as graft patency with angiographic evidence of normal flow, without evidence of residual thrombus. Incomplete thrombolysis, or failure, was determined to be the inability to open the graft or incomplete arteriographic resolution of the thrombus. All patients had a completion arteriogram to document the effect of thrombolytic therapy. Percutaneous transluminal angioplasty (PTA) in 12 patients (26%), surgical reconstruction in 17 patients (37%), or a combination of both in 7 patients (15%) was performed to correct angiographically identified lesions that were felt to be the underlying cause of the graft occlusion. When thrombolysis was incomplete, all patients underwent a surgical reconstruction with the exception of 5 cases in which 3 amputations and 2 sympathectomies were performed. Cases were grouped according to factors believed to impact upon long-term patency and limb salvage: group 1, complete thrombolysis followed by reconstruction or angioplasty or both; group 2, complete thrombolysis alone; and group 3, total failure of thrombolysis requiring reconstruction or amputation. The influence of individual risk factors that may affect the prognosis was determined using the chi-square test and Student’s t-test. A Kaplan-Meier survival analysis was used to predict patency and limb salvage rates for each group. The significance of differences in patency and limb salvage was determined using the Wilcoxon rank-sum test. For analysis of initial outcome and long-term patency, multiple episodes of graft occlusion in the same patient were treated independently. This study conformed to usual practices for clinical research in our institution. Informed consent was obtained from each patient. Patients were closely followed up after the treatment for more than 1 year, at regular l- to 2-month intervals. Follow-up continued until further lytic therapy, reconstructive procedure, amputation, loss of patient to follow-up, or death of patient. Graft patency was determined by clinical examination, noninvasive hemodynamic measurements, arteriography, or a combination of these tests.
RESUL.TS There were 17 women and 29 men in the study, with an average age of 64 years (range 46 to 75). Diabetes mellitus was present in 18 cases (39%), and 4 cases (9%) were insulin-dependent. Hypertension was present in 28 (61%), coronary artery disease in 15 (33%), and hyperlipidemia in 9 (20%). of the 46 cases, 40 (87%) abused tobacco and 5 (11%) had undergone previous coronary artery bypass surgery. The indication for treatment was acute onset of disabling claudication in 15 cases (33%) and ischemic pain or tissue loss in 31 cases (67%). A comparison of pretreatment laboratory data among the three treatment groups revealed that there was no significant difference in sex, age, hemoglobin, prothrombin time, partial thromboplastin time, and fibrinogen. Additionally, there was no difference in the incidence of diabetes, hypertension, coronary artery disease, and smoking. The initial ankle brachial index and the duration of occlusion were also similar among the three groups (Table I). FEBRUARY
1996
THROMBOLYSIS
Forty-six thrombosed peripheral arterial bypass grafts were treated by intra-arterial urokinase infusion. Complete thrombolysis was achieved in 30 (65%) graft occlusions. The duration of urokinase infusion ranged from 0.25 to 94 hours (mean 28). The total dose of urokinase ranged from 250,000 to 12,550,OOO IU with a mean infusion of 3,416,OOO IU. The duration of occlusion, duration of urokinase infusion, the total dose of urokinase, and number of grafts completely lysed did not significantly vary among the three groups (Table I). Complications occurred in 15 (33%) cases. Eleven (24%) cases resulted in bleeding complications. Nine (20%) cases involved a local hematoma that was treated by pressure alone. Two patients had local bleeding at the catheter site. Two patients had a distal embolization which were lysed without sequelae. Other complications included subcutaneous leakage of urokinase (1 ), and acute renal failure ( 1); however, there were no fatal complications. There was no significant difference in the number of complications when all groups were compared. In group 1 (n = 25), patency and limb salvage at 3 years were determined to be 12% and 77%, respectively. In group 2 (n = 5), patency at 3 years was 20% and limb salvage was 80%. In group 3 (n = 16), the 3-year patency rates were 8% and the limb salvage rates were 40% (Table II). There was a statistically significant difference in limb salvage rates comparing group 1 and 2 with group 3 (I’ ~0.01). There was no statistically significant difference, however, among the three groups, however, when the rate of patency was compared.
COMMENTS Thrombosis of peripheral artery bypass grafts occurs despite careful monitoring of graft function. The reported incidence of specific risk factors in patients with peripheral artery disease varies. Smoking is reported in 30% to 77% of the patients, hypertension in 47% to 63%, coronary artery disease in 34% to SO%, and diabetes mellitus in 16% to 51%.22-‘6 In our study, the incidence of hypertension, coronary artery disease, and diabetes mellitus was comparable to reported rates; however, the incidence of smoking (87%) was higher. Smoking is recognized as a factor that adversely affects patients with peripheral grafts. Once graft thrombosis has occurred, standard surgical therapy has relatively poor results. 3 Intra-arterial thrombolysis for occluded arterial bypass grafts has been effectively used for initial recanalization of both venous grafts and synthetic bypass grafts. ‘I’~ Published initial success rates for thrombolytic therapy vary from 49% to 100%.4.6~“J”-‘” In our study, urokinase achieved complete lysis in 65% of the cases, a rate that is comparable to published initial success rates. McNamara et al+” stressed that the initial rate of administration rather than the total dose of urokinase had a positive influence on success rate. We, therefore, used a highdose regimen. Price et al” found no correlation between total dose or duration of lytic treatment with the initial success rate. Our study agreed with those findings. Hallett et all5 found no association between the indication for treatment (limb salvage versus claudication) and initial success but did find that the severity of ischemia (whether the ankle brachial index was below 0.25) was a significant predictor of complete thrombolysis. Other authors believe THE AMERICAN
TABLE
THERAPY
WITH GRAFT OCCLUSlONllKEDA
ET AL
II Comparison of Cumulative Patency and Limb Salvage Rates in the Three Groups Number
Patency rates Group 1 Group 2 Group 3 Limb salvage rates Group 1 Group 2 Group 3
1 Year
25 5 16
44% (11)’ 40% (2) 31% (5)
25 5 16
92% (23) 100% (5) 56% (9)+
2 Years
3 Years
29% (5) 20% (1) 8% (1)
12% (2) 20% (1) 8% (1)
77% (13) 80% (2) 40% (5)+
77% (6) 80% (1) 40% (4)+
There IS a stat~st~~//y significant chfference rn limb salvage rate comparing groups7 and 2 with group 3 (P 4071. However. there is no stat& cal difference among the three groups in patency rate ‘Numbers in parentheses Indicate bypasses at risk. TP CO.01
that duration of occlusion (time from the onset of symptoms until the initial dose of urokinase) have an impact on initial success.+~~t(.‘0J6 In this study, however, there was no difference in the duration of occlusion, as was found by others.“l’s The mean initial ABIs in the successful group were slightly higher than in the unsuccessful group; however, this did not reach statistical significance. The disadvantages of lytic therapy are well known. Intracranial or retroperitoneal bleeding may be fatal. Multiple contrast-dye loads increase the risk of nephrotoxicity. Our data show that complications occurred in 15 (33%) cases. Of the 15 cases, however, 9 involved a local hematoma that was treated by pressure alone. All complications were treated with conservative therapy, and there were no fatal complications. In several reported series of intra-arterial thrombolytic therapy of thrombosed infrainguinal grafts, long-term patency was poor despite definitive correction of graft lesions by surgery or percutaneous angioplasty.‘“J’ In this study, the long-term patency rates remained poor. Tunis et al” reported poor limb salvage associated with multiple reconstructions of the lower extremity. Our study indicates that limb salvage after failure of lytic therapy and followed by reconstruction (group 3) is significantly decreased from the other groups. Nevertheless, the 3-year limb salvage rate remained 77% if thrombolysis was successful, regardless of additional reconstructive procedures. With all these results, we believe that the development of collateral circulation and the possibility for secondary reconstructive procedures in the successful thrombolysis therapy increase the likelihood of limb salvage. In conclusion, the use of intra-arterial urokinase followed by secondary vascular reconstructive procedures was studied. The patient with synthetic graft occlusions still has a reasonably favorable prognosis for long-term limb salvage when thrombolysis is successful. To what extent late Rraft occlusitrns can he treated by thrombolysis
and how
effective
symptomatic
therup~
is in
thelong
run
remain to be established. A single Japanese hospital’s experience with thrombolysis for femoropopliteal synthetic graft occlusion shows that patients with synthetic graft occlusions have a reaJOURNAL
OF SURGERYa
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HROMBOLYSIS
son&
THERAPY
WITH GRAFT OCCLUSION/IKEDA
ET AL 1
fauorabk response for long-term limb salvage when
thrombolysis
is immediately
success&l.
REFERENCES 1. O’Donnell TF Jr, Mackey W, McCullough JL, et al. Correlation of operative findings with angiographic and noninvasive hemodynamic factors associated with failure of polytetrafluoroethylene grafts. ] Vux Surg. 1984;1:136-148. 2. Aster E, Collier P, Gupta SK, et al. Reoperation for polytetrafluoroethylene bypass failure: the importmce of distal outflow site and operative technique in determining outcome. .I Vast Strrg. 1987;5: 298-3 10. 3. Green RM, Oueiel K, Ricotta JJ, et al. Revision of failed infrainguial bypass graft: principles of management. Surgq. 1986;lOO: 646453. 4. McNamara TO, Bomherger RA. Factorj affecting initial and SIXmonth patency rates after intra-arterial thrombolysis with high-dose urokinase. AmJ Surg. 1986;152:709-712. 5. Seabrook CR, Mewissen MW, Schmitt DD, et al. Percutaneous intra-arterial thrombolysis in the treatment of lower extremxy arterial reconstructions. J Vast Surg. 1991;13:646&51. 6. Gardiner GA Jr, Harrington DP, Coltun W, et al. Salvage of occluded arterial bypass grafts by means of thrombolysis. J Vast Surg. 1989;9:426&43 1r 7. Comerata AJ, Rubin RN, Tyson RR, et al. Intra-arterial thrombolytic therapy in peripheral vascular disease. Surg Gynecol Obstet. 1987;165:1-8. 8. Eisenbud DE, Brener BJ, Shoenfeld R, et al. Treatment of acute vascular occlusions with intra-arterial urokinase. Am J Surg. 1990;160: 160-165. 9. Graor RA, Risius B, Young JR, et al. Thrombolysis of peripheral arterial bypass grafts: surgical thromhectomy compared with thrombolysis: a preliminary report. J Vast Surg. 1988;7:347-355 10. Durham JD, Geller SC, Abbott WM, et al. Regional infusion of urokinase into occluded lower-extremity bypass grafts: long-term clmical results. Radio&y. 1989;172:83-87. 11. Price C, Jacocks MA, Tytle T, et al. Thrombolytic therapy in acute arterial thrombosis. Am J Surg. 1988;156:188-191. 12. Dacey LJ, Row RW, McDaniel MD, et al. Cost-effectiveness of intraarterial thrombolytic therapy. Arch Surg. 1988;123:1218-1223. 13. McNamara TO, Fischer JR. Thrombolysls of peripheral arterial and
254
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graft occlusions: improved results usmg high-dose urokinase. AJR Am J Roentgenol. 1985;144:769-775, 14. Arnold TE, Maekawa T, &ohdrd T, et al. Thrombolytic therapy of synthetic graft occlusions before vascular reconstructive procedures. Am J Surg. 1992;164:241-247. 15. Hallett JW Jr, Greenwood LH, Ynzarry JM. et al. Statistical determinants of success and complications of thromholytic therapy for arterial occlusion of lower extremity. Surr Gynecoi O&t. 19.85;161: 431437. 16. Penes JM, Vitoux JF, Brenoit I’, et al. Acute peripheral arterial and graft occlusion: treatment with selecnve Infusion of urokinase and lysyl plasminogen. Radiology. 1986;158:481485. 17. Traughber I’D, Cook I’S, MicklosTJ. et al. Intra-arterial fibrinolytic therapy for popliteal and tibia1 artery obstruction: comparison of streptokinase and urokinase. AJR Am J Roentgenol. 1987;149:453-456. 18. Lonsdale RJ. Whitaker SC, Berridge 1x1, et al. Peripheral arterial thrombolysis: intermediate-term results. l3r ,/ Surg. 1993;80:592-595. 19. Belkin M, Belkin B, Bucknam CA, et al. Intra-arterial fibrinolytic therapy; efficacy of streptokinase vs urokmz5e. Arch Surg. 1986;121: 769-773. 20. Parent FN, Piotrowski JJ, Bernhard VM, et al. Outcome of intraarterial urokinase for acute vascular cwlusion. I Curdioumc Surg. 1991;32:680-690. 21. Belkin M, Donaldson MC, Whlttemore AD, et al. Observations on the use of thrombolytic agents for thromhotic occlusion of infrainguinal vein LTafts. J Vast Surg. 19YO;11:289-296. 22. Criado E, Bumham SJ, Tinsley EA Jr, et al. Femorofemoral bypass graft: analysis of patency and factors influencing long-term outcome. J Vast Surg. 1993;18:495-505. 23. McCurdy JR, Lain KC, Allgood RJ, et al. An&graphic determinants of femoropopliteal bypass graft patency. Am J Surg. 1972; 124: 789-793. 24. Carpenter Jr, Owen RS, Baum RA, Ct al. Magnetic response angiography of peripheral runoff vessels. J VUC Surg. 1992;16:807-815. 25. Adlar GJ, Vroonhoven TJMV. Polytetrafluoroethylene versus human umbilical vein in above-knee femorclpopliteal bypass: six-year results of a randomized clinical trial. J’ Vrrsc Surg. 1992;16:81&824. 26. Karacagll S, Almgren B, Bowald S, Enksson I. Bypass grafting to the popliteal artery in limbs with occluded crural xtenes. Am J Surg. 1991;162:19-23. 27. Tunis SR, Bass EB, Steinberg ES. The use of angioplasty, bypass surgery, and amputation in the management of peripheral vascular dlsease. NEJM. 1991;325:556-562.
FEBRUARY
1996
Therapy in Patients With Synthetic Graft Occlusions
Yasuharu Ikeda, MD, Mark C. Rummel, MD, Pankaj K. Bhatnagar, MD, Charles K. Field, MD, Paul A. Khoury, MD, Audrey R. Wilson, MD, Morris D. Kerstein, MD, FACS, Teruo Matsumoto, MD, PhD, FACS, Philadelphia, Pennsylvania
BACKGROUND: The aim of this study was to evaluate the efficiency of thrombolysis in the presence of an occluded femoropopliteal synthetic graft. PATIENTS AND METHODS: Over a 3-year period, 46 occluded femoropopliteal grafts were treated with urokinase and reconstruction. The cases were divided into three groups: group 1 (n = 25), complete thrombolysis followed by reconstruction or angioplasty or both; group 2 (n = 5), complete thrombolysis alone; and group 3 (n = 16), failure of thrombolysis requiring reconstruction or leading to amputation. Patients were closely observed after the treatment for more than 1 year. RESULTS: There are no fatal complications among patients with thrombolytic therapy. In group 1, the 3-year patency rates were 12% and the 3-year limb salvage rates were 77%. In group 2, the 3-year patency rates and the limb salvage rates were 20% and 80%, respectively. The group 3 patency rates and the limb salvage rates were 8% and 40%, respectively. The best results were achieved in patients who had thrombolysis followed by reconstruction (group 1) and in those who had thrombolysis alone (group 2). Limb salvage was poor in patients with failure of lytic therapy regardless of the reconstruction (P
D
etection of impending graft failure is a difficult but important aspect of vascular surgery.’ Thrombosis of a bypass graft often results in limb-threatening ischemia.* Standard surgical therapy, such as thrombectomy or angioplasty, has relative poor results in this setting.’ Intra-arterial thrombolysis with high-dose urokinase is now a recognized treatment of occluded arteries.+” Although the durability of thrombolytic therapy alone in failed synthetic grafts is discouraging, 4.5 lysis of an occluding thrombus allows better visualization of inflow and outflow vessels and often discloses the cause of the thrombosis.6 Successful lysis results in an immediate improvement in circulation and allows for a less extensive reconstructive procedure to address the inciting lesion.; Compared with surgical thrombectomy, thrombolytic therapy effectively recanalizes additional small-diameter, branching, or collateral vessels” and reduces outflow resistance.’ Percutaneous thrombolysis is a less invasive procedure in a situation in which multiple previous surgeries make a further surgical approach less desirable.‘” Additionally, better short-term patency and limb salvage rates can be obtained with thrombolysis and an adjunctive surgical revision compared with surgical revision alone.’ At our institution, patients with acutely or subacutely occluded prosthetic grafts were treated with a combination of urokinase therapy and a vascular reconstructive procedure. Over a 3-year period, we reviewed our experience with patients who underwent urokinase therapy followed by a vascular reconstructive procedure for acutely or subacutely occluded prosthetic grafts. All patients had suffered a sudden recent onset or deterioration of symptoms of lower-limb ischemia within the preceding 30 days. The goal of this study was to evaluate the efficacy of thromholysis and multiple secondary vascular reconstructive procedures in patients who have had an occlusion of a previously placed peripheral arterial synthetic bypass graft.
PATIENTS
From the Department of Surgery (YI, MCR, PKB, CKF, MDK, TM) and the Department of Radiology (PAK, ARW), Hahnemann University Hospital, Philadelphia, Pennsylvania. Requests for reprints should be addressed to Yasuharu Ikeda, MD, Department of Surgery, Kameyama Eiko Hospital, 58 Befu Shime-machi Kasuya-Gun, Fukuoka 81 i-22, Japan. Manuscript submitted June 14, 1994 and accepted in revised form November 21, 1994.
THE AMERICAN
AND METHODS
From February 1989 through June 1992, 30 patients had 46 episodes of acute or subacute thrombosis of synthetic vascular grafts treated with percutaneously delivered intra-arterial urokinase. Patients who had acute onset of limb-threatening ischemia or disabling claudication in a limb previously reconstructed with a synthetic bypass were considered for thrombolytic therapy. Patients with imminent tissue loss, defined as an inability to tolerate an additional 24 hours of ischemia,“,” were taken directly to surgery. Absolute contraindications to thrombolysis using urokinase included recent stroke or active gastrointestinal bleeding; abdominal, chest, JOURNAL
OF SURGERYa
VOLUME
171
FEBRUARY
1996
251
THROMBOLC TABLE
cause of thrombolysis
I Influence of Various Patient Factors With Thrombolytic Therapy in 46 Cases
Factor
Group 1 (n = 25)
Sex (M:F) 12:13 Mean age (y) 64 Mean laboratory values Hemoglobin (mg/dL) 12 Prothrombin time (s) 13 Partial thromboplastin time (s) 36 Fibrinogen (mg/dL) 283 Diabetes 13 Hypertension 15 Coronary disease 10 Current smoking 22 Mean initial ankle brachial index 0.18 Indication Claudication 7 Limb salvage 18 Mean duration of occlusion (h) 143 Mean duration of urokinase 27 infusron (h) Total dose of urokinase (IU) 3,118,OOO Complications (%) 7 (28)
Group 2 (n = 5)
Group 3 (n = 16)
4:l 67
13:3 63
12 13 33 336 3 3 1 4 0.19
13 12 38 315 2 10 4 14 0.11
2 3 132 22
6 10 185 33
4,643,OOO 3,498,OOO 1
(20)
7 (44)
A compares of vauous factors ln patients with thrombolylic therapy was done. No factors were assooated wth a s/gnbcant difference !n outcome (P ~3 05)
or neurologic surgery within 3 weeks; cc,agulopathy; or a central nervous system tumor.ss’ All patients in this study had undergone from one to four previous vascular reconstructive procedures and had at least 1 synthetic arterial graft in place. Occlusion occurred in 46 femoropopliteal grafts terminated in suprageniculate popliteal artery. An arteriogram was obtained before treatment to demonstrate the area of proximal occlusion, the inflow and the runoff vessels. The urokinase infusion catheter was inserted by way of the contralateral common femoral artery in 39 (85%) of the cases. Other sites for insertion of the infusion catheter included the brachial artery, direct puncture of the graft, and the contralateral limb of an aortobifemoral graft. A loading dose of 250,000 to 1,OOO,OOO 1U (4,000 IU/mL in sterile saline solution) of urokinase was laced throughout the thrombus by way of a tract made with a guidewire. The initial infusion took place over a 20- to 60-minute period. Urokinase was then infused at 4,000 lU/min until antegrade blood flow was reestablished and subsequently at 1,000 to 2,000 IU/min until clot lysis was complete. Intravenous heparin (600 to 1,000 N/h) was administered concurrently and for at least 24 hours after termination of urokinase infusion. Fluoroscopic angiography or arteriography was performed every 6 to 24 hours to evaluate the graft and run-off vessels. Patients were admitted to the intensive care unit after the urokinase infusion and were prescribed bed rest. The prothromhin time, partial thromboplastin time, platelet count, and fibrinogen, creatinine, and hemoglobin levels were measured hefore Infusion of urokinase. These tests, as well as fibrin degradation products, were monitored at 4- to 6-hour intervals during urokinase infusion and for 24 hours thereafter. Therapy was continued until complete lysis occurred, or, be252
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JOURNAL
OF SURGERYa
VOLUME
171
failure, other therapy was chosen by the angiographer and vascular surgeon. Complete or successful thrombolysis was defined as graft patency with angiographic evidence of normal flow, without evidence of residual thrombus. Incomplete thrombolysis, or failure, was determined to be the inability to open the graft or incomplete arteriographic resolution of the thrombus. All patients had a completion arteriogram to document the effect of thrombolytic therapy. Percutaneous transluminal angioplasty (PTA) in 12 patients (26%), surgical reconstruction in 17 patients (37%), or a combination of both in 7 patients (15%) was performed to correct angiographically identified lesions that were felt to be the underlying cause of the graft occlusion. When thrombolysis was incomplete, all patients underwent a surgical reconstruction with the exception of 5 cases in which 3 amputations and 2 sympathectomies were performed. Cases were grouped according to factors believed to impact upon long-term patency and limb salvage: group 1, complete thrombolysis followed by reconstruction or angioplasty or both; group 2, complete thrombolysis alone; and group 3, total failure of thrombolysis requiring reconstruction or amputation. The influence of individual risk factors that may affect the prognosis was determined using the chi-square test and Student’s t-test. A Kaplan-Meier survival analysis was used to predict patency and limb salvage rates for each group. The significance of differences in patency and limb salvage was determined using the Wilcoxon rank-sum test. For analysis of initial outcome and long-term patency, multiple episodes of graft occlusion in the same patient were treated independently. This study conformed to usual practices for clinical research in our institution. Informed consent was obtained from each patient. Patients were closely followed up after the treatment for more than 1 year, at regular l- to 2-month intervals. Follow-up continued until further lytic therapy, reconstructive procedure, amputation, loss of patient to follow-up, or death of patient. Graft patency was determined by clinical examination, noninvasive hemodynamic measurements, arteriography, or a combination of these tests.
RESUL.TS There were 17 women and 29 men in the study, with an average age of 64 years (range 46 to 75). Diabetes mellitus was present in 18 cases (39%), and 4 cases (9%) were insulin-dependent. Hypertension was present in 28 (61%), coronary artery disease in 15 (33%), and hyperlipidemia in 9 (20%). of the 46 cases, 40 (87%) abused tobacco and 5 (11%) had undergone previous coronary artery bypass surgery. The indication for treatment was acute onset of disabling claudication in 15 cases (33%) and ischemic pain or tissue loss in 31 cases (67%). A comparison of pretreatment laboratory data among the three treatment groups revealed that there was no significant difference in sex, age, hemoglobin, prothrombin time, partial thromboplastin time, and fibrinogen. Additionally, there was no difference in the incidence of diabetes, hypertension, coronary artery disease, and smoking. The initial ankle brachial index and the duration of occlusion were also similar among the three groups (Table I). FEBRUARY
1996
THROMBOLYSIS
Forty-six thrombosed peripheral arterial bypass grafts were treated by intra-arterial urokinase infusion. Complete thrombolysis was achieved in 30 (65%) graft occlusions. The duration of urokinase infusion ranged from 0.25 to 94 hours (mean 28). The total dose of urokinase ranged from 250,000 to 12,550,OOO IU with a mean infusion of 3,416,OOO IU. The duration of occlusion, duration of urokinase infusion, the total dose of urokinase, and number of grafts completely lysed did not significantly vary among the three groups (Table I). Complications occurred in 15 (33%) cases. Eleven (24%) cases resulted in bleeding complications. Nine (20%) cases involved a local hematoma that was treated by pressure alone. Two patients had local bleeding at the catheter site. Two patients had a distal embolization which were lysed without sequelae. Other complications included subcutaneous leakage of urokinase (1 ), and acute renal failure ( 1); however, there were no fatal complications. There was no significant difference in the number of complications when all groups were compared. In group 1 (n = 25), patency and limb salvage at 3 years were determined to be 12% and 77%, respectively. In group 2 (n = 5), patency at 3 years was 20% and limb salvage was 80%. In group 3 (n = 16), the 3-year patency rates were 8% and the limb salvage rates were 40% (Table II). There was a statistically significant difference in limb salvage rates comparing group 1 and 2 with group 3 (I’ ~0.01). There was no statistically significant difference, however, among the three groups, however, when the rate of patency was compared.
COMMENTS Thrombosis of peripheral artery bypass grafts occurs despite careful monitoring of graft function. The reported incidence of specific risk factors in patients with peripheral artery disease varies. Smoking is reported in 30% to 77% of the patients, hypertension in 47% to 63%, coronary artery disease in 34% to SO%, and diabetes mellitus in 16% to 51%.22-‘6 In our study, the incidence of hypertension, coronary artery disease, and diabetes mellitus was comparable to reported rates; however, the incidence of smoking (87%) was higher. Smoking is recognized as a factor that adversely affects patients with peripheral grafts. Once graft thrombosis has occurred, standard surgical therapy has relatively poor results. 3 Intra-arterial thrombolysis for occluded arterial bypass grafts has been effectively used for initial recanalization of both venous grafts and synthetic bypass grafts. ‘I’~ Published initial success rates for thrombolytic therapy vary from 49% to 100%.4.6~“J”-‘” In our study, urokinase achieved complete lysis in 65% of the cases, a rate that is comparable to published initial success rates. McNamara et al+” stressed that the initial rate of administration rather than the total dose of urokinase had a positive influence on success rate. We, therefore, used a highdose regimen. Price et al” found no correlation between total dose or duration of lytic treatment with the initial success rate. Our study agreed with those findings. Hallett et all5 found no association between the indication for treatment (limb salvage versus claudication) and initial success but did find that the severity of ischemia (whether the ankle brachial index was below 0.25) was a significant predictor of complete thrombolysis. Other authors believe THE AMERICAN
TABLE
THERAPY
WITH GRAFT OCCLUSlONllKEDA
ET AL
II Comparison of Cumulative Patency and Limb Salvage Rates in the Three Groups Number
Patency rates Group 1 Group 2 Group 3 Limb salvage rates Group 1 Group 2 Group 3
1 Year
25 5 16
44% (11)’ 40% (2) 31% (5)
25 5 16
92% (23) 100% (5) 56% (9)+
2 Years
3 Years
29% (5) 20% (1) 8% (1)
12% (2) 20% (1) 8% (1)
77% (13) 80% (2) 40% (5)+
77% (6) 80% (1) 40% (4)+
There IS a stat~st~~//y significant chfference rn limb salvage rate comparing groups7 and 2 with group 3 (P 4071. However. there is no stat& cal difference among the three groups in patency rate ‘Numbers in parentheses Indicate bypasses at risk. TP CO.01
that duration of occlusion (time from the onset of symptoms until the initial dose of urokinase) have an impact on initial success.+~~t(.‘0J6 In this study, however, there was no difference in the duration of occlusion, as was found by others.“l’s The mean initial ABIs in the successful group were slightly higher than in the unsuccessful group; however, this did not reach statistical significance. The disadvantages of lytic therapy are well known. Intracranial or retroperitoneal bleeding may be fatal. Multiple contrast-dye loads increase the risk of nephrotoxicity. Our data show that complications occurred in 15 (33%) cases. Of the 15 cases, however, 9 involved a local hematoma that was treated by pressure alone. All complications were treated with conservative therapy, and there were no fatal complications. In several reported series of intra-arterial thrombolytic therapy of thrombosed infrainguinal grafts, long-term patency was poor despite definitive correction of graft lesions by surgery or percutaneous angioplasty.‘“J’ In this study, the long-term patency rates remained poor. Tunis et al” reported poor limb salvage associated with multiple reconstructions of the lower extremity. Our study indicates that limb salvage after failure of lytic therapy and followed by reconstruction (group 3) is significantly decreased from the other groups. Nevertheless, the 3-year limb salvage rate remained 77% if thrombolysis was successful, regardless of additional reconstructive procedures. With all these results, we believe that the development of collateral circulation and the possibility for secondary reconstructive procedures in the successful thrombolysis therapy increase the likelihood of limb salvage. In conclusion, the use of intra-arterial urokinase followed by secondary vascular reconstructive procedures was studied. The patient with synthetic graft occlusions still has a reasonably favorable prognosis for long-term limb salvage when thrombolysis is successful. To what extent late Rraft occlusitrns can he treated by thrombolysis
and how
effective
symptomatic
therup~
is in
thelong
run
remain to be established. A single Japanese hospital’s experience with thrombolysis for femoropopliteal synthetic graft occlusion shows that patients with synthetic graft occlusions have a reaJOURNAL
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HROMBOLYSIS
son&
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ET AL 1
fauorabk response for long-term limb salvage when
thrombolysis
is immediately
success&l.
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1996