In occluded arteries of the limb, thrombolytic treatment has become a successful alternative to bypass surgery [3, 4]. Reperfusion by thrombolysis might be more acceptable than surgical reconstruction to the patient with aortoiliac disease. The main disadvantages of thrombolytic treatment are the inability to predict successful thrombolysis and the risk for hemorrhage. We know of no reports on the outcome of thrombolysis or on the use of thrombolytic agents in chronic infrarenal aortic occlusions. Therefore, we did an uncontrolled pilot study on thrombolysis in aortoiliac disease using three different thrombolytic drugs.

Methods

Top Methods Results Discussion Author & Article Info References

Patients

Forty-three patients with aortoiliac disease were referred to the Division of Angiology of the Department of Internal Medicine or to the Department of Vascular Surgery during the study period. Thirty-nine of these patients were considered eligible for aortobifemoral prosthetic bypass grafting. Twenty-five fulfilled the inclusion criteria for systemic thrombolysis: age less than 65 years, localized aortoiliac disease with occlusive lesions confined to the distal aorta or the common iliac arteries or both without obstructions of the lower-extremity arteries documented by angiography, a history of lifestyle-limiting claudication of less than 3 years, and unchanged symptoms for more than 6 months. Patients with acute gastroduodenal ulcers, previous cerebrovascular events, an obstructed carotid artery, or atrial fibrillation with dilated cardiac chambers were excluded from the study. Each patient gave written informed consent, and the study protocol was approved by the ethics committee of Karl-Franzens University. Baseline data of the patients are given in Table 1.

Eligible patients were randomly assigned to three groups, using a standard design for conducting clinical trials [5]. Patients received either streptokinase (Streptase, Behring; Marburg, Germany): an intravenous bolus of 250 000 IU followed by 100 000 IU/h; urokinase (Urokinase, Serono; Milano, Italy): an intravenous bolus of 600 000 IU followed by 150 000 IU/h; or recombinant tissue-type plasminogen activator (rt-PA; Actilyse, Bender; Vienna, Austria): 0.05 mg/kg body weight per hour. Heparin was administered to all patients whose thrombin times were less than twice the control value.

On the basis of our experience using fibrinolytic drugs in peripheral occlusive disease and in deep venous thrombosis, we discontinued thrombolytic therapy after day 7 in the streptokinase group and in the rt-PA group and after day 14 in the urokinase group, regardless of whether recanalization had occurred. Criteria for premature cessation of therapy were major hemorrhage, cerebral embolism, anaphylactic reaction, or presumed recanalization. Peripheral arterial circulation was assessed daily by palpating pulses, obtaining the ankle/arm pressure ratio, and estimating the blood flow velocity by duplex scanning in the common femoral arteries.

All patients had follow-up angiography either if recanalization of at least one iliac artery was presumed because of an increase (>0.2) in the ankle/arm pressure ratio and in the maximal systolic blood flow velocity (>0.5 m/s) in a common femoral artery or after completion of the scheduled thrombolytic treatment period.

If residual stenosis or one-sided occlusion of the common iliac artery still existed after thrombolytic therapy, percutaneous transluminal angioplasty was attempted. Patients without any reopened arterial segment after thrombolytic treatment had a prosthetic aortobifemoral bypass graft inserted. All patients had anticoagulation therapy after recanalization, initially by intravenous heparin (1000 IU/h) followed by a vitamin K-antagonist for at least 24 months.

Definition of Results

Recanalization was considered to be complete when the aortic bifurcation was reperfused in the follow-up angiogram, regardless of any residual stenosis. Recanalization was considered to be partial when the aorta and one common and external iliac artery were reperfused and the contralateral iliac artery was still occluded. Clinical success was defined as an improvement by at least one stage according to the classification of peripheral arterial occlusive disease proposed by Rutherford and colleagues [6] and an increase of the ankle/arm pressure ratio by at least 0.2.

Assays of Blood Coagulation and Fibrinolysis

Blood was collected twice daily into two polyethylene tubes from a short, indwelling peripheral venous catheter. One tube contained 0.5-mL sodium citrate (final concentration, 0.01 mol/L), whereas the other contained 0.5-mL sodium citrate and aprotinin (final concentration, 250 kIU/mL) to prevent in vitro fibrinogenolysis. Plasma was obtained by centrifugation at 800g for 15 minutes and was then stored in six 0.5-mL aliquots at –70°C.

Complete blood counts and measurements of prothrombin time, activated partial thromboplastin time, and thrombin time were obtained twice daily within 30 minutes after the blood was drawn. Fibrinogen levels and cross-linked fibrin degradation products were estimated in the restored plasma as a single unit within 4 months.

Plasma fibrinogen was measured by the sodium sulfite precipitation method [7], and cross-linked fibrin degradation products were measured by a quantitative enzyme-linked immunoassay with a specific monoclonal antibody (ELISA-D-DIMER, Boehringer Mannheim; Mannheim, Germany) [8]. Complete blood counts were obtained with a Coulter Counter (Coulter; Hialeah, Florida); prothrombin time and activated partial thromboplastin time were measured by thromboplastin C (Instrumentation Laboratory SpA; Milano, Italy) and thrombin time by the human thrombin method (Instrumentation Laboratory Sud S.p.A.; Ascoli Piceno, Italy).

Statistical Analysis

All values are expressed as mean ±SD. Significant changes from baseline values or among groups were evaluated by the paired and unpaired t-test, respectively, based on a 95% CI. Differences in the recanalization rate of three groups were assessed using the chi-square test [9].

Results

Top Methods Results Discussion Author & Article Info References

Recanalization

Thrombolytic treatment resulted in a complete recanalization of the aortic bifurcation in seven (28%) patients; in eight (32%) patients, recanalization of the aorta and one iliac artery was observed. Thrombolytic treatment failed in 10 (40%) patients. Subsequent balloon angioplasty of residual stenosis or one-sided iliac artery occlusion was successfully done in 8 of 15 patients with successful thrombolysis. Balloon dilatation failed in 2 patients; these 2 patients and the 10 patients in whom thrombolytic treatment had failed underwent bypass grafting (Figure 1).

View larger version (11K): [in this window] [in a new window]   Figure 1. Overall results of thrombolytic treatment and subsequent therapy in patients with totally occluded aortic bifurcation. PTA = percutaneous transluminal angioplasty.

Five of the 15 patients with complete recanalization had received streptokinase; 4, urokinase; and 6, rt-PA. The failure rate was 3 of 8 (38%) in the streptokinase group; 3 of 7 (42%) in the urokinase group; and 4 of 10 (40%) in the rt-PA group.

On day 5 of treatment, successful thrombolysis was ascertained in 6 of 10 patients in the rt-PA group but in none of the patients in the streptokinase group or the urokinase group (P < 0.005) (Figure 2).

View larger version (16K): [in this window] [in a new window]   Figure 2. Cumulative recanalization rates with different types of thrombolytic therapy. Ten patients received 0.05 mg/kg body weight per hour of recombinant tissue-type plasminogen activator (rt-PA) for a maximum of 5 days; 8 patients received 100 000 IU/h of streptokinase (SK) for a maximum of 7 days; and 7 patients received 150 000 IU/h of urokinase (UK) for a maximum of 14 days.

Clinical Improvement

The ankle/arm pressure ratio increased significantly (P < 0.001) in all patients after the aortic bifurcation was reopened by thrombolysis and subsequent balloon dilatation. In the patients who underwent bypass grafting, the ankle/arm pressure ratio increased as well (Figure 3). No patients had any further symptoms of claudication.

View larger version (20K): [in this window] [in a new window]   Figure 3. Ankle/arm pressure ratio in patients with totally occluded aortic bifurcation before and after reopening and during the follow-up period. PTA = percutanous transluminal angioplasty.

Side Effects and Complications

No major complications occurred. Streptokinase induced fever in four of eight patients (maximum temperature, 38.5 °C), which responded promptly to administration of 125 mg of prednisolone. Peripheral emboli occurred in four patients. Total lysis of the emboli was confirmed by angiography in all patients at the end of thrombolytic treatment. Minor bleeding from venous puncture sites occurred in 17 (68%) patients: in 4 patients in the streptokinase group (50%) after day 5 of treatment; in 3 patients in the urokinase group (43%) after day 8; and in 7 patients in the rt-PA group (70%) after day 3 of treatment. Thrombolytic treatment with rt-PA was discontinued on day 6 in 4 patients because of increasing hematomas located around the venous puncture sites. Eleven of the 12 patients who had bypass grafting also had no major complications; 1 patient had a nonfatal myocardial infarction 4 days after the operation. Hypertensive crisis (systolic blood pressure, 240 mm Hg) in 2 patients and angina pectoris in 3 other patients occurring during the first 3 postoperative days were treated successfully.

Laboratory Findings

Fibrinogen levels were significantly influenced to a greater extent by streptokinase than by urokinase (P = 0.006) or by rt-PA (P = 0.002). After 96 hours of thrombolytic treatment, the fibrinogen level was decreased by 61% in the streptokinase group (mean ±SD; 289 ±49 mg/dL [95% CI, 249 to 330 mg/dL] to 112 ±49 mg/dL [CI, 71 to 153 mg/dL]); 35% in the urokinase group (307 ±32 mg/dL [CI, 278 to 337 mg/dL] to 198 ±47 mg/dL [CI, 154 to 242 mg/dL]), and 24% in the rt-PA group (285 ±42 mg/dL [CI, 246 to 323 mg/dL] to 217 ±30 mg/dL [CI, 189 to 245 mg/dL]). The maximal cross-linked fibrin degradation product levels did not differ significantly among the treatment groups (streptokinase group, 51 628 ±21 139 mg/mL [CI, 33 950 to 69 306 mg/dL]; urokinase group, 42 211 ±8172 mg/mL (CI, 34 397 to 50 598 mg/dL); rt-PA-group, 35 099 ±8115 mg/mL [CI, 25 018 to 45 180 mg/mL]). However, the peak value was determined after 48 hours in the streptokinase group, after 120 hours in the urokinase group, and after 96 hours in the rt-PA group. The thrombin time and activated partial thromboplastin time values did not differ at any time among the three groups, reflecting similar and sufficient anticoagulation with heparin in all groups. Hematocrit values remained constant in all patients during thrombolysis.

Follow-up

All 25 patients were assessed at 6-month intervals by ascertaining the maximum painless walking distance and the ankle/arm pressure ratio of both legs (see Figure 3). Follow-up averaged 21 months [range, 6 to 36 months]. One patient from the urokinase group died of a myocardial infarction 2 years after thrombolysis, and two patients who underwent implantation of a prosthetic bypass graft were lost to follow-up. No reobstructions occurred in patients with successful thrombolysis or in patients with a prosthetic bypass graft. None of the patients evaluated complained about recurrent claudication.

Discussion

Top Methods Results Discussion Author & Article Info References

Our pilot study showed that a totally occluded aortic bifurcation could be reopened by thrombolytic therapy and subsequent balloon dilatation in 13 of 25 patients (52%). In 2 additional patients with residual one-sided iliac occlusion, reperfusion was obtained by femoro-femoral bypass grafting. In these 15 (61%) patients, aortobifemoral prosthetic bypass grafting was avoided.

Our results are limited by the small number of patients studied; however, this is the first report on thrombolysis of occluded aortic bifurcation. Prosthetic bypass surgery achieves a primary patency rate approximating 100%. A similarly high reopening rate cannot be expected from thrombolytic therapy in chronic aortoiliac disease because not all components of the arteriosclerotic occlusion can be lysed. Therefore, the low rate (20%) of complete recanalization by thrombolytic treatment alone is not unexpected. This study showed, however, that after parts of the aortoiliac occlusion have been resolved by thrombolytic therapy, the residual obstructions become accessible to subsequent mechanical recanalization in 8 of 10 (80%) patients without peripheral embolism. Therefore, the goal of thrombolytic treatment in chronic aortoiliac disease may not be to completely recanalize the obstructed arterial segment but rather to unmask the obstructing lesion in order to recanalize it mechanically. Thus, thrombolytic therapy in chronic aortoiliac disease must not be seen as a single treatment but as a part of a combined recanalizing approach consisting of a biochemical and a mechanical component. Overall, this treatment regimen resulted in a 52% reopening rate with no major bleeding complication or death. No patient required a blood transfusion, and 52% of the patients improved clinically without incurring the costs of surgery or being exposed to the risk of aortobifemoral prosthetic bypass grafting. Large-scale clinical trials are needed to show a net reduction of risk for the combined approach of preliminary thrombolysis followed by surgery in the event of failure compared with immediate surgery.

Our second goal was to compare the available plasminogen activators. We used well-established dose schedules for streptokinase and urokinase. The rt-PA dose schedule was chosen to approximate the streptokinase and urokinase schedules. International units (IU) of rt-PA cannot be compared directly with streptokinase or urokinase units because the log dose-response curves of the three drugs are not parallel. When the different plasma half-lives of streptokinase, urokinase, and rt-PA (30 minutes, 30 minutes, and 5 minutes, respectively), were compared, 72 mg of rt-PA was thought to be approximately equivalent to our daily dose of 3 600 000 IU of urokinase and of 2 400 000 IU of streptokinase. The average daily dose of rt-PA in our study was 90 mg.

The number of patients was too small to detect differences among streptokinase, urokinase, and rt-PA therapy in the overall recanalization rate. However, the average time to achieve lysis was 6 days in the streptokinase group, 9 days in the urokinase group, and only 4 days in the rt-PA group. In addition, the high fibrin specificity of rt-PA caused significantly less systemic fibrinogenolysis than did streptokinase or urokinase. On the other hand, the dose of rt-PA we used resulted in a 70% rate of minor bleeding complications. The conventional use of rt-PA therapy is in acute thrombotic events such as myocardial infarction, pulmonary embolism, and deep vein thrombosis. The results of this study show that rt-PA is also effective in chronic thrombotic occlusion of the aorta and iliac arteries.

Thrombolytic treatment followed by balloon dilatation seems to be an effective and safe treatment regimen in patients with chronic aortoiliac disease. Thrombolysis with rt-PA might be faster than with streptokinase or urokinase in patients with this disease. The optimal dose and selection of patients for thrombolysis require further study. The results of our pilot trial do not allow us to recommend thrombolytic treatment in chronic aortoiliac disease as the therapy of first choice; however, they are encouraging and justify a randomized trial comparing bypass surgery with systemic thrombolysis.