Author + information
- Received December 30, 1998
- Revision received April 11, 2000
- Accepted June 2, 2000
- Published online October 1, 2000.
- Johannes Schweizer, MD∗,* (, )
- Wilhelm Kirch, MD†,
- Rainer Koch, PhD‡,
- Holger Elix, MD∗,
- Grit Hellner, MD∗,
- Lutz Forkmann, MD∗ and
- Andreas Graf, MD§
- ↵*Reprint requests and correspondence: Dr. Johannes Schweizer, Klinik Chemnitz gGmbH, Krankenhaus Küchenwald, Klinik für Innere Medizin I, Bürgerstraβe 2, D-09113 Chemnitz, Germany
The goal of this study was to assess the short- and long-term efficacy of different thrombolytic therapy regimens in patients with leg or pelvic deep venous thrombosis (DVT).
It is unclear whether locoregional or systemic thrombolysis is superior in treating acute leg DVT or even whether lysis is more effective than anticoagulation therapy in preventing postthrombotic syndrome.
A total of 250 patients averaging 40 years of age with acute DVT were randomized into five groups to receive full heparinization (1,000 IU/h) and compression treatment, with four groups also administered locoregional tissue plasminogen activator (20 mg/day) or urokinase (100,000 IU/day) or systemic streptokinase (3,000,000 IU daily) or urokinase (5,000,000 IU daily). All groups then received anticoagulation and compression treatment for one year. Primary efficacy criteria included the change after one year in the number of closed vein segments and the occurrence of postthrombotic syndrome.
Systemic thrombolytic therapy significantly reduced the number of closed vein segments after 12 months in patients with acute DVT compared with conventional treatment (p < 0.05). Postthrombotic syndrome also occurred with less frequency in systemically treated patients versus controls (p < 0.001). High-dose thrombolysis led to better rates of complete recanalization after seven days (p < 0.01) than locoregional lysis. However, 12 patients receiving thrombolysis (9 systemic, 3 local) suffered major bleeding complications; 9 patients on systemic treatment developed pulmonary emboli.
Systemic thrombolytic treatment for acute DVT achieved a significantly better short- and long-term clinical outcome than conventional heparin/anticoagulation therapy but at the expense of a serious increase in major bleeding and pulmonary emboli. Given the inherent risks for such serious complications, systemic thrombolysis, although effective, should be used selectively in limb-threatening thrombotic situations.
Although numerous studies have been conducted for well over a decade to assess the efficacy and safety of thrombolytic therapy for deep venous thrombosis (DVT), no consensus has emerged with regard to the drug of choice, best route of administration (locoregional vs. systemic) and optimal dosing regimen. Various ways and means of improving recanalization rates and preventing bleeding complications have been suggested (1–6), but diverse protocols and conflicting results have only served to obfuscate the clinical picture. For example, two studies on acute leg DVT carried out in 1992 indicated that locoregional fibrinolysis with either recombinant tissue plasminogen activator (rt-PA) (7) or urokinase (8) was safer and more effective than systemic thrombolysis. However, a more recent investigation (9) appeared to negate these findings in favor of systemic treatment. Moreover, because long-term studies after thrombolysis treatment have not rigorously monitored compliance with respect to follow-up compression therapy, it is unclear whether thrombolytic treatment strategies are more effective than exclusive anticoagulation therapy in preventing the subsequent development of the postthrombotic syndrome (PTS). Consequently, the use of thrombolytic therapy is far from being generally accepted, and the benefits and risks of such treatment must be weighed with care for each patient (10–13). Against this background, the aim of this randomized controlled study was to determine the rate of primary recanalization in comparable DVT patient groups receiving low-dose locoregional (rt-PA or urokinase) or high-dose systemic (urokinase or streptokinase) thrombolytic therapy. We also sought to establish whether such treatments prevented the long-term occurrence of PTS when compared with the use of anticoagulation therapy and compression bandages only.
Between January 1992 and January 1998, 250 patients (mean age 39.9 ± 10.4 years) with recent, acute leg or pelvic thromboses (mean duration of symptoms 5.6 ± 2.1 days), but without clinically relevant signs of pulmonary embolism, were recruited at our hospitals in Chemnitz and Dresden for this trial which consisted of a four- to seven-day randomized acute treatment phase (thrombolytic therapy) followed by a year-long phase during which patients received standard anticoagulant and compression treatment. The diagnosis and onset of the thrombosis were based upon the nature and date of the initial clinical symptoms, venography and the findings of color-coded duplex sonography after two independent examinations. Evidence of thrombosis on color-coded duplex sonography was carried out through compression findings and by diagnosing the absence of color flow. Patients could only be included if the estimated age of the leg or pelvic DVT in the two sonographic examinations did not differ by more than three days (thereby excluding the emergence of a new obstruction) and provided that the thrombosis was less than nine days old.
Proximal leg DVT was defined as thrombosis of the popliteal or more proximal veins with or without concomitant calf vein thrombosis. The anatomical levels of the thrombi were defined as follows: lower leg, thrombus in the tibial vein or anterior or posterior or fibular or soleus veins; popliteal, thrombus in the popliteal or gastrocnemius veins; thigh, thrombus in the superficial femoral or deep femoral veins; pelvic, thrombus in the pelvic veins. Exclusion criteria were as follows: patients with DVT solely at one level; existence of DVT for more than nine days; previous DVT in the same leg or thrombosis in calf veins only; urogenital or gastrointestinal bleeding; inflammatory bowel disease within the last 12 months; acute pancreatitis; surgical intervention or cerebral trauma within the last three months; intramuscular injections within the last 10 days; arterial hypertension or diabetes (stages III to IV retinopathy); history of cerebral disease; malignant disease; renal failure (creatinine >350 μM); hepatic failure (ASAT > 100 U/l; prothrombin time >50%), hemorrhagic diathesis; pregnancy or lactation; delivery within the last 20 days. Written informed consent for the study was obtained from all subjects, and the protocol was approved by the local ethics committee of the University of Dresden.
Upon eligibility for inclusion, patients were randomly assigned to one of the five following groups.
Twenty-mg rt-PA (Alteplase, Thomae, Boehringer Ingelheim, Germany) was infused directly into the affected leg via a dorsal pedal vein over a 4-h period each day for four to seven days. During this time, standard unfractionated heparin (Liquemin, Hoffmann-La Roche, Grenzach-Wyhlen, Germany) was continuously administered intravenously at a rate of 1,000 IU/h, with the dosage adjusted according to the aPTT value (2.0 to 3.0 times normal value). Patients were kept in bed, and the affected leg was bandaged from forefoot to groin as described by Timmermann et al. (7).
A clinical evaluation was performed daily. If clinical improvement was noted, a second venography was performed after the first four days of treatment. However, if venography showed no improvement or only a minor thrombolytic effect (partial thrombolysis >50%), treatment was continued for another three days. A third and final venography was then performed within 24 h after cessation of treatment. After day 7, this and the other four groups were placed on a 12-month regimen consisting of compression treatment and oral anticoagulation with phenprocoumon (Falithrom, Hexal, Holzkirchen, Germany) given in individual doses so that the international normalized ratio was greater than 2.5 but less than 4.0.
In the same way, 100,000 IU/h urokinase (urokinase, Hoechst, Berlin, Germany) was infused directly and continuously for up to seven days. Infusion was stopped if the fibrinogen value was below 1.5 g/l or if the plasminogen values were less than 60%. Concomitant treatment was carried out with unfractionated heparin and compression bandages.
The patients received a bolus of 5,000,000 IU urokinase (Hoechst) daily, infused over a 4-h period for a maximum of seven days along with unfractionated heparin and compression bandages.
After premedication with 100 mg hydrocortisone, 50 mg ranitidine and 2 mg clemastine, patients were given a daily intravenous infusion of 3,000,000 IU streptokinase (Awelysin, Dresden Drug Co., Dresden, Germany) over 6 h, in conjunction with heparinization and compression bandages for up to seven days.
During the first seven days or less, the only treatment received, aside from compression bandages, was heparinization.
Efficacy and safety outcome measures
The primary outcome measures used to assess drug efficacy in the five treatment groups included: 1) the change in the number of closed vein segments (≥50% stenosis or total occlusion) after 12 months; and 2) the degree of PTS after 12 months as determined by venography. Secondary efficacy assessment criteria included the number of closed vein segments after seven-day lysis treatment and the phlebodynamically measured rates of venous reflux, reflux time and pressure decreases after 12 months.
In order to assess short-term thrombolytic efficacy, all patients underwent renewed venography and color-coded duplex sonography at the end of seven-day lysis treatment. One dedicated radiologist, blinded to the patients’ treatment regimens, evaluated the venograms, while another assessed the sonographic data. Based on visual quantitative assessment, results were classified into five categories: progression of thrombosis, no thrombus reduction, partial thrombolysis < 50%, partial thrombolysis ≥50%, complete recanalization of all affected veins. Categorization into the latter two groups was based on detection of continuous flow of contrast medium in the affected veins.
The accuracy and reproducibility of the phlebographic results were also determined. For this purpose, intraobserver variability was initially ascertained in 20 patients and by 100 measurements of all venous segments. Additionally, interobserver variance was established in separate experiments involving three observers taking four repeated measurements of the venous segments for each of 20 patients. For phlebographic evaluation of venous segments, intraobserver variance was found to be 2.5%, and interobserver variance was also 2.5%, while phlebodynamic measurements yielded intra- and interobserver variances of 4% and 5%, respectively. Upon evaluation of the maximal rates of reflux and reflux times by color-coded duplex sonography, both intra- and interobserver variance were found to be 5%.
Safety assessments after seven-day thrombolysis treatment included clinical observations of the number, types, intensity and duration of adverse events (bleeding complications, embolism, etc.) as well as determination of laboratory parameters. Biochemical parameters assessed before and at the end of treatment included electrolytes, creatinine and ASAT. Measurements of hemoglobin, hematocrit, platelets, as well as coagulation tests (aPTT, thrombin time, PTT and fibrinogen) were performed twice daily. Antithrombin III levels were determined before administration of heparin. Adverse events were considered to be major if they required early cessation of treatment.
After 12 months, all patients attended a follow-up examination during which they filled in a standardized questionnaire describing their subjective symptoms indicative of the clinical grade of PTS: stage I, no symptoms; stage II, slight symptoms corresponding to mild, perimalleolar edema formation reversible overnight, perimalleolar “piston veins,” coronal phlebectasia; stage III, moderate symptoms, i.e., visible, palpable edema up to the midcalf level, hyperpigmentation in the distal calf region, hyperdermitic changes in the subcutis, especially in the perimalleolar region, hypereczematization and induration of the subcutaneous lipid tissue (lipodermatosclerosis); stage IV, serious symptoms, i.e., healed or active ulceration and additional signs of congestion as in stage III.
An evaluation of the deep venous system in the affected extremity was then performed. In order to estimate the degree of PTS after 12 months, the following venographic criteria was used: 1) recanalized vessel with smooth vessel wall, 2) clear damage to the vessel wall with partial recanalization but residual multiple stenoses and formation of collateral venous vessels, 3) only slight recanalization with clear collateralization, 4) lack of recanalization with complete collateral circulation and venous occlusions remaining unchanged. This venographic study was carried out by two independent investigators who were blinded to the therapeutic regimen.
For additional validation of venous function, phlebodynamic measurements were also performed. The values were newly assigned. Such measurements make it possible to describe venous reflux function (drainage function) quantitatively by determining peripheral blood pressure (dorsal pedal vein) with the patient standing upright. Thereafter, standardized weight-bearing on the toes was performed and the loading phlebodynamics measured. Immediately after the normalized toe-standing exercises, the absolute maximal drop in pressure was determined. The latter variable is one of the best reproducible indicators of venous pump function and can be classified into the following grades: grade I, no PTS, i.e., unremarkable valve function with pressure drop of 60 mm Hg ± 8 mm Hg; grade II, pressure drop 50 mm Hg ± 20 mm Hg; grade III, pressure drop 20 mm Hg ± 11 mm Hg; grade IV, no pressure drop, i.e., completely obliterated valve function reflecting serious PTS.
Before venography, all patients were examined in a standing position using continuous wave Doppler, B-mode sonography and color-coded duplex sonography with and without flow rate measurements in the common femoral, superficial femoral and popliteal veins. Discrete refluxes in the deep veins of the lower leg were not considered. Using color-coded duplex sonography, a change in color was sought in the low-flow area (0.5 to 20 cm/s) by means of three Valsalva maneuvers. Only a change lasting more than 0.5 s, in the color-coded direction of flow during application of pressure, was defined as reflux. The measurements were recorded at an angle below 60°. The mean value of the maximal reflux speed (cm/s) was calculated from three measurements. B-mode sonography in the deep veins of the leg was based on pathological vessel wall changes, the so-called inner reflexes. Additionally, the reflux above the popliteal vein was measured under standardized conditions. Rates of reflux exceeding 10 cm/s and reflux times greater than 2 s were considered to be pathological. The reference method used in all patients was antegrade venography with pressure tests using the customary technique.
The Doppler examination was carried out using the bidirectional continuous wave Doppler Vasoscop (Kranzbühler, Solingen, Germany) with 4- and 8-MHZ probes. Color-coded duplex sonography was performed using the Sonos 1000 system (Hewlett Packard, Frankfurt, Germany), with 5- and 7.5-MHZ transducers. Finally, follow-up sonography, just as for venography, was carried out by a blinded investigator with no knowledge as to the initial treatment procedures that had been used.
Data are expressed as mean ± standard deviation. Comparisons between the groups were carried out using Bonferoni-adjusted chi-square and Mann-Whitney U tests. For the analysis of the vein segments, statistical tests were carried out on the basis of Bonferoni-Holm-adjusted contrasts in a logistic regression model. For this purpose, the outcome variable was a “closed vein segment,” while the three factors included follow-up time, treatment group and level of affected area and with an exchangeable correlation matrix for all outcomes within the individual patients (14). These tests examined the hypotheses concerning the equality of the expected number of closed vein segments between each of the treatment groups: 1) before lysis, 2) after 12 months, and 3) the expected decrease in closed vein segments after 12 months. For this analysis, the SAS procedure GENMOD (SAS Institute; Cary, North Carolina) was used. With a presumed dropout rate of 20%, we estimated that a sample size of 5 × 40 patients was necessary to achieve sufficient statistical power of at least 90% for a relative effect equal to 60% of the standard deviations of the variables tested.
A total of 250 patients were equally randomized to the five treatment groups. As seen in Table 1, no significant intergroup differences emerged with respect to demographic and baseline characteristics. The principal causes of thrombosis were immobilization (32%), idiopathic thrombosis (32%), antithrombin deficiency (16%), patients with familial thrombophilia taking hormonal contraceptives (16%) and protein C defects (4%).
In the course of the acute treatment phase, lysis treatment had to be terminated earlier than seven days in a total of 12 patients due to major bleeding complications: two because of persistent nosebleeds, three due to important skin hematomas (>8 cm diameter), one patient with gastrointestinal bleeding, two with hematuria and four with retroperitoneal bleeding. Three of these patients received local thrombolytic treatment, while the other nine underwent systemic thrombolysis. All complications could be well controlled conservatively, and no cerebral hemorrhaging or fatal complications occurred. In contrast with patients receiving thrombolytic treatment, no gastrointestinal bleeding, hematuria or retroperitoneal bleeding occurred in the control group. After initiation of lysis on the first day of treatment, five and four patients in the systemic streptokinase and urokinase groups, respectively, showed clinical signs of pulmonary embolism, accompanied by lack of air, thoracic pain and a slight drop in blood pressure. Lysis treatment was continued, and the symptoms did not last longer than 30 min. No symptomatic pulmonary embolism was observed among controls.
The follow-up examination at month 12 was not attended by four patients in the systemic urokinase group, four in the systemic streptokinase group and four in the control group. These were primarily patients who suffered from very few symptoms and did not appreciate the reasons for compression treatment, let alone the need for the follow-up examination. There was no mortality, hemorrhagic complications or evidence of pulmonary embolisms among patients during the one-year follow-up phase.
Primary outcome measures
When changes in the number of closed vein segments (≥50% stenosis or total occlusion) were assessed for all patients (n = 238) attending the follow-up examination at 12 months, the number of remaining closed segments was significantly lower (p < 0.05) in patients who had undergone systemic thrombolysis compared with those on conventional treatment (Table 2). No significant differences in outcome emerged between controls and the patients treated locoregionally.
Upon analyzing the results in terms of the number of anatomical levels affected (Table 2), there were no intergroup differences in closed vein segments at 12 months for patients affected at two levels. When three levels (lower leg, popliteal and femoral veins) were involved, patients receiving either local or systemic lysis treatment showed significant improvement (all p < 0.05) versus controls. However, when evaluating those patients affected at four levels (previous set plus pelvic vein), only the systemically treated patients demonstrated significant differences compared with controls (p < 0.05).
With respect to the second primary end point, Table 3summarizes the degree of PTS after 12 months as defined by venography. There was a significantly greater number of patients with a more favorable degree of PTS among those treated with systemic thrombolysis versus controls (p < 0.001). A total of 76 out of 92 patients (83%) in the former group could be classified as having first- or second-degree PTS versus 26/46 patients (57%) treated conventionally and 57/100 (57%) patients in the locoregional group.
Secondary outcome measures
When comparing functional parameters at 12 months among patients with any degree of PTS (Table 4), the drop in peripheral blood pressure and the decrease in the maximal rates of reflux and reflux times were significantly more pronounced in systemically treated patients (p < 0.001) versus controls.
Finally, short-term thrombolytic findings are presented in Table 5. No reduction or worsening of thrombotic findings occurred in 80% of controls, 31% of patients on local thrombolysis and in 20% of patients infused systemically. By contrast, thrombus reduction ≥50% or complete recanalization was observed in 6%, 36% and 54% of controls, patients on local treatment and systemic lysis, respectively. The results of the systemic grouping with respect to the frequency of completely reopened vessel sections were statistically significant when compared with the groups on local lytic treatment (p < 0.01). No intergroup differences emerged in terms of any of the hematological, biochemical or coagulation parameters assessed before or after lysis treatment.
Thrombolysis for acute DVT: conflicting evidence, trial design issues
At present, recourse to the use of thrombolytic therapy in patients with acute leg DVT is not widespread among physicians. For one thing, the potential immediate benefit of preventing pulmonary embolism with thrombolysis must actually be balanced against the potential immediate harm of iatrogenically causing pulmonary embolization or major bleeding by thrombolysis of DVT. Another cautionary factor has been conflicting evidence as to whether DVT thrombolysis can prevent PTS. One influential study by Kakkar and Lawrence (15) reported no difference between systemic streptokinase and heparin/coumadin alone in preventing chronic venous insufficiency in the long term, but several other investigations carried out about 15 to 20 years ago appear to indicate that lytic therapy reduces late postthrombotic sequelae to a markedly greater extent than anticoagulant therapy alone (16–21). Unfortunately, the variegated design of these trials has limited their comparability, thereby failing to resolve such key issues as what types of DVT patients would benefit most from thrombolysis and which thrombolytic agent(s) and dosing regimen(s) would be the most effective.
A particularly problematic factor in previous investigations is the question of longer-term follow-up. In fact, studies of later sequelae after lysis treatment should be run ideally for five to 10 years. But this is an inordinately long time to monitor patient compliance, especially with regard to controlled compression therapy. It is well known that patients with vascular complaints are likely to avoid this form of treatment during summer months, favoring the development of PTS. In order to achieve a practical and uniform regimen for follow-up, the end point of our study was set at one year. In addition to receiving oral anticoagulation, all patients underwent compression treatment using custom-measured class 2 compression stockings fitted by the orthopedic technician. These stockings were refitted every three months, at which time patients were required to hand in their compression stockings for visual inspection. In this respect, compliance was surprisingly good in all patients who attended the final checkup after 12 months despite the subjectively stressful compression treatment.
Another issue in the design of trials to assess postthrombotic venous changes is the difficulty in initially assigning a clinical age to the thrombosis based on the duration of symptoms. It must be assumed that some patients are inadvertently included with asymptomatic thromboses but which only become apparent when clinical symptoms arise. Indeed, PTS grades 3 and 4 were found in all our groups after one year although it is well known that such conditions only develop after five to 10 years. This demonstrates the difficulties in carrying out studies intended to include only those patients with primary manifestations of venous thrombosis.
It is also true that a standardized questionnaire such as that filled in by patients to assess the presence and degree of PTS is subject to bias due to the absence of blinding. To avoid such bias, a venographic study was carried out by independent investigators who were blinded to the therapeutic regimen. Additionally, a phlebodynamic comparison of no symptoms versus any symptoms was carried out (Table 4).
Principal efficacy and safety results
Upon taking into account all 238 patients who could be followed up for 12 months, a significant difference emerged for the number of closed vessel segments after one year between patients who had received systemic thrombolytic therapy and those administered heparin plus oral anticoagulants. This difference did not extend to those patients who had undergone locoregional treatment. Venographic evidence of PTS at month 12 was also clearly ameliorated with systemic treatment versus controls. However, while this study was positive for both end points, it should be emphasized that these improvements were obtained at the expense of important bleedings in 12 lysis patients and symptomatic pulmonary emboli in 9 patients on thrombolysis, whereas no complications arose in patients on conventional therapy. As this important rate of serious adverse effects occurred in a 40-year-old target population, the extrapolation of using such a therapeutic strategy to a more elderly population would conceivably result in a more unfavorable ratio of risk to reward.
Reconciling recanalized veins and PTS
As pointed out by Evers and Wupperman (22), it is not infrequent to encounter patients who claim to suffer from considerable PTS symptoms but in whom no objective skin changes can be seen. However, by determining the rate of flow and the reflux times, they claimed that it was possible to objectively estimate the extent to which PTS has developed (22). In accordance with their findings, we observed that those patients with venographically unremarkable deep veins who complained about considerable postthrombotic symptoms after 12 months had significantly higher rates of reflux and longer reflux times. We also found that patients without any clinical symptoms of PTS demonstrated unremarkable results on venography and had no pathological reflux times or reflux measured over the popliteal vein in color-coded duplex sonography (Table 4). Not only did our phlebodynamic measurements and those by color-coded duplex sonography correlate well for reflux (r = 0.87, p = 0.001) and for reflux time (r = 0.93, p = 0.001), but we also found a positive correlation between phlebodynamic measurements and clinical symptoms of PTS (r = 0.96, p = 0.001). It would, thus, appear that for the longer-term development of postthrombotic conditions, not only is the patency of the deep veins an important factor but the quality of venous valve function is as well. Postthrombotic syndrome cannot, therefore, be ruled out, even if the veins have regained full patency after lysis treatment since venous valves may have been destroyed. Additionally, the use of reflux measurements can help provide a basis for judging the need for compression therapy.
Conservative treatment options with heparin and compression bandages also gave good recanalization rates after one year. But it should be noted that relatively poor functional results (low reflux pathology) emerged in heparin control patients, giving rise to more symptoms of PTS, possibly on account of the relatively slow recanalization process that developed over the course of one year. We observed also that patients affected by thromboses at only two levels seemed to benefit less from lysis treatment than those with thrombus formation at three levels or more. The patients in this former group often had thrombi in the pelvic region, which are know to be less susceptible to successful lysis due to early collateral formation. Lysis medication may, thereby, fail to reach thromboses pelvic veins due to circulatory bypasses (21). Finally, this may also explain the differing results reported by Kakkar and Lawrence (15) versus others (16–21) with respect to the efficacy of thrombolysis, namely that the selected study populations would have differed in the percentages of patients with thromboses at two, three or four anatomical levels, thereby making them more or less susceptible to benefitting from lysis treatment.
In conclusion, in this relatively younger population of patients with acute leg or pelvic DVT, systemic thrombolytic therapy reduced the number of closed vein segments after 12 months and was better able to prevent postphlebitic disability than conventional anticoagulation treatment. However, thrombolysis was also associated with major bleeding in 6% of cases and thromboembolism in nine patients (4.5%), compared with no occurrences in those receiving conventional regimens. These findings indicate that systemic thrombolysis is effective in improving the longer-term outcome of DVT but should be used selectively in limb-threatening thrombotic situations, given the inherent risks for serious complications. An equally important observation that emerged is that PTS cannot be excluded even if deep leg veins have regained their full patency after lysis treatment because venous valves may have been pathologically damaged. Reflux measurements can be useful in determining the quality of venous valve function and in assessing the need for compression therapy.
- deep venous thrombosis
- postthrombotic syndrome
- recombinant tissue plasminogen activator
- Received December 30, 1998.
- Revision received April 11, 2000.
- Accepted June 2, 2000.
- American College of Cardiology
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- Lijnen H.R
- Timmermann J,
- Rudofsky G,
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