Correspondence
A Comparison of Recombinant Urokinase with Vascular Surgery for Acute Arterial Occlusion of the Legs
N Engl J Med 1998; 339:564-565August 20, 1998
- Article
To the Editor:
The primary conclusion drawn by the authors of the Thrombolysis or Peripheral Arterial Surgery (TOPAS) trial (April 16 issue)1 was that recombinant urokinase reduced the need for open surgical procedures. It would have been remarkable if this were not the case, since the study design required the randomization of half the patients to open surgical procedures as the initial treatment. The authors apparently did not recognize that after the initial treatment, the urokinase group required a greater number of surgical procedures. The data presented suggest that most of these were open surgical procedures. If one counts all subsequent procedures, including percutaneous treatments, it appears that the urokinase group had a far greater need for secondary procedures than the surgery group. It is likely that this need was associated with significantly higher cost than primary surgical treatment. An alternative conclusion would be that initial treatment with urokinase subjected patients to an increased risk of needing subsequent surgery and other interventional procedures and may have resulted in increased costs.
The authors also conclude that there was “no significant increased risk of . . . death” with urokinase treatment. Unfortunately, 30-day mortality rates are not presented. Did the hemorrhagic complications that occurred in the urokinase group result in an increased risk of death in the initial post-treatment period? A six-month mortality end point in a population of elderly high-risk patients is not valid.
Conclusions drawn from prospective, randomized trials should reflect the questions posed in the study design. Ascribing benefit to reducing the need for open surgical procedures suggests that this reduction has primary intrinsic value, as opposed to improving outcomes, reducing patients' suffering, and reducing costs.
1 ReferencesChristopher K. Zarins, M.D.
Stanford University Medical Center, Stanford, CA 943051
Ouriel K ,Veith FJ ,Sasahara AA . A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs. N Engl J Med 1998;338:1105-1111
Full Text | Web of Science | Medline
To the Editor:
The study by Ouriel et al. of Abbott's recombinant urokinase in acute peripheral arterial occlusion showed that although intraarterial urokinase was at least as effective as surgery, its use was accompanied by a 12.5 percent incidence of major hemorrhage, including a 1.6 percent incidence of intracranial bleeding. As a result, Porter concluded in his editorial in the same issue that recombinant urokinase was not to be regarded as first-line treatment for acute arterial thromboembolism of the legs.1 In a comparison with urokinase, intraarterial tissue plasminogen activator (t-PA) was associated with a similar incidence of bleeding.2 Therefore, bleeding complications remain the main impediment to thrombolysis as first-line treatment for peripheral arterial occlusion.
Bleeding has been shown to be directly related to the nonspecific effects of urokinase or t-PA, since “fibrinogen depletion predicted hemorrhagic complications (P<0.01)” with either agent.2 A fibrin-specific thrombolytic agent would therefore be highly desirable for use in patients with peripheral arterial occlusion. Why, then, did Abbott choose to test nonspecific recombinant urokinase rather than their fibrin-specific prourokinase?
As the precursor to urokinase, prourokinase is the only plasminogen activator that is a zymogen, and at the low infusion rates used in patients with peripheral arterial occlusion, it is inert in blood, becoming activated and converted to urokinase only on the fibrin-clot surface. Its fibrin specificity under these conditions was well illustrated by a previous study of 35 patients.3 That study showed that Abbott's recombinant prourokinase induced rapid thrombolysis (in a mean of 6.6 hours, as compared with about 12 hours for urokinase) in 92 percent of the patients, with a patency rate of 97 percent one month later. In striking contrast to urokinase, t-PA, or streptokinase, prourokinase was associated with little fibrinogen or plasminogen depletion, and the authors concluded that intraarterial recombinant prourokinase was safe and effective.
After this experience, whatever considerations went into Abbott's decision to develop recombinant urokinase for this indication, the public's interest in a safer thrombolytic agent for the treatment of acute peripheral arterial occlusion seems not to have been included.
3 ReferencesVictor Gurewich, M.D.
Beth Israel Deaconess Medical Center, Boston, MA 022151
Porter JM . Thrombolysis for acute arterial occlusion of the legs. N Engl J Med 1998;338:1148-1150
Full Text | Web of Science | Medline2
The STILE Investigators
CrossRef | Web of Science | Medline3
Hartmann JR ,Enger EL ,Villiard EM ,Sasahara AA . Dose ranging trial of intraarterial r-prourokinase (A-74187) for thrombolysis of total peripheral arterial occlusions. J Am Coll Cardiol1994;95A-95A abstract.
Web of Science
Author/Editor Response
The authors reply:
To the Editor: Dr. Zarins suggests that the reduction in the need for open surgical procedures after the treatment of acute limb ischemia with recombinant urokinase in the TOPAS trial was a feature of the study design and that an increase in procedures after the initial thrombolytic treatment was not recognized. The TOPAS trial was not designed to compare thrombolytic therapy and surgery as definitive treatments for peripheral arterial occlusion. On the contrary, the use of thrombolytic therapy is only part of a total treatment strategy involving subsequent interventions as necessary to correct or bypass any underlying lesions.1 The results of the TOPAS trial demonstrated that a treatment strategy of initial thrombolysis with recombinant urokinase, followed by necessary interventions to correct any underlying lesions, resulted in a lower rate of open surgical procedures, without significantly increasing the negative clinical outcome of death or amputation. Furthermore, the reduction in the need for open surgery resulted in a benefit likely to be appreciated as an important outcome by the patient and the health care system alike.
Zarins also takes issue with the use of a six-month end point in a population with a relatively high risk of death from other causes. He suggests that 30-day mortality might be more appropriate. In this regard, there were no important differences in mortality between the urokinase group and the surgery group 30 days after randomization (8.8 percent in the urokinase group and 7.0 percent in the surgery group); these rates were similar in relative magnitude to the differences at 6 months and 1 year.
Dr. Gurewich asks why recombinant urokinase was chosen as the thrombolytic agent for the TOPAS trial when more “fibrin-specific” agents (e.g., single-chain prourokinase) were available. He quotes the results of a phase 1 study of prourokinase,2 which suggested that the safety and efficacy of this newer agent may exceed those of the two-chain urokinases. The design of the TOPAS trial, however, was formulated in the early 1990s, two years before the data on prourokinase became available. Today, we share Gurewich's optimism about prourokinase. The Prourokinase versus Urokinase for Recanalization of Peripheral Occlusions Safety and Efficacy (PURPOSE) trial, a multicenter evaluation of prourokinase in the treatment of peripheral arterial occlusion, is well under way. Enrollment of patients in the dose-ranging portion of the PURPOSE trial was completed in May 1998, and data collection and analysis are in progress.
2 ReferencesKenneth Ouriel, M.D.
University of Rochester, Rochester, NY 146421
Sullivan KL ,Gardiner GA Jr ,Kandarpa K , et al. Efficacy of thrombolysis in infrainguinal bypass grafts. Circulation 1991;83:Suppl 1:I-992
Hartmann JR ,Enger EL ,Villiard EM ,Sasahara AA . Dose ranging trial of intraarterial r-prourokinase (A-74187) for thrombolysis of total peripheral arterial occlusions. J Am Coll Cardiol 1994;23:95A-95A abstract.
Author/Editor Response
Dr. Gurewich suggests that my only reason for objecting to the study by Ouriel et al. was the high incidence of bleeding. Please be assured that this was not my only objection. Other important problems include a conspicuous lack of proof of efficacy and the likelihood of increased cost with urokinase. Even if the prourokinase recommended by Gurewich were to eliminate or reduce greatly the problem of bleeding, my other objections would remain. On balance, I am currently unable to generate any enthusiasm for the use of thrombolytic therapy for arterial occlusive disease of the legs.
John M. Porter, M.D.
Oregon Health Sciences University, Portland, OR 97201-3098
