Michael F. Meyerovitz

RANDOMISED CONTROLLED TRIAL OF RECOMBINANT TISSUE PLASMINOGEN ACTIVATOR VERSUS UROKINASE IN THE TREATMENT OF ACUTE PULMONARY EMBOLISM

The effect of intravenous recombinant human tissue-type plasminogen activator (rt-PA) was compared with that of urokinase in 45 patients with angiographically documented pulmonary embolism (PE) in a randomised controlled trial. The two principal end-points were clot lysis at 2 h, as assessed by angiography, and pulmonary reperfusion at 24 h, as assessed by perfusion lung scanning. All patients received the full dose of rt-PA but urokinase infusions were terminated prematurely (on average after 18 h) in 9 patients because of allergy in 1 and uncontrollable bleeding in 8. By 2 h, 82% of rt-PA-treated patients showed clot lysis, compared with 48% of urokinase-treated patients (p = 0.008; 95% CI for the difference = 10-58%). Improvement in lung scan reperfusion at 24 h was identical in the two treatment groups. The reduction in fibrinogen did not differ significantly between the rt-PA and urokinase groups (45% vs 39% at 2 h and 34% vs 40% at 24 h). The results indicate that in the dose regimens employed, rt-PA acts more rapidly and is safer than urokinase in the treatment of acute PE.

Recombinant tissue-type plasminogen activator versus a novel dosing regimen of urokinase in acute pulmonary embolism: a randomized controlled multicenter trial

Thrombolysis of acute pulmonary embolism can be accomplished more rapidly and safely with 100 mg of recombinant human tissue-type plasminogen activator (rt-PA) (Activase) than with a conventional dose of urokinase (Abbokinase) given as a 4,400-U/kg bolus dose, followed by 4,400 U/kg per h for 24 h. To determine the effects of a more concentrated urokinase dose administered over a shorter time course, this trial enrolled 90 patients with baseline perfusion lung scans and angiographically documented pulmonary embolism. They were randomized to receive either 100 mg/2 h of rt-PA or a novel dosing regimen of urokinase: 3 million U/2 h with the initial 1 million U given as a bolus injection over 10 min. Both drugs were delivered through a peripheral vein. To assess efficacy after initiation of therapy, repeat pulmonary angiograms at 2 h were performed in 87 patients and then graded in a blinded manner by a panel of six investigators. Of the 42 patients allocated to rt-PA therapy, 79% showed angiographic improvement at 2 h, compared with 67% of the 45 patients randomized to urokinase therapy (95% confidence interval for the difference in these proportions [rt-PA minus urokinase] is -6.6% to 30.4%; p = 0.11). The mean change in perfusion lung scans between baseline and 24 h was similar for both treatments. Three patients (two treated with rt-PA and one with urokinase) had an intracranial hemorrhage, which was fatal in one. The results indicate that a 2-h regimen of rt-PA and a new dosing regimen of urokinase exhibit similar efficacy and safety for treatment of acute pulmonary embolism.

ACUTE PULMONARY EMBOLISM TREATED WITH TISSUE PLASMINOGEN ACTIVATOR

Recombinant human tissue-type plasminogen activator (rt-PA) was given via a peripheral vein to 36 patients with angiographically documented pulmonary embolism. The regimen was 50 mg/2 h followed by repeat angiography and, if necessary, an additional 40 mg/4 h. By 6 h, 34 of 36 patients had angiographic evidence of clot lysis, slight in 4, moderate in 6, and marked in 24. The quantitative score improved 21% by 2 h and 49% by 6 h. Fibrinogen decreased 30% from baseline at 2 h and 38% from baseline at 6 h. 2 patients had major complications: in one, bleeding from a pelvic tumour required surgery; in the other, who had had coronary artery bypass surgery eight days earlier, pericardial tamponade developed. These initial results in selected patients make a case for expanded investigational use of peripheral intravenous rt-PA in pulmonary embolism.

Patency Results of Percutaneous and Surgical Revascularization for Femoropopliteal Arterial Disease

To estimate the patency results of percutaneous transluminal angioplasty and bypass surgery in the treatment of femoropopliteal arterial disease, a Medlars search of the English-language medical literature was performed. Inclusion required that studies 1) report original data, 2) report patency with a life table or Kaplan-Meier analysis with the number at risk or standard errors, 3) define patency as hemodynamic improvement, 4) report the distribution of co variates, and 5) not duplicate other published material. Using a method based on the pro portional-hazards model and the actuarial life-table approach, the results were adjusted for differences in case-mix of the study populations and patency was predicted for subgroups at various levels of risk for failure. The unadjusted pooled life tables yielded five-year pa tencies of 45% (± 2%) for angioplasty, 73% (± 2%) for bypass surgery using a vein graft, and 49% ( ± 3%) for bypass surgery using a polytetrafluoroethylene graft. Adjusted five- year primary patencies after angioplasty varied from 12% to 68%, the best results being for patients with claudication and stenotic lesions. Adjusted five-year primary patencies after surgery varied from 33% to 80%, the best results being for saphenous vein bypass performed for claudication. The authors conclude that pooling life-table data without adjustment for covariates can be misleading. Indication, lesion type, vein graft availability, and site of the distal graft anastomosis need to be considered in predicting patency results of revascular ization for femoropopliteal arterial disease. Key words: arteries, femoral; arteries, popliteal; arteries, transluminal angioplasty; arteries, surgery; review; meta-analysis. (Med Decis Mak ing 1994;14:71-81)

Randomized controlled trial of tissue plasminogen activator in proximal deep venous thrombosis

PURPOSE To compare the efficacy and safety of recombinant human tissue-type plasminogen activator (rt-PA, supplied as Activase) with heparin alone or rt-PA plus heparin in the treatment of venographically documented proximal deep venous thrombosis (DVT) of the leg. PATIENTS AND METHODS Sixty-four patients underwent 65 randomizations to rt-PA alone (n = 36), rt-PA plus heparin (n = 17), or heparin alone (n = 12) in a prospective, multicenter, randomized, open-label trial, with efficacy assessed by a radiology panel unaware of treatment assignment. Patients randomly assigned to rt-PA received 0.05 mg/kg/hour for 24 hours via a peripheral vein, with a maximum dose of 150 mg. All patients then received heparin and warfarin for the remainder of the hospitalization. Follow-up venography was performed 24 to 36 hours after initiation of therapy. RESULTS Complete or more than 50% lysis occurred in 10 (28%) patients treated with rt-PA, five (29%) patients with rt-PA plus heparin, and no patient treated with heparin. No lysis occurred in 16 (44%) patients treated with rt-PA plus heparin, and 10 (83%) patients who received heparin alone (p = 0.04). There was one major complication, a nonfatal intracranial hemorrhage in a patient who received rt-PA alone. At 7 to 10 days after initiation of treatment, the level of serum glutamic oxaloacetic transaminase nearly doubled among all patients, including those assigned to receive heparin alone. CONCLUSION (1) rt-PA and rt-PA plus heparin cause more clot lysis than heparin alone; (2) the addition of heparin to rt-PA does not improve the lysis rate; (3) DVT treated with heparin is commonly associated with a rise in the transaminase level; (4) heparin does not increase the risk of bleeding from rt-PA therapy; and (5) alternative dosing regimens and modes of administration of rt-PA should be investigated to improve further its efficacy and safety in the treatment of acute DVT.

Risks and benefits of femoropopliteal percutaneous balloon angioplasty

PURPOSE The purpose of this study was to evaluate the efficacy of angioplasty in the treatment of femoropopliteal arterial disease. METHODS From 1980 to 1991, 126 angioplasty procedures were performed in 131 limbs of 106 patients with 175 femoropopliteal lesions (26 common femoral, 118 superficial femoral, and 31 popliteal). Critical ischemia was present in 55 limbs (42%), and claudication was present in 76 (58%). Angioplasty was performed for a single lesion in 87 limbs (66%) and for multiple lesions in 44 (34%). In 13 limbs (10%) the most severe lesion was an occlusion; in 118 (90%) all lesions were stenoses. Distal runoff was good (2 or 3 vessels patent) in 72 limbs (55%) and poor (0 or 1 vessel patent) in 59 (45%). RESULTS Death within 30 days occurred in 0.8%, nonfatal systemic morbidity in 7.1%, and local morbidity in 1.6% of procedures. Multivariate analysis revealed that indication and age were predictive of increased morbidity and mortality rates. Immediate success was achieved in 95% of limbs treated. Mean follow-up time was 2.0 years. The overall 5-year cumulative primary patency rate was 45% (+/- 5%). In a proportional hazards model indication and lesion type were predictive (p < 0.01) of long-term failure, with relative risks of 2.0 (1.2 to 3.3) and 2.7 (1.3 to 5.6), respectively. The 5-year primary patency rate after angioplasty for stenoses and claudication was 55% (+/- 7%), for stenoses and critical ischemia it was 29% (+/- 11%), and for occlusions it was 36% (+/- 14%). CONCLUSION These results suggest that femoropopliteal angioplasty is a low-risk procedure with acceptable long-term results in patients with claudication and stenoses.

Thrombolytic therapy of acute pulmonary embolism: Current status and future potential

Recombinant human tissue-type plasminogen activator (rt-PA), a relatively clot-specific fibrinolytic agent, represents a novel and promising approach to thrombolytic therapy of pulmonary embolism. Therefore, the efficacy and safety of peripheral intravenous rt-PA therapy were assessed in 47 patients with angiographically documented pulmonary embolism. The drug regimen was 50 mg over 2 hours followed by repeat angiography and, if necessary, an additional 40 mg over 4 hours. By 6 hours, 44 of the 47 patients had angiographic evidence of clot lysis that was slight (n = 5), moderate (n = 12) or marked (n = 27). Among the 34 patients with pulmonary hypertension before treatment (mean pulmonary artery pressure exceeding 17 mm Hg), the pressure decreased from 43/17 (mean 27) to 31/13 (mean 19) mm Hg (p less than 0.0001). Fibrinogen decreased 33% from baseline at 2 hours and 42% from baseline at 6 hours. There were two major complications that required surgical control of bleeding: hemorrhage from a pelvic tumor and mediastinal tamponade in a patient 8 days after coronary artery bypass surgery. The initial results demonstrate that, among selected patients, peripheral intravenous rt-PA can rapidly and, for the most part, safely lyse pulmonary embolism within 6 hours.

Treatment of fibromuscular dysplasia and renal artery aneurysm with use of a stent-graft.

A Jostent stent-graft was placed in a renal artery with a focal stenosis and an associated aneurysm in a young patient with fibromuscular dysplasia. Arteriographic follow-up at 16 months showed that the stent-graft remained patent and the aneurysm was excluded.

Comparative efficacy of pulse-spray thrombolysis and angioplasty versus surgical salvage procedures for treatment of recurrent occlusion of PTFE dialysis access grafts.

Purpose: To compare the efficacy of surgery versus pulse-spray thrombolysis and angioplasty in patients with recurrent thrombosis of polytetrafluoroethylene (PTFE) dialysis access grafts. Methods: We analyzed 96 consecutive interventions for thrombosed PTFE dialysis access grafts in 18 patients. Primary patency after thrombolysis and angioplasty (n= 25) was compared with primary patency following thrombectomy alone (n= 50) or thrombectomy followed by graft revision (n= 21) using life-table analysis. A Cox proportional hazards model that accounted for graft age and number of previous interventions was used to generate the relative risk for recurrent occlusion following therapy. Results: Life-table analysis showed that patency after thrombolysis and angioplasty was greater than that following thrombectomy alone (p= 0.02). After accounting for the age of the graft and the number of previous interventions (average six per patient), the relative risk for recurrent occlusion [3.0; 95% confidence intervals (CI): 1.5, 6.4] was greater for thrombectomy alone than for thrombolysis/angioplasty [0.6; CI = 0.3, 1.3]. The relative risks of repeat occlusion following thrombolysis/angioplasty [0.6; CI = 0.3, 1.3] and thrombectomy/surgical revision [1.0; CI = 0.5, 1.7] were similar. Conclusion: Outcome data from our retrospective study on recurrent thrombosis of PTFE dialysis access grafts suggest that thrombolysis/angioplasty is superior to thrombectomy alone, and equivalent to thrombectomy/surgical revision.

Thrombolytic Therapy Compared with Mechanical Recanalization in Non-acute Peripheral Arterial Occlusions: A Randomized Trial

PURPOSE To evaluate whether thrombolytic therapy followed by angioplasty has any added benefit compared with angioplasty alone for the treatment of chronic peripheral arterial occlusions. PATIENTS AND METHODS Twenty patients with claudication or limb-threatening ischemia of at least 3 weeks duration due to iliac or femoropopliteal artery occlusions were randomized either to thrombolytic therapy with recombinant tissue-type plasminogen activator for up to 4 hours (n = 11) followed by angioplasty or to angioplasty alone (n = 9). Clinical follow-up was obtained for 1 year. RESULTS Life-table analysis revealed a significant improvement in the cumulative primary patency rate for patients with claudication treated initially with thrombolysis followed by angioplasty (n = 7; 86% at 6 months; 51% at 1 year) compared with angioplasty alone (n = 9; 11% at 6 months and 1 year) (P < .02). All four patients with limb-threatening ischemia were randomized to thrombolytic therapy, and none exhibited continued patency at 1 year. The most common complication in the thrombolysis group was peripheral embolization; three of these four patients were among those who had limb-threatening ischemia as the indication for entry into this study. There was no increased incidence of bleeding with thrombolytic therapy. CONCLUSIONS A short course of thrombolytic therapy prior to angioplasty appears to improve the 1-year patency rate for claudication due to iliac or femoropopliteal occlusions. However, patients with limb-threatening ischemia have a high prevalence of peripheral embolization and dismal patency rates with this form of therapy. A larger scale study is necessary to confirm these findings.