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Background: Normal D-dimer levels after withdrawal of anticoagulant therapy are associated with a reduced risk for recurrence in patients with unprovoked venous thromboembolism (VTE) and may justify stopping treatment., Objective: To determine whether patients with a first unprovoked VTE and negative D-dimer test result who stop anticoagulant therapy have a low risk for recurrence., Design: Prospective management study with blinded outcome assessment. (ClinicalTrials.gov: NCT00720915)., Setting: 13 university-affiliated clinical centers., Patients: 410 adults aged 75 years or younger with a first unprovoked proximal deep venous thrombosis or pulmonary embolism who had completed 3 to 7 months of anticoagulant therapy., Intervention: Anticoagulant therapy was stopped if D-dimer test results were negative and was not restarted if results were still negative after 1 month., Measurements: Recurrent VTE during an average follow-up of 2.2 years., Results: In 319 patients (78%) who had 2 negative D-dimer results and did not restart anticoagulant therapy, rates of recurrent VTE were 6.7% (95% CI, 4.8% to 9.0%) per patient-year overall (42 of 319), 9.7% (CI, 6.7% to 13.7%) per patient-year in men (33 of 180), 5.4% (CI, 2.5% to 10.2%) per patient-year in women with VTE not associated with estrogen therapy (9 of 81), and 0.0% (CI, 0.0% to 3.0%) per patient-year in women with VTE associated with estrogen therapy (0 of 58) (P = 0.001 for the 3-group comparison)., Limitations: Imprecision in female subgroups. Results may not be generalizable to different D-dimer assays from the one used in the study., Conclusion: The risk for recurrence in patients with a first unprovoked VTE who have negative D-dimer results is not low enough to justify stopping anticoagulant therapy in men but may be low enough to justify stopping therapy in women., Primary Funding Source: Canadian Institutes of Health Research.

Pulmonary embolism is a common, yet often unsuspected and unrecognised disease associated with a high mortality. New, objective, "user friendly" and cost effective diagnostic strategies are being explored. D-dimers, the fibrinolytic degradation products of crosslinked fibrin, have emerged as the most useful of the procoagulant activity and ongoing fibrinolysis markers. D-dimer measurements are very sensitive in excluding a diagnosis of pulmonary embolism in the setting of normal values, a low clinical suspicion, and non-diagnostic lung scans. Several assays have been developed and are reviewed.

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.

Pulmonary embolism is diagnosed over 100,000 times yearly in the United States and is the recognized primary cause of death in at least 10,000 cases. Thrombolytic therapy has been successful in reducing clot burden substantially; however, clinical data are lacking to indicate that thrombolytic therapy improves mortality rates in patients with pulmonary emboli or that the pharmacologic removal of clot will improve future quality of life. The use of thrombolytic agents has been limited by the potential for producing hemorrhagic complications. This paper discusses the pharmacology of numerous thrombolytic agents and their clinical use in research studies intended to determine the safest and most efficacious regimens. Recombinant t-PA infusions appear quite safe and produce very rapid lyses of pulmonary emboli. Innovative administration regimens of urokinase also appear promising. The availability of extremely safe and efficacious treatment regimens should allow for large epidemiologic studies to be conducted to determine whether thrombolytic therapy will improve the morbidity and mortality of pulmonary embolism.

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.

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.

Pulmonary embolism is diagnosed 120,000 times yearly in the United States and contributes to 30,000 deaths. This probably represents an underestimate of incidence because massive acute pulmonary embolism may often result in rapid and therefore unexplained death in the absence of autopsy confirmation. The innovative and judicious use of thrombolytic agents by emergency department and paramedical ambulance personnel may lead to a decreased mortality for this disease. Clinical studies are necessary to determine if the cardiopulmonary compromise associated with massive pulmonary embolism can be rapidly reversed through thrombolysis and whether that reversal will lead to increased survival. The use of thrombolytic agents will gain favor only if their risk:benefit and cost:benefit ratios are acceptable. We discuss the results of using first- and second-generation thrombolytic agents in the treatment of pulmonary embolism and review the encouraging data that have emerged from our studies with recombinant tissue-type plasminogen activator (tPA). This agent has relative fibrin specificity and may provide therapeutic advantages over the conventional thrombolytic agents, urokinase and streptokinase, particularly when the latter are administered in the currently recommended dose schedules for treatment of pulmonary embolism.

We assessed the efficacy and safety of peripheral intravenous recombinant human tissue-type plasminogen activator (rt-PA) in 47 patients with angiographically documented pulmonary embolism (PE). We administered 50 mg/2 h and, if necessary, an additional 40 mg/4 h. By 6 hours, 94% of the patients had angiographic evidence of clot lysis that was slight in 5, moderate in 12, and marked in 27 patients. Among the 34 patients with pulmonary hypertension prior to treatment, average pulmonary artery pressure decreased from 43/17 (27) to 31/13 (19) mm Hg (P less than 0.0001). The average lung scan perfusion defect decreased from 37% before therapy to 16% (P less than 0.01) after therapy among the 19 patients who had pre- and post-treatment lung scans. Of 7 patients with pre- and post-treatment imaging and Doppler echocardiograms, hypokinetic right ventricular wall movement (mild in 1, moderate in 2, and severe in 4) normalized in 5 and improved to mild hypokinesis in 2. Right ventricular diameter decreased from 3.9 +/- 1.0 to 2.0 +/- 0.5 cm (P less than 0.005). Fibrinogen decreased 33% from baseline at 2 h and 42% from baseline at 6 h. However, patients with the greatest degree of angiographic clot lysis at 2 h had a preponderance of fibrinogenolysis over fibrinolysis, demonstrated by a lower ratio of cross-linked fibrin degradation products to fibrin(ogen) degradation products (0.14 +/- 0.09 vs. 0.54 +/- 0.82) (P less than 0.04). Among selected patients, peripheral intravenous rt-PA is associated with rapid lysis of PE, improved pulmonary perfusion, and improved right ventricular function.

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.