To evaluate the incidence of cardiovascular events in the long-term clinical course of patients with a first episode of symptomatic, objectively confirmed pulmonary embolism.Three hundred and sixty patients with a first episode of pulmonary embolism were included in a prospective study: 209 with idiopathic pulmonary embolism and 151 with pulmonary embolism associated with transient risk factors. The study outcomes were cardiovascular events (recurrent venous thrombo-embolism, acute myocardial infarction, stroke, sudden otherwise unexplained death), cardiovascular death, and death due to any cause. The median follow-up was 38 months. Sixty-four patients had at least one cardiovascular event (5.5% patient-year). Recurrent venous thrombo-embolism occurred in 45 patients (3.9% patient-year), acute myocardial infarction in 12 patients (1.0% patient-year), stroke in six patients (0.5% patient-year), and sudden otherwise unexplained death in four patients (0.3% patient-year). A cardiovascular event occurred in 47 patients with idiopathic pulmonary embolism (7.5% patient-year) and in 17 patients with pulmonary embolism associated with transient risk factors (3.1% patient-year) (RR 2.0; 95% CI 1.20-3.34; P=0.006). Twenty patients with idiopathic pulmonary embolism (3.2% patient-year) and two patients with pulmonary embolism associated with transient risk factors (0.4% patient-year) presented an arterial cardiovascular event (RR 7.2; 95% CI 1.71-30.45; P=0.001). Thirty-three patients died (9.2%). Cardiovascular mortality and cancer mortality accounted for 42.4 and 21.2% of overall mortality, respectively. Idiopathic pulmonary embolism was an independent predictor of cardiovascular events after adjusting for age.Cardiovascular events are more common in patients with idiopathic pulmonary embolism than in patients with pulmonary embolism associated with transient risk factors. Cardiovascular events are the major cause of death in patients with idiopathic pulmonary embolism.
Summary The aim of this study was to evaluate the thrombolytic activity of two hybrid plasminogen activators (HPAs) in a rabbit jugular vein thrombosis model. In the two HPAs the kringle-2 domain (K2tu-PA) or the finger and the kringle-2 domains (FK2tu-PA) of tissue-type plasminogen activator (t-PA) are linked to the catalytic protease domain of single chain urokinase type plasminogen activator (scu-PA). The two HPAs were compared with rt-PA and scu-PA on a weight/weight basis. K2tu-PA, FK2tu-PA, rt-PA and scu-PA were infused at doses of 0.4, 0.8 and 1.2 mg/kg over 3 h. Saline served as control. Saline produced 11 ± 2% thrombolysis. The three doses of K2tu-PA led to 38 ± 4%, 66 ± 5% and 89 ± 7% thrombolysis, respectively; the three doses of FK2tu-PA: 18 ± 3%, 29 ± 5% and 33 ± 6%, respectively; the three doses of rt-PA 32 ± 2%, 49 ± 3% and 68 ± 6%, respectively; the three doses of scu-PA 16 ± 2%, 24 ± 3% and 32 ± 4%, respectively. K2tu-PA and rt-PA showed a statistically significant higher thrombolytic activity than FK2tu-PA and scu-PA at the three tested doses (p <0.01). The thrombolytic activity of K2tu-PA was significantly higher than rt-PA at the two higher doses (p <0.01). Both K2tu-PA and rt-PA produced a statistically significant reduction of fibrinogen, α2-antiplasmin and plasminogen 3 h after the start of the infusions of the two higher doses. No statistically significant differences between K2tu-Pa and rt-PA were observed. Concomitant with the lower thrombolytic activity, the systemic proteolytic effects of FK2tu-PA and scu-PA were less pronounced. We conclude that the two HPAs we tested are effective thrombolytic agents. K2tu-PA deserves particular attention in future experiments.
Anticoagulation therapy with unfractionated heparin, low-molecular-weight heparins and oral vitamin K antagonists is currently the mainstay of treatment and prevention of thromboembolic disorders (such as deep vein thrombosis, pulmonary embolism and stroke prevention in patients with atrial fibrillation). Although these therapies have proven benefits, they also have important limitations that result in their underuse in routine clini- cal practice. Consequently, many patients identified by guidelines as requiring anticoagulant therapy receive no or inadequate treatment. Heparins require parenteral administration and pose the risk of heparin-induced thrombocytopenia. Vitamin K antagonists have a narrow separation of antithrombotic and haemorrhagic effects and numerous food and drug-drug interactions, and require frequent coagulation monitoring and dose adjustment to ensure effective antithrombotic protection while minimizing the risk of bleeding complications. In response to these limitations, several new anticoagulants have recently been developed, including selective factor Xa inhibitors such as fondaparinux and ximelagatran, the first oral agent in the new class of direct thrombin inhibitors and the first new oral anticoagulant for almost 60 years. Ximelagatran possesses many of the properties of an ideal agent for anticoagulation therapy. With its oral formulation, consistent and predictable pharmacological profile and no coagulation monitoring, ximelagatran has the potential to increase the use and duration of anticoagulation treatment in thromboembolic disorders and to reduce the burden associated with long-term management.