Recombinant hirudin (lepirudin) for the improvement of thrombolysis with streptokinase in patients with acute myocardial infarction: results of the HIT-4 trial.

OBJECTIVES: The purpose of this study was to compare recombinant hirudin and heparin as adjuncts to streptokinase thrombolysis in patients with acute myocardial infarction (AMI). BACKGROUND: Experimental studies and previous small clinical trials suggest that specific thrombin inhibition improves early patency rates and clinical outcome in patients treated with streptokinase. METHODS: In a randomized double-blind, multicenter trial, 1,208 patients with AMI < or =6 h were treated with aspirin and streptokinase and randomized to receive recombinant hirudin (lepirudin, i.v. bolus of 0.2 mg/kg, followed by subcutaneous (s.c.) injections of 0.5 mg/kg b.i.d. for 5 to 7 days) or heparin (i.v. placebo bolus, followed by s.c. injections of 12,500 IU b.i.d. for 5 to 7 days). A total of 447 patients were included in the angiographic substudy in which the primary end point, 90-min Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 of the infarct-related artery, was evaluated, while the other two-thirds served as "safety group" in which only clinical end points were evaluated. As an additional efficacy parameter the ST-segment resolution at 90 and 180 min was measured in all patients. RESULTS: TIMI flow grade 3 was observed in 40.7% in the lepirudin and in 33.5% in the heparin group (p = 0.16), respectively. In the entire study population the proportion of patients with complete ST resolution at 90 min (28% vs. 22%, p = 0.05) and at 180 min (52% vs. 48%, p = 0.18) after start of therapy tended to be higher in the lepirudin group. There was no significant difference in the incidence of hemorrhagic stroke (0.2% vs. 0.3%) or total stroke (1.2% vs. 1.5%), reinfarction rate (4.6% vs. 5.1%) and total mortality rate (6.8% vs. 6.4%) at 30 days, as well as the combined end point of death, nonfatal stroke, nonfatal reinfarction, rescue-percutaneous transluminal coronary angioplasty and refractory angina (22.7 vs. 24.3%) were not statistically different between the two groups. CONCLUSIONS: Lepirudin as adjunct to thrombolysis with streptokinase did not significantly improve restoration of blood flow in the infarct vessel as assessed by angiography, but was associated with an accelerated ST resolution. There was no increase in the risk of major bleedings with lepirudin compared to heparin.

The lupus anticoagulant and its role in thrombosis.

The lupus anticoagulant is usually found in the plasma of patients with systemic lupus erythematosus. Lupus anticoagulants are antibodies to phospholipids and probably to phosphodiester-linked phosphate groups. A high frequency of thrombotic events in patients with lupus anticoagulant has been reported. Nevertheless the pathogenesis of thrombosis in these patients remains unknown. Endothelium which plays a key role in the antithrombogenic-thrombogenic balance could be a target for the lupus anticoagulant and alterations of some endothelial-cell functions could be responsible for the thrombotic events. The effects of the lupus anticoagulant on the phospholipids of the protein C-thrombomodulin complex may be important although evidence of such a reaction in vivo is awaited.

Pharmacokinetics of recombinant hirudin in hemodialyzed end-stage renal failure patients.

Recently, hirudin was used for the first time as an anticoagulant during hemodialysis in men. Pharmacokinetic data of this compound in end-stage renal failure are however not available. In this study, the pharmacokinetics of recombinant hirudin (HBW 023) was evaluated in hemodialysis-treated end-stage renal failure patients. HBW 023 was administered as a bolus at the start of a single dialysis (0.02 to 0.08 mg/kg) in 20 patients, and plasma hirudin levels were followed during this and the 5 following dialyses, without additional hirudin administration. The initial dialysis (HD1) was performed with a low flux polysulfone dialyzer, the following dialyses (up to HD6) with a high flux polysulfone dialyzer and regular heparin. Hirudin levels averaged 504.0 +/- 214.0 and 527.7 +/- 217.1 ng/ml in the middle and at the end of HD1, and then gradually decreased to 15.2 +/- 15.2 ng/ml at the end of HD6. Pharmacokinetic data were compared to those obtained in healthy controls (n = 5), receiving the same dose, and reaching the same peak hirudin level. Hirudin half-life was > 30 times longer in hemodialysis patients (51.8 +/- 15.6 vs. 1.7 +/- 1.5 h, p < 0.001), whereas area under the curve was > 60 times higher (34,669 +/- 14,898 vs. 545 +/- 205 ng/ml x h, p < 0.001). Distribution volume was lower in hemodialysis patients (11.0 +/- 3.1 vs. 14.1 +/- 2.01, p < 0.05). Hirudin disappearance rate was the same during high flux polysulfone dialysis as during interdialytic periods. Hirudin removal was markedly higher in those patients still maintaining some residual renal function and parameters of hirudin removal were significantly correlated to residual creatinine clearance. It is concluded that hirudin removal from the body is markedly depressed in hemodialyzed end-stage renal failure patients and that even minor residual renal function may increase this removal rate.

A pilot study of subcutaneous recombinant hirudin (HBW 023) in the treatment of deep vein thrombosis.

BACKGROUND: Recombinant hirudin, a pure, specific antithrombin could be more effective than heparin in the treatment of deep vein thrombosis, but its short half-life requires constant intravenous infusion, whereas subcutaneous administration of recombinant hirudin can ensure stable and prolonged plasma levels. The aim of our study was to assess the pharmacokinetics, the results on the coagulation variables, and the safety of a recombinant hirudin (HBW 023) administered subcutaneously in patients suffering from deep vein thrombosis. METHODS: Recombinant hirudin (HBW 023) was administered subcutaneously to 10 patients with recent deep vein thrombosis, at a dose of 0.75 mg/kg of body weight twice daily for 5 days, after which standard heparin and acenocoumarol were introduced. Bilateral lower limb venography, and pulmonary angiography, and/or ventilation-perfusion lung scan were carried out on day 1 prior to recombinant hirudin injection and repeated on day 5. aPTT and recombinant hirudin plasma levels were serially assessed after the 1st and the 10th injections. Prothrombin fragments 1 + 2, thrombin-antithrombin III complexes, fibrin degradation products were collected on days 1 and 5. RESULTS: Clinical evolution was uneventful in all but one patient who had a probable recurrence of pulmonary embolism on day 4. No hemorrhagic complication, no untoward biological event was observed. On days 5, Marder score was unchanged or had decreased. Plasma levels of recombinant hirudin peaked in between 3 and 4 h following the injection. aPTT values paralleled, and were significantly correlated with plasma levels of recombinant hirudin on day 1 as well on day 5 (r = 0.903, r = 0.948 respectively). Fragment 1 + 2, and thrombin antithrombin complexes non-significantly decreased from day 1 to day 5. CONCLUSIONS: Subcutaneous administration of recombinant hirudin ensures prolonged stable plasma levels of recombinant hirudin which results in efficient anticoagulation. A dose-ranging study conducted with subcutaneous recombinant hirudin in comparison to conventional heparin therapy may answer the question as to efficacy.

Subcutaneous recombinant hirudin (HBW 023) versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legs: a multicentre prospective dose-ranging randomized trial. International Multicentre Hirudin Study Group.

The aim of this multicentre, prospective, randomised, dose-ranging study was to compare the safety and efficacy of subcutaneous recombinant hirudin (HBW 023) against intravenous sodium heparin in acute lower limb deep venous thrombosis (DVT). Patients were randomized to treatment with either HBW 023 or heparin for 5 +/- 1 days. HBW 023 was given according to body-weight in three dose groups. Thromboembolic disease was assessed by phlebography and ventilation/perfusion (V/Q) scanning on Day 1 and Day 5 +/- 1. One hundred and fifty-five patients were enrolled, of these 121 were evaluable for efficacy analysis. Significantly fewer patients on HBW 023 developed new V/Q abnormalities during the treatment period, (p = 0.006). There was no difference between the groups in thrombus extension or regression, major bleeding complications or serious adverse events. There were significantly fewer findings of new V/Q mismatch after treatment with HBW 023, and anticoagulant control was superior in these patients.

[Subcutaneous recombinant hirudin in the treatment of deep venous thrombosis. A pharmacokinetic study]. / Hirudine recombinée par voie sous-cutanée dans le traitement de la thrombose veineuse profonde constituée. Etude pharmacocinétique.

Recombinant hirudin (HBW 023) has a pure and specific antithrombotic activity. It could be more effective than heparin in the treatment of deep venous thrombosis. Its half life is about three hours when administered intravenously which requires continuous infusion whereas subcutaneous administration can ensure stable plasma concentrations and antithrombotic activity over a period of approximatively 12 hours. The aim of the study was to check the safety and clinical and radiographic efficacy of recombinant hirudin administered subcutaneously to patients with recent deep venous thrombosis and to analyse the pharmacokinetics of the product and its effects on tests of coagulation. Ten patients were treated with 0.75 mg/kg of subcutaneous recombinant hirudin twice a day for 5 days. Anticoagulation was performed with standard heparin and acenocoumarol. Bilateral phlebography, pulmonary angiography or ventilation and perfusion scintigraphy were carried out before and on the 5th day of recombinant hirudin treatment. The activated cephalin time and standard anticoagulant tests and the plasma kinetics of recombinant hirudin were assayed between the 1st and 12th hour on the first and fifth days of treatment. The clinical course was simple in all but one patient who had a recurrence of pulmonary embolism on the 4th day justifying thrombolytic treatment. No haemorrhagic complications or secondary biological effects were observed. On the 5th day, control phlebography was unchanged or improved in all patients. The peak plasma concentration of recombinant hirudin was observed between the 3rd and the 4th hour following subcutaneous injection. The activated cephalin time was increased in parallel with increased concentrations of recombinant hirudin.(ABSTRACT TRUNCATED AT 250 WORDS)

[Refludan. First line of treatment for type II heparin-induced thrombopenia]. / Refludan. Le premier traitement de la thrombopénie induite par l'héparine (TIH) de type II.

OBJECTIVES: To assess morbidity and mortality in patients treated with Refludan for heparin-induced thrombocytopenia type II in comparison with controls. PATIENTS AND METHODS: One hundred thirteen patients with heparin-induced thrombocytopenia were treated with Refludan in two studies, HAT1 and HAT2. Clinical outcome was assessed in a meta analysis and compared to results in 91 control patients from a former series. Patients with no associated thrombolytic treatment were given an intravenous bolus injection of Refludan (0.4 mg/kg) then a continuous infusion of Refuldan (0.15 mg/kg/h). When a thrombolytic treatment was associated, patient were given a 0.2 mg/kg) bolus followed by a 0.10 mg/kg/h infusion. RESULTS: The rate of thromboembolism complications, amputations and death was significantly lower in patients treated with Refludan than in controls. There was a clinically acceptable increase in episodes of bleeding with Refludan. The benefit/risk ratio was optimum for APTT between 1.5 and 3.

[Course of the manifestations associated with the antiprothrombinase circulating anticoagulant]. / Evolution des manifestations associées à l'anticoagulant circulant antiprothrombinase.

Fifteen patients (9 females and 6 males) with the "lupus type" circulating anticoagulant have been studied. The underlying disease was an auto-immune disorder in 11 cases and a malignant hemopathy in 4 cases. The manifestations frequently associated with the lupus inhibitor, such as thrombosis, thrombocytopenia and false-positive VDRL test were analysed. Hemorrhagic syndrome occurred only when thrombocytopenia or acquired abnormality of Willebrand's factor was present. Thrombotic events (8 cases) were frequent. Deep venous thrombosis was complicated with pulmonary embolism in 4 patients. Platelet abnormality, decreased fibrinolytic response or acquired Willebrand's syndrome were found in all patients with a thrombotic event. These different manifestations followed diverging courses in some patients with persistent thrombocytopenia although the anticoagulant had disappeared in 3 cases, negativation of the false-positive VDRL test while the anticoagulant remained unchanged in 1 case, occurrence of a thromboembolic episode although the anticoagulant had disappeared in 1 case.

[The promises of new antithrombotic agents]. / Les promesses des nouveaux antithrombotiques.

Most new antithrombotic drug development projects are focused on the improvement of myocardial infarction treatment at the acute phase. New thrombolytic drugs do not seem to be as attractive as adjunctive therapy, such as antiplatelet and antithrombotic agents, as well as inhibitors of thrombin generation. The current tendency is to select very specific molecules. The difficulty in developing these drugs must not be underestimated: they will be compared to very active drugs, such as aspirin, heparin or streptokinase; the therapeutic margin of antithrombotic therapy is very narrow; a clinical benefit will have to be shown.

Impact of adalimumab treatment on health-related quality of life and other patient-reported outcomes: results from a 16-week randomized controlled trial in patients with moderate to severe plaque psoriasis.

BACKGROUND: Health-related quality of life (HRQOL) and other patient-reported outcomes (PROs) are important in evaluating the impact of psoriasis and its treatment. OBJECTIVES: To assess the impact of adalimumab treatment on HRQOL and other PROs in patients with moderate to severe psoriasis. METHODS: A 16-week, double-blind, double-dummy, randomized controlled trial evaluated the efficacy and safety of adalimumab in 271 adults with moderate to severe chronic plaque psoriasis. Patients were randomized in a 2:2:1 ratio to adalimumab, methotrexate (MTX) or placebo. PROs were evaluated throughout the study and included the Dermatology Life Quality Index (DLQI), Patient's Global Assessment of disease severity, plaque psoriasis and psoriatic arthritis pain visual analogue scale (VAS), Psoriasis-Related Pruritus Assessment and EuroQOL 5D (EQ-5D). RESULTS: Statistically significant differences were observed between the adalimumab- and placebo-treated and the MTX-treated groups on mean DLQI total scores during the 16-week double-blind study (both P<0.001). Significant differences, favouring adalimumab compared with placebo, were also observed on the Patient's Global Assessment of disease severity (P<0.001), VAS for pain (P<0.001), Psoriasis-Related Pruritus Assessment (P<0.001), EQ-5D VAS (P<0.001) and EQ-5D index score (P<0.01). Compared with MTX, adalimumab resulted in statistically significantly greater improvements in the Patient's Global Assessment of disease severity (P<0.001), the VAS for pain (P<0.01) and the Psoriasis-Related Pruritus Assessment (P<0.001). CONCLUSIONS: Adalimumab was efficacious in improving dermatology-specific HRQOL, disease control and symptom outcomes in patients with moderate to severe psoriasis.

Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION).

BACKGROUND: Biologic therapies such as adalimumab, a tumour necrosis factor antagonist, are safe and effective in the treatment of moderate to severe chronic plaque psoriasis. OBJECTIVES: To compare a biologic agent with methotrexate, a traditional systemic agent, to define clearly the role of biologics in psoriasis. METHODS: Patients with moderate to severe plaque psoriasis were randomized to adalimumab (80 mg subcutaneously at week 0, then 40 mg every other week, n=108), methotrexate (7.5 mg orally, increased as needed and as tolerated to 25 mg weekly; n=110) or placebo (n=53) for 16 weeks. The primary efficacy endpoint was the proportion of patients achieving at least a 75% improvement in the Psoriasis Area and Severity Index (PASI 75) after 16 weeks. Safety was assessed at all visits through week 16. RESULTS: After 16 weeks, 79.6% of adalimumab-treated patients achieved PASI 75, compared with 35.5% for methotrexate (P<0.001 vs. adalimumab) and 18.9% for placebo (P<0.001 vs. adalimumab). Statistically significantly more adalimumab-treated patients (16.7%) than methotrexate-treated patients (7.3%) or placebo-treated patients (1.9%) achieved complete clearance of disease. The response to adalimumab was rapid, with a 57% improvement in mean PASI observed at week 4. Adverse events were similar across treatment groups. Adverse events leading to study discontinuation were greatest in the methotrexate group, primarily because of hepatic-related adverse events. CONCLUSIONS: After 16 weeks, adalimumab demonstrated significantly superior efficacy and more rapid improvements in psoriasis compared with either methotrexate or placebo.

[Angiogenic factors]. / Les facteurs angiogéniques.

Angiogenesis is an important step in tumor growth. From tumor angiogenic factor (TAF) to angiogenin, 14 years of research led to purification, sequencing and cloning of a strong tumor angiogenic factor. Tumor angiogenesis can be inhibited by a cartilage factor, by protamine or by heparin plus cortisone. Heparin by its interactions with the growth factor has an interesting pharmacological role in the angiogenesis phenomenon. Its effect on the growth of vascular cells (endothelial cells, smooth muscle cells, fibroblasts) seems promising.

Human platelet-tumor cell interactions vary with the tumor cell lines.

Platelets may promote the development of metastasis, and tumor cells that aggregate platelets are believed to be more malignant. We studied three different human mammary carcinoma cell lines, which had different interactions with human platelet-rich plasma (PRP). The MCF-7 and the T47-D cell lines induced an adenosine diphosphate (ADP)-mediated platelet aggregation. The third cell line, MDA-MB 231 did not induce any platelet aggregation. On the contrary, this cell line inhibited ADP- and arachidonic acid-induced platelet aggregation. This inhibiting activity is mainly adenosine-mediated. The mechanism by which platelets may contribute to the dissemination of cancer could be related to platelet growth factors. MCF-7 and T47-D cell lines induced a release of platelet-derived growth factor (PDGF). On the contrary, the MDA-MB 231 cell line did not induce any platelet release. The role of these platelet growth factors in tumor cell growth is discussed.

Recombinant hirudin: a specific thrombin inhibiting anticoagulant for hemodialysis.

The first experience with hirudin as an alternative anticoagulant for heparin in hemodialysis is reported. Recombinant hirudin (HBW 023) was administered in 20 patients as a bolus before dialysis with low flux polysulfone dialyzers (PS400), the dosage being adapted stepwise from patient to patient by 0.02 mg/kg to the occurrence of clotting or bleeding. Four different administration schedules were studied. The first three schedules (0.02 mg/kg, N = 1; 0.04 mg/kg, N = 1; 0.06 mg/kg, N = 4) were discontinued because of clotting. The 0.08 mg/kg schedule was maintained without clotting event in 14 patients. Bleeding was not observed. Plasma hirudin averaged 503.9 +/- 214.0 and 527.7 +/- 217.1 ng/ml after two and four hours of dialysis, and decreased during an interdialytic interval of 44 hours to 223.2 +/- 86.2 ng/ml. Modified antithrombin III (P < 0.05) and activated partial thromboplastin times were lower (P < 0.01) under hirudin compared to heparin; these coagulation parameters were closer to normal during hirudin treatment. The patients developing clotting could be distinguished from those without clotting by the registration of the activated clotting times (9.2 +/- 3.0 vs. 18.7 +/- 3.2 min after 2 hr, P < 0.01; 8.1 +/- 3.0 vs. 16.2 +/- 3.8 min after 4 hr of dialysis, P < 0.05); cut-off value below which clotting is to be expected was 12 min). It is concluded that administration of hirudin as a bolus before the start of dialysis, at a dosage of 0.08 mg/kg, is not complicated by clotting or by bleeding. Coagulation tendency can optimally be monitored by the registration of the activated clotting time.(ABSTRACT TRUNCATED AT 250 WORDS)

Recombinant hirudin (HBW 023): biological data of ten patients with severe venous thrombo-embolism.

This study reports on the biological data of ten patients with acute venous thrombo-embolism. They were treated for 5 days with continuous intravenous infusion of a fixed dose (0.05 mg/kg/hr) of a recombinant hirudin (r-H HBW 023 Behringwerke, Germany). The plasma level of r-H (HBW 023), assessed by an anti-factor IIa amidolytic activity, was stable after Day 2 and showed considerable individual variations. It correlated with APTT ratio, suggesting that this test is a reliable tool to monitor therapy. In contrast, thrombin time was constantly over 120 sec (control 15 sec) and consequently was not a useful parameter. Prothrombin time showed a slight, but significant, prolongation, which was correlated with the increase of APTT ratio. There was no bleeding time prolongation, platelet count, or ATIII level decrease. Levels of thrombin-antithrombin III complexes, and D-dimers, which were high in all patients on admission, decreased during the course of the treatment but remained abnormal on Day 5, showing an ongoing hemostasis and fibrinolysis activation: this is consistent with the delayed, but only slightly decreased thrombin generation evidenced by thrombin generation test performed on Day 3. These results suggest that thrombin inhibition by rH-hirudin at this dosage is only partial, which allows the generation of traces of thrombin needed for the feed-back thrombin production generated by factor V and VIII activation.