Thromboxane Antagonism with terutroban in Peripheral Arterial Disease: the TAIPAD study.

BACKGROUND: Terutroban is a selective prostaglandin endoperoxide (TP) receptor antagonist with antithrombotic, antivasoconstrictive and antiatherosclerotic properties and is currently in development for long-term cardiovascular secondary prevention. OBJECTIVES: TAIPAD is an international, double-blind, randomized controlled study comparing the effects of five dosages of oral terutroban vs. aspirin and placebo on platelet aggregation in peripheral arterial disease (PAD) patients. PATIENTS/METHODS: After 10 day's placebo run-in, included patients (n = 435; ankle-brachial pressure index, 0.7 ± 0.1) were randomly allocated to aspirin 75 mg day(-1), terutroban 1, 2.5, 5, 10 or 30 mg day(-1) or placebo. On day 5, the placebo group was reallocated to one of the terutroban groups for the rest of the study (day 83). Ex vivo platelet aggregation induced by the thromboxane analog U46619 (7 µm) was measured 24 h after dosing, as well as platelet aggregation induced by arachidonic acid (AA), collagen and ADP. RESULTS: Terutroban dose-dependently inhibited U46619-induced platelet aggregation at days 5 and 83. At day 5, the inhibition was significant vs. placebo for all terutroban dosages (P < 0.001). Terutroban (5, 10 and 30 mg day(-1)) was at least as effective as aspirin in inhibiting platelet aggregation induced by arachidonic acid (AA), collagen and adenosine diphosphate (ADP). Terutroban was well tolerated, with a safety profile similar to aspirin. CONCLUSIONS: In PAD patients, terutroban dose-dependently inhibited platelet aggregation 24 h after dosing, and was at least as effective as aspirin at 5, 10 and 30 mg day(-1). Terutroban was well tolerated.

[Endovascular repair of a tuberculous aortic false aneurysm]. / Traitement par voie endovasculaire d'un faux anévrisme tuberculeux de l'isthme aortique.

INTRODUCTION: Aortic aneurysms are a well known but rare complication of tuberculosis. Their major complication is aneurysmal rupture, unforeseeable and lethal. EXEGESIS: Chest pain and hemoptoic expectoration revealed a false aneurysm of the aortic isthmus in a 48-year-old man. Endovascular repair with a stent graft was urgently undertaken. Tuberculosis was diagnosed 6 weeks thereafter by the growth of gastric juice cultures and medically treated. Most tuberculous aortic aneurysms are false aneurysms, caused by an adjacent tuberculous focus eroding the aortic wall. They present with pain, bleeding or as para-aortic masses. CONCLUSION: Tuberculous false aneurysms of the aorta necessitate an early intervention before they rupture. Surgical treatment remains the preferred option but endovascular repair with a stent graft is a therapeutic alternative, to be considered in high-risk surgical patients.

Thromboangiitis obliterans or Buerger's disease: challenges for the rheumatologist.

Thromboangiitis obliterans (Buerger's disease)--a type of vasculitis in young, mostly male subjects--remains strangely linked to smoking, which determines its occurrence, progression and prognosis by currently unknown mechanisms. It affects the small and medium-sized arteries and veins of the limbs. Despite the usual absence of systemic signs and symptoms, initially intermittent arthritis, even if not observed in all cases, confer on this disease the status of a systemic vasculitis. Diagnosis requires the elimination of many other diseases. The severity of the disease lies in the need for amputation in more than a quarter of all patients. Complete cessation of smoking remains the cornerstone of therapy. Local care is the second essential element of treatment. Prostacycline analogues can be used to help the patient through critical ischaemia. Blockade with antagonists of cannabinoid or endothelin receptors and the use of gene- or cell-based therapy to induce therapeutic angiogenesis have opened up new possibilities for treatment.

Effectiveness of written guidelines on the appropriateness of thromboprophylaxis prescriptions for medical patients: a prospective randomized study.

OBJECTIVE: To assess the effectiveness of providing doctors with written thromboprophylaxis prescription aids based on current recommendations. DESIGN: A prospective trial of specific anticoagulant prescription forms: a 1-day survey before and after the intervention in each centre. SETTING: 30 Internal Medicine departments of Assistance Publique-Hôpitaux de Paris. SUBJECTS: All inpatients were included, except those who were either admitted or discharged on the day of the survey, and those receiving curative anticoagulant treatment. INTERVENTIONS: The study included three parts: (i) a 1-day baseline survey; (ii) over the following 3-month period, departments were randomized into two groups: all practitioners in wards allocated to the intervention group were required to systematically use specific anticoagulant prescription forms, whilst doctors in the control group continued prescribing according to their usual practices and (iii) a 1-day postintervention survey. MAIN OUTCOME MEASURE: The proportion of prescriptions in accordance with the recommendations. RESULTS: 1,469 patients were included. The intervention produced a significant reduction in the frequency of over-prescriptions, from 25% to 14% of the patients who did not meet the guideline criteria (adjusted OR: 0.3; 95% CI: 0.1-0.8). Using specific forms did not improve under-prescription of anticoagulants. A little over 60% of the patients who met guideline criteria for thromboprophylaxis were prescribed anticoagulants in both intervention and control wards, either at baseline or after intervention. CONCLUSIONS: Multitargeted interventions using a variety of means and strategies should still be considered to improve prescriptions that may have a significant impact on health expenses and, most importantly, on patients outcomes.

The specific thromboxane receptor antagonist S18886: pharmacokinetic and pharmacodynamic studies.

OBJECTIVES AND PATIENTS: We conducted a multicenter double-blind pharmacokinetic/pharmacodynamic (PK/PD) study of the new oral thromboxane receptor antagonist S18886 in 30 patients with peripheral artery disease, who were randomized to receive five different oral dosages of S18886 (1, 2.5, 5, 10 or 30 mg) for 12 weeks (83 days). Primary objective was to determine the effect of S18886 on platelet aggregation ex vivo. RESULTS: Pharmacokinetics of S18886 was linear, with peak plasma levels being reached between 30 min and 2 h and a terminal half-life of 5.8-10 h. No significant accumulation of S18886 in plasma was observed after repeated dosing. The relationship between the S18886 concentration and platelet inhibition was examined in terms of U46619-induced platelet aggregation. Over the range of doses studied, there was a predictable relation between the plasma drug concentration and the degree of platelet inhibition at each dose. Maximal inhibition of U46619-induced platelet aggregation was achieved within 1 h with all oral doses of S18886, and this effect was maintained for at least 12 h. The PK/PD relationship was direct, and U46619-induced platelet aggregation was strongly inhibited by S18886 plasma concentrations above 10 ng mL(-1). This concentration was thus the minimal effective antiplatelet level in this population, and was maintained only by the dosages of 10 and 30 mg. The safety profile of S18886 was excellent, whatever the unit dose, with no attributable adverse events. CONCLUSION: The results of this study, which included modeling and simulation, help identify the minimal effective plasma concentration of S18886 required for potent antiplatelet efficacy in patients with stable peripheral arterial disease.

The factor II G20210A gene polymorphism, but not factor V Arg506Gln, is associated with peripheral arterial disease: results of a case-control study.

BACKGROUND: The FIIG20210A polymorphism has been associated with arterial wall thickness and atherothrombotic diseases in selected subgroups. The FVArg506Gln polymorphism does not seem to be associated with arterial diseases. Few data are available on these polymorphisms and the risk of peripheral arterial disease (PAD). OBJECTIVES: To study the association between the FIIG20210A and FVArg506Gln polymorphisms and PAD and its clinical severity. To examine the potential interactions with traditional vascular risk factors. PATIENTS AND METHODS: We studied 184 consecutive male patients under 70 years of age with symptomatic PAD and 330 age-matched male controls free of symptomatic PAD and with no cardiovascular history. We evaluated the FIIG20210A and FVArg506Gln polymorphisms in all subjects. RESULTS: Mean age was 57.1 +/- 7.2 years (cases) and 56.7 +/- 7.6 years (controls). The FII20210A allele was more frequent in PAD patients with odds ratios (OR) of 3.77 (1.39-10.2) in univariate analysis and 4.30 (1.3-14.7) after adjustment for diabetes, smoking, hypertension and hypercholesterolemia. In smokers or past smokers the magnitude of the association was markedly increased but there was no evidence of an interaction between tobacco exposure and FIIG20210A. In case subjects, the FII20210A allele was also associated with critical ischemia [OR = 4.1 (1.1-15.7), P = 0.039 in multivariate analysis]. FVArg506Gln was not associated with PAD [OR = 0.65 (0.27-1.54) and 0.77 (0.28-2.1) in univariate and multivariate analyses, respectively]. CONCLUSIONS: The FIIG20210A gene polymorphism may be a risk factor for PAD and its severity. In contrast, the FVArg506Gln polymorphism is not associated with PAD.

[Microvascular involvement in pseudoxanthoma elasticum. Capillaroscopic findings]. / Microangiopathie du pseudoxanthome élastique. Aspects capillaroscopiques.

OBJECTIVE: The aim of this study was to describe, for the first time, the capillary angio-architecture during pseudoxanthoma elasticum, a rare genetic disease related to mutations in the ABCC6 gene, of which the systemic calcifying involvement is responsible notably for very severe cardiovascular complications. Method Seven patients suffering from clinically and histologically documented confirmed pseudoxanthoma elasticum were examined with capillaroscopy, the absence of concomitant connective tIssue disease or diabetes having been checked beforehand. RESULTS: All the patients exhibited a microangiopathy, characterised by normal capillary density, frequent pericapillary oedema, excessively coiled fibres with a significantly increased number of minor dystrophies and, to varying degrees, a slowing down of capillary blood flow demonstrated by a sludge phenomenon. CONCLUSION: This descriptive study shows that a microangiopathy exists during pseudoxanthoma elasticum. However, the latter is not specific and a double blind controlled study is required to confirm these results. The discovery of genotype/phenotype correlations in this disease would provide a place for capillaroscopy in the diagnostic strategy in young patients or in the assessment of the cardiovascular involvement.

Incidence and prognosis of cancer associated with bilateral venous thrombosis: a prospective study of 103 patients.

BACKGROUND: A strong association between bilateral deep vein thrombosis (DVT) and cancer had been found in one retrospective study. To confirm this finding, consecutive patients with an objective diagnosis of bilateral DVT were followed over 12 months. PATIENTS AND METHODS: One-hundred and three patients, hospitalized for bilateral DVT, were included in the study. Twenty-six patients (25.2%) were already known to have a cancer, 26 (25.2%) had a previous history of venous thromboembolic disease, 44 (42.7%) had a symptomatic pulmonary embolism. The patients were scheduled to be prospectively followed up at 3, 6 and 12 months as outpatients. Information on recurrence, evidence of a new overt cancer and the cause of death were recorded for all patients. RESULTS: A new cancer was diagnosed in 20 (26%) of the 77 patients without known cancer at admission. The risk of cancer was significantly more important in idiopathic thrombosis than in patients with secondary thrombosis (40.5% vs. 12.5%; odds ratio 4.8, 95% confidence interval 1.4, 18.8). Seventy percent of the cancers discovered had already spread. Age, gender, presence of pulmonary embolism, recurrence and location of the thrombosis were not statistically associated with the risk of cancer. The 1-year survival rates of patients with a previously known cancer and patients with a newly discovered cancer were, respectively, 26% and 35% (P = 0.33). CONCLUSIONS: Bilateral DVT is a significant risk indicator of malignancy. Cancer is present in 45% of patients with bilateral DVT and is associated with a poor prognosis.

[New anticoagulants in the treatment of venous thrombo-embolic disease]. / Les nouveaux anticoagulants dans la maladie thromboembolique veineuse.

OBJECTIVE: Treatment of deep venous thrombosis is founded on the association of low molecular heparins and oral anticoagulants for 3-6 months. In spite of their uncontested efficacy, these therapeutics bring an hemorrhagic risk and the need of regular laboratory controls for the whole duration of the treatment. The clinical need to extend the indications of anticoagulants have made necessary the development of new antithrombotic treatments. NEW FEATURES: Two new molecules, fondaparinux and ximelagatran, have been recently developed and are, at present, in very advanced phase of clinical research. Already published phase III studies on venous thromboembolism (VTE) prophylaxis show the efficacy of these new molecules towards this indication. The results of phase III study in patients with acute VTE have not been published yet. PROJECTS AND PERSPECTIVES: The new anticoagulant molecules fondaparinux and ximelagatran could open the way to new therapeutic possibilities that could simplify the managing of patients under anticoagulant treatment.

[Subintimal angioplasty. Technique, results and role in the treatment of peripheral arterial occlusive disease]. / La recanalisation sous-intimale. Technique, résultats et place actuelle dans la stratégie de prise en charge de l'artériopathie des membres inférieurs.

Subintimal angioplasty consists in entering the subintimal space proximal to the occlusion, traversing the occlusion creating by angioplasty a subintimal channel exiting downstream in the natural lumen. Major complications rarely occur but compromising important collaterals or run-off vessels may be very deleterious. Subintimal angioplasty is indicated in patients with critical limb ischemia, unfit for anesthesia or in the absence of a suitable venous conduit. This technique is mainly effective in long and tibioperoneal occlusions, a location in which transluminal angioplasty usually fails. Further studies are required to determine the modalities of associated anti-thrombotic treatment and if subintimal angioplasty can be used as primary treatment in critical leg ischemia.

Follow-up electron beam CT for the management of early phase Takayasu arteritis.

PURPOSE: The purpose of this work was to assess typical findings of Takayasu arteritis on serial CT examinations following therapy. METHOD: Serial CT studies were performed on 16 patients with early phase Takayasu arteritis. Mural or luminal changes of the aorta on successive CT scans were compared with clinical data. RESULTS: Vascular lesions progressed during follow-up in 6 of 16 patients. In one patient, progression of lesions was symptomatic. In the other five of six patients with worsening lesions, vascular progression occurred without new clinical symptoms and was first identified on CT scans. One of these five had dilatation of the ascending aorta and required aortic repair. Four others had progression of stenotic vascular lesions leading to changes in medical treatment only or in combination with either surgery or angioplasty. For two of them, CT examinations showed decreased mural lesions after changes in medical treatment. CONCLUSION: CT examinations performed in treated patients with Takayasu arteritis demonstrate either regression, stabilization, or progression of vascular lesions. Serial CT examinations may thus be useful for evaluating response to treatment.

[Value of helical CT in Takayasu arteritis]. / Apport du scanner hélicoïdal dans la maladie de Takayasu.

In the past, the diagnosis and course of Takayasu arteritis were monitored by following angiographic findings, in addition to clinical symptoms and biological tests. More recently, cross-sectional imaging techniques especially Computed Tomography (CT) depicted mural changes in aorta and main vessels in this disease. Within the same acquisition, spiral mode also allows to show luminal changes, similarly to conventional angiography. In addition to its diagnostic value especially in the early phase of the disease, CT seems accurate in the follow-up of treated patients and may be proposed as a therapeutic guide. CT features are presented, according to the stage of the disease and the vessels involved.

Factors V leiden and II 20210A in patients with symptomatic pulmonary embolism and deep vein thrombosis.

PURPOSE: Factor V Leiden and factor II 20210A are inherited disorders of the clotting system that occur frequently in patients with deep vein thrombosis. We conducted this study to determine whether these factors are also common in patients with pulmonary embolism. SUBJECTS AND METHODS: We determined the prevalence of factor V Leiden and factor II 20210A in 773 consecutive patients with objectively documented symptomatic deep vein thrombosis or symptomatic pulmonary embolism, or with a combination of these disorders. RESULTS: Isolated symptomatic deep vein thrombosis occurred in 345 patients; isolated symptomatic pulmonary embolism occurred in 236; and both anomalies occurred in 192. Factor V Leiden was present in 21 (9%) of the patients with isolated symptomatic pulmonary embolism, in 30 (16%) with both manifestations, and in 63 (18%) with isolated symptomatic deep vein thrombosis (P = 0.007). Factor V Leiden was more common among patients with deep vein thrombosis (odds ratio [OR] = 2.1; 95% confidence interval [CI]: 1.2 to 3.7; P = 0.006) or both pulmonary embolism and deep vein thrombosis (OR = 1.8; 95% CI: 1.0 to 3.3; P = 0.07) than among patients with isolated pulmonary embolism. Factor V Leiden was less common in massive pulmonary embolism (5% [7 of 127]) than in submassive pulmonary embolism (13% [21 of 155], P = 0.03). We found no significant difference in the prevalence of factor II 20210A among the three groups. CONCLUSION: Factors V Leiden and II 20210A vary in prevalence among patients with pulmonary embolism and deep vein thrombosis, suggesting that the risk of pulmonary embolization may vary among patients who have different causes of venous thromboses.

[Treatment of deep vein thrombosis. Current and future questions]. / Le traitement des thromboses veineuses profondes. Questions actuelles et perspectives.

Treatment of deep vein thrombosis is founded on the association of low molecular weight heparin and oral anticoagulant for three or six months. However efficacy and safety of low molecular weight heparin are not different from that of unfractionated heparin. Moreover measurement of anti-Xa activity does not permit a clear definition of therapeutic range in patients with a high hemorrhagic risk. Oral anticoagulant prevent recurrences of venous thrombosis, however the high risk of major haemorrhages limits their long term use. Pentasaccharide and Melagatran are news potent drugs that should deeply modify the treatment of venous thrombo-embolism.

The role of B-mode ultrasonography and electron beam computed tomography in evaluation of Takayasu's arteritis: a study of 43 patients.

OBJECTIVES: To evaluate the capacity of B-Mode ultrasonography (B-Mode US) and electron-beam computed tomography (EBCT) to detect arterial changes in Takayasu's arteritis. METHODS: EBCT angiography of the thoracoabdominal aorta and pulmonary artery, and B-mode US of large superficial arteries (common carotid, subclavian, and common femoral arteries) were performed prospectively in 43 consecutive patients with established Takayasu's arteritis. The arterial wall thickness was measured, and lumen changes (stenosis, aneurysm) were noted. RESULTS: The combined results of B-Mode US and EBCT examinations showed that every patient had at least one abnormality at the studied sites. The median score of abnormal sites was 7. The most frequent lesion was a characteristic long, homogeneous, circumferential thickening, visualized in 52% of examined sites and in all patients but one (98%). Stenosis was detected by US and by EBCT, respectively, in 44% and 32% of patients, and aneurysm in 0.4% and 68%. CONCLUSIONS: In Takayasu's arteritis, B-Mode US and EBCT was able to visualize the classical caliber abnormalities (stenosis, aneurysm) and, in contrast to angiography, to depict vessel wall thickening, a major pathologic feature of the disease. Both these safe techniques seem more useful than angiography to characterize and map the vascular lesions of Takayasu's arteritis.

[Left ventricular thrombus revealed by electron bean computed tomography, in a patient with antiphospholipid syndrome]. / Thrombus de la pointe du ventricule gauche révélé par le scanner à faisceau d'électrons, chez une patiente atteinte d'un syndrome des antiphospholipides.

The authors report a case of a 48 year old woman admitted to hospital because of digital ischemia, in a context of antiphospholipid syndrome. The electrocardiogram-triggered electron beam computed tomography revealed an apical thrombus associated with a thinning left ventricular wall, suggesting painless myocardial infarction. The diagnosis was secondary confirmed by coronarography.