Anemia, an independent predictive factor for amputation and mortality in patients hospitalized for peripheral artery disease.

OBJECTIVES: Anemia is associated with poorer outcome in coronary artery disease (CAD) and heart failure (HF), but data on patients with peripheral artery disease (PAD) are scarce, especially regarding the local (limb) prognosis. It was hypothesized that anemia is associated with poorer prognosis in patients hospitalized for PAD, and this relationship would be proportional to the severity of the anemia. DESIGN: Prospective cohort study. MATERIALS: The Cohorte des Patients Artéritiques (COPART) is a multicenter registry of patients hospitalized for PAD in three university hospitals in southwestern France. METHODS: Clinical and biological data were collected at entry. Patients were followed up to 1 year. Anemia was defined by Hb < 8.2 mmol/L in men and <7.6 mmol/L in women. The primary outcome was 1-year survival free from major amputation. The secondary outcome was 1-year major amputation. RESULTS: Data of 925 consecutive patients (70.7 ± 12.8 years, 29.2% females) were analyzed. Patients were hospitalized either for revascularization or medical therapy, with Rutherford categories 3 (25%), 4 (9.1%), 5 or 6 (55.1%) as well as acute limb ischemia (10.8%). Anemia was present in 471 patients (50.9%). These patients were significantly older, with higher rates of hypertension, diabetes, clinical CAD, HF, chronic kidney disease, and cancer, and with lower rates of smoking and dyslipidemia than their counterparts (p < .05 for all). In multivariate models, anemia was significantly and independently associated (p < 0.001) with death and amputation (HR 1.44; 95% CI 1.15-1.80) with similar findings for secondary outcomes. A lower level of hemoglobin is associated with a higher risk of mortality and amputation (HR 1.20; 95% CI 1.09-1.32). CONCLUSION: Anemia and its severity are independent predictors of mortality and limb loss in patients hospitalized for PAD.

[Anticoagulant clinics are they effective in France? Performance evaluation of six anticoagulant clinics concerning the management of vitamin K antagonists]. / Les cliniques d'anticoagulants sont-elles efficaces en France ? Évaluation des performances de six cliniques dans la gestion des traitements par antivitamines K.

PURPOSE: Recent data show that the quality of anticoagulation evaluated in patients receiving vitamin K antagonists (VKA) is not optimal in France. The aim of this retrospective study was to estimate the performances of six French anticoagulant clinics that manage VKA treatments over a 3-year period, from 2009 to 2011. METHODS: All clinics used the same rule based software. We determined the time spent in the therapeutic range (TTR), a surrogate end-point of quality of treatment with VKA. RESULTS: The overall duration of follow-up was 2755 patient-years concerning 2385 patients. The time spent in the therapeutic range 2 to 3 assigned for 89% of the patients, was 73%. On the other hand the time spent in the therapeutic range for the other two INR ranges (2.5-3.5 and 3-4.5) concerning 11% of patients with prosthetic heart valve was lower (63.7% and 68.8% respectively) with an imbalance in favour of the time below the range. In this study, warfarin (Coumadine(®)) and fluindione (Previscan(®)) allowed an equivalent quality of anticoagulation. The 1728 patients of age ranged from 60 to 100 years spent more time in TTR than the 651 younger patients. The percentage of time spent with an INR greater than 5 was extremely reduced which is a guarantee of safety. CONCLUSION: These results prove that anticoagulant clinics in France have the same good performances as their counterparts abroad. It can be assumed that a high TTR contributes to a low incidence of both bleedings and thrombosis.

A hospital discharge risk score for 1-year all-cause mortality or non-fatal cardiovascular events in patients with lower-extremity peripheral artery disease, with and without revascularisation.

OBJECTIVES: This study aims to determine a hospital discharge prognostic risk score for patients with lower-extremity peripheral artery disease (PAD) with and without revascularisation. DESIGN, MATERIALS AND METHODS: A prognostic score on mortality or non-fatal cardiovascular events was determined using the database of a multicentre prospective study enrolling consecutive patients hospitalised for PAD (COhorte de Patients ARTeriopathes, COPART). RESULTS: We analysed the data of 640 patients in the derivation cohort and 517 in the validation cohort. The risk score (and corresponding points) included the following factors: age 75-84 years (+2), ≥ 85 years (+3); previous myocardial infarction (+1); creatinine clearance: ≤ 30 ml min(-1) 1.73 m⁻² (+1.5), 0.30-0.59 (+1), ankle-brachial index: <0.3 (+2), 0.3-0.49 (+1.5) and >1.3 (+2); C-reactive protein (CRP) ≥ 70 mg l⁻¹ (+2); and association of statins, anti-platelet agents and renin-angiotensin system inhibitors (-1.5). The frequency of the composite outcome increased significantly with the predicted risk: low risk (≤ 0 point), 2%; medium (0.5-2 points), 12.8%; high (2.5-4 points), 23%; very high (≥ 4.5 points): 42.2%. The model had a good performance in terms of discrimination (C-statistic 0.74 and 0.76) and calibration (Hosmer-Lemeshow 0.65). CONCLUSIONS: We propose the validated COPART risk score for hospitalised severe PAD. This prognostic risk score is based on six variables easily identifiable in clinical practice. Our study highlights the favourable prognostic impact of the prescription at discharge of combined drug therapies.

Operant self-administration of a sigma ligand improves nociceptive and emotional manifestations of neuropathic pain.

BACKGROUND: The treatment of neuropathic pain is unsatisfactory at the present moment and the sigma 1 receptor has been identified as a new potential target for neuropathic pain. The aim of this study was to use an operant self-administration model to reveal the potential interest of a new sigma 1 receptor antagonist, S1RA, in chronic pain that was developed in mice by a partial ligation of the sciatic nerve. METHODS: Once that chronic pain had reached a steady state, mice were trained to maintain an operant behaviour to self-administer S1RA. The possible abuse liability of the analgesic compound was determined by evaluating operant self-administration in sham-operated mice. The influence of S1RA on the anhedonic state related to chronic pain was also evaluated by measuring the preference for palatable drink (2% sucrose solution) using a recently validated and highly sensitive behavioural device. RESULTS: Nerve-injured mice, but not sham-operated animals, acquired the operant responding to obtain S1RA (6 mg/kg/infusion). After 10 days of S1RA self-administration, neuropathic pain was significantly reduced in nerve-injured mice. In addition, an anhedonic state was revealed in nerve-injured mice by a decreased consumption of palatable drink, which was significantly attenuated by S1RA (25 mg/kg). CONCLUSIONS: These results reveal the analgesic efficacy of the sigma antagonist, S1RA, in neuropathic pain associated with an improvement of the emotional negative state and that was devoided of reinforcing effects. The operant responses evaluated in this new mouse model can have a high predictive value to estimate the clinical benefit/risk ratio of new analgesic compounds to treat chronic pain, such as S1RA.

Pharmacological properties of S1RA, a new sigma-1 receptor antagonist that inhibits neuropathic pain and activity-induced spinal sensitization.

BACKGROUND AND PURPOSE: The sigma-1 (σ(1) ) receptor is a ligand-regulated molecular chaperone that has been involved in pain, but there is limited understanding of the actions associated with its pharmacological modulation. Indeed, the selectivity and pharmacological properties of σ(1) receptor ligands used as pharmacological tools are unclear and the demonstration that σ(1) receptor antagonists have efficacy in reversing central sensitization-related pain sensitivity is still missing. EXPERIMENTAL APPROACH: The pharmacological properties of a novel σ(1) receptor antagonist (S1RA) were first characterized. S1RA was then used to investigate the effect of pharmacological antagonism of σ(1) receptors on in vivo nociception in sensitizing conditions and on in vitro spinal cord sensitization in mice. Drug levels and autoradiographic, ex vivo binding for σ(1) receptor occupancy were measured to substantiate behavioural data. KEY RESULTS: Formalin-induced nociception (both phases), capsaicin-induced mechanical hypersensitivity and sciatic nerve injury-induced mechanical and thermal hypersensitivity were dose-dependently inhibited by systemic administration of S1RA. Occupancy of σ(1) receptors in the CNS was significantly correlated with the antinociceptive effects. No pharmacodynamic tolerance to the antiallodynic and antihyperalgesic effect developed following repeated administration of S1RA to nerve-injured mice. As a mechanistic correlate, electrophysiological recordings demonstrated that pharmacological antagonism of σ(1) receptors attenuated the wind-up responses in spinal cords sensitized by repetitive nociceptive stimulation. CONCLUSIONS AND IMPLICATIONS: These findings contribute to evidence identifying the σ(1) receptor as a modulator of activity-induced spinal sensitization and pain hypersensitivity, and suggest σ(1) receptor antagonists as potential novel treatments for neuropathic pain.

Short-term effects of the smoke-free legislation on haemostasis and systemic inflammation due to second hand smoke exposure. The AERER study.

It was the objective of this study to assess the effect of the implementation of the smoke-free legislation on haemostasis and systemic inflammation in second-hand smoking (SHS)-exposed healthy volunteers. Fibrin-rich clot properties, platelet reactivity and inflammatory biomarkers were measured before and four months following the implementation of the smoke-free legislation in gender and age-matched healthy volunteers exposed (n=23, exposed) and unexposed (n=23, controls) to occupational SHS. The primary objective was to compare fibrin-rich clot stiffness before and after implementation of the smoke-free legislation. There was 40% reduction in fibrin-rich clot stiffness following the implementation of the smoke-free legislation in SHS-exposed volunteers (17 ± 7 vs. 10.6 ± 7 dynes/cm², before and after, respectively, p=0.001). These dramatic changes were associated with a 20% reduction in fibrin fiber density (p<0.01) and a 20% reduction in clot lysis time (p=0.05). No change in fibrin properties was observed in the control group of SHS-unexposed volunteers related to the implementation of the smoke-free legislation. Of interest, neither platelet reactivity nor systemic inflammatory biomarkers were changed in either group. The smoke-free legislation is associated with significant changes in fibrin-rich clot properties toward a less thrombogenic conformation with a better fibrinolysis response while neither platelet reactivity nor systemic inflammatory biomarkers are modified. These improvements may explain the observed reduction in acute coronary syndrome following the implementation of the smoke-free legislation.

Deficiency of CB2 cannabinoid receptor in mice improves insulin sensitivity but increases food intake and obesity with age.

AIMS/HYPOTHESIS: The endocannabinoid system has a key role in energy storage and metabolic disorders. The endocannabinoid receptor 2 (CB2R), which was first detected in immune cells, is present in the main peripheral organs responsible for metabolic control. During obesity, CB2R is involved in the development of adipose tissue inflammation and fatty liver. We examined the long-term effects of CB2R deficiency in glucose metabolism. METHODS: Mice deficient in CB2R (Cb2 ( -/- ) [also known as Cnr2]) were studied at different ages (2-12 months). Two-month-old Cb2 (-/-) and wild-type mice were treated with a selective CB2R antagonist or fed a high-fat diet. RESULTS: The lack of CB2R in Cb2 (-/-) mice led to greater increases in food intake and body weight with age than in Cb2 (+/+) mice. However, 12-month-old obese Cb2 (-/-) mice did not develop insulin resistance and showed enhanced insulin-stimulated glucose uptake in skeletal muscle. In agreement, adipose tissue hypertrophy was not associated with inflammation. Similarly, treatment of wild-type mice with CB2R antagonist resulted in improved insulin sensitivity. Moreover, when 2-month-old Cb2 (-/-) mice were fed a high-fat diet, reduced body weight gain and normal insulin sensitivity were observed. CONCLUSIONS/INTERPRETATION: These results indicate that the lack of CB2R-mediated responses protected mice from both age-related and diet-induced insulin resistance, suggesting that these receptors may be a potential therapeutic target in obesity and insulin resistance.

Characteristics and outcome of patients hospitalised for lower extremity peripheral artery disease in France: the COPART Registry.

OBJECTIVES: To assess the current 'real-world' management of hospitalised patients with lower-extremity peripheral artery disease (LE-PAD) and to assess the 1-year outcome. DESIGN, MATERIALS AND METHODS: The prospective and multicentre registry COhorte des Patients ARTériopathes (COPART) recruited consecutive patients from the departments of vascular medicine of three academic hospitals in Southwestern France. RESULTS: Among the 940 patients, 27.4% had intermittent claudication (IC), 9.3% ischaemic rest pain, 54.3% ulceration or gangrene and 9.3% acute limb ischaemia (ALI). Patients with IC were younger and more likely to be men, with a history of smoking (89.5%) and chronic obstructive pulmonary disease (17%). Among those with IC, 8.9% had bypass surgery and 41.5% were treated with percutaneous angioplasty. Those with tissue loss had higher rates of cardiovascular disease (CVD) risk factors and co-morbidities. At entry to the study, the level of control of the CVD risk factors was poor. The 1-year mortality rate was of 5.7% in patients with IC, 23.1% in patients with ischaemic rest pain, 28.7% in patients with tissue loss and 23% in those with ALI. Compliance with evidence-based medicine and pharmacological treatment was sub-optimal. CONCLUSION: This registry underscores the differences in patient profiles in the daily clinical setting, compared to those enrolled in several trials.

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.

Molecular bases of antithrombin deficiency in French families: identification of seven novel mutations in the antithrombin gene.

We have investigated the molecular bases of familial antithrombin deficiency in eight French families. Eight mutations in the antithrombin coding exons were identified, seven of which were novel mutations. In all cases, individuals were heterozygous for the mutation. We found two small frameshift deletions in exon 3a, leading to type I deficiency. Five missense mutations in exons 3b or 5 also caused type I deficiency and their potential consequences on the antithrombin three-dimensional structure were analysed. The last mutation in exon 4 was associated with a type II 'reactive site' deficiency: a dysfunctional antithrombin that is affected in its interaction with thrombin was present in circulation.

The incidence of venous thromboembolism in asymptomatic carriers of a deficiency of antithrombin, protein C, or protein S: a prospective cohort study.

Deficiencies of antithrombin, protein C, and protein S are associated with an increased risk of venous thromboembolism. The objective of this study was to prospectively assess the incidence of venous thromboembolism in nontreated asymptomatic subjects with such a deficiency. We conducted a prospective cohort study in asymptomatic family members of unselected patients who presented with a venous thromboembolic event and who were found to have a deficiency of antithrombin, protein C, or protein S. No anticoagulant prophylaxis was given to the study participants, except during risk periods for venous thromboembolism. All venous thromboembolic events were diagnosed by objective diagnostic tests. A total of 208 individuals with a mean age of 37 years (range, 15 to 79) were included in the study. A total of 611 patient observation years was obtained. Nine venous thromboembolic events occurred, resulting in an annual incidence of 1.5% (95% confidence interval [CI], 0.7 to 2.8) for the 3 deficiencies combined. Five of these events occurred spontaneously, resulting in an annual incidence of spontaneous venous thromboembolism of 0.8% (95% CI, 0.3 to 1.9). For antithrombin, protein C, and protein S deficiencies separately, this figure was 1.6%, 1.0%, and 0.4%, respectively. Thirty-four subjects experienced a total of 40 risk periods during which 4 venous thromboembolic events occurred (10% per risk period). We conclude that the use of continuous anticoagulant prophylaxis seems not warranted in asymptomatic individuals with a deficiency of antithrombin, protein C, or protein S. During risk periods for venous thromboembolism, adequate anticoagulant prophylaxis is necessary.

Homozygous variant of antithrombin with lack of affinity for heparin: management of severe thrombotic complications associated with intrauterine fetal demise.

Patients with homozygous heparin-binding-site (HBS) qualitative antithrombin deficiencies are at significant risk of venous and arterial thrombosis. We report on the eighth case of homozygous HBS deficiency, and the fourth case concerning the Arg 47-Cys mutation. The proposita is a 25 year old, without known thrombotic antecedent, despite an oral contraceptive therapy for 7 years. After 25 weeks of a first pregnancy, she presented an intrauterine fetal demise complicated with deep vein thrombosis and pulmonary embolism. Heparin therapy was inefficient (no clinical nor angiographic improvement, no biological hypocoagulability). Heparin cofactor activity was < 10%, antigen concentration was normal. The crossed immunoelectrophoresis of patient's plasma, with and without heparin, showed a typical profile of qualitative HBS antithrombin deficiency. The molecular analysis revealed an homozygous Arg 4-Cys mutation. Antithrombotic therapy was achieved with continuous infusion of antithrombin concentrates (80 IU/kg/day) and unfractionated heparin (500 IU/kg/day) during 12 days, leading to clinical improvement, and followed by treatment with vitamin K antagonists. This observation emphasizes the risk of intrauterine fetal demise and the inefficiency of heparin therapy without antithrombin infusion in type II HBS homozygous deficiency. The management of a future pregnancy will probably require repeated infusions of antithrombin.

A novel nonsense mutation in the antithrombin III gene (Cys-4-->stop) causing recurrent venous thrombosis.

We describe a novel mutation identified in the antithrombin III (AT-III) propeptide responsible for AT-III deficiency. This mutation, a C to A transversion in exon 2, converts the cysteine at position -4 into a stop codon (TGC-->TGA). In this family with severe thrombophilia, the mutation co-segregates with the clinical phenotype.

Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep vein thrombosis. A meta-analysis.

OBJECTIVE: To quantitatively assess the efficacy and safety of published randomized trials comparing subcutaneous heparin with continuous intravenous heparin for the initial treatment of deep vein thrombosis. DATA IDENTIFICATION: Studies published between January 1986 and April 1991 were identified through computer searches of the MEDLINE database and through reviews of the Science Citation Index, Current Contents, proceedings and abstract books, and references cited in the identified articles. Complete manuscripts were obtained from the authors if only abstracts were available. STUDY SELECTION: Eight clinical trials were identified that compared subcutaneous with intravenous heparin administration in patients with venographically confirmed deep vein thrombosis. DATA EXTRACTION: Each study was independently analyzed for the percentage distribution of thrombosis, the method of outcome measurement, and the heparin dose. The methodologic strength of each study was assessed using predefined standards for the proper evaluation of a therapeutic intervention with particular emphasis on the type of patient allocation and objective measurements. RESULTS OF DATA ANALYSIS: The overall relative risk for efficacy (defined as prevention of extension and recurrence of venous thromboembolism) of subcutaneous compared with intravenous heparin treatment was 0.62 (95% CI, 0.39 to 0.98), whereas for safety (defined as major hemorrhage) it was 0.79 (CI, 0.42 to 1.48). CONCLUSIONS: The results of our meta-analysis indicated that heparin administered subcutaneously twice daily in the initial treatment of deep vein thrombosis is more effective and at least as safe as continuous intravenous heparin administration. Administration of heparin subcutaneously may simplify patient treatment and could facilitate home treatment.