A randomized, double-blind, placebo-controlled trial on the efficacy of tranexamic acid combined with rivaroxaban thromboprophylaxis in reducing blood loss after primary cementless total hip arthroplasty.

AIMS: Cementless primary total hip arthroplasty (THA) is associated with risks of bleeding and thromboembolism. Anticoagulants are effective as venous thromboprophylaxis, but with an increased risk of bleeding. Tranexamic acid (TXA) is an efficient antifibrinolytic agent, but the mode and timing of its administration remain controversial. This study aimed to determine whether two intravenous (IV) TXA regimens (a three-hour two-dose (short-TXA) and 11-hour four-dose (long-TXA)) were more effective than placebo in reducing perioperative real blood loss (RBL, between baseline and day 3 postoperatively) in patients undergoing THA who receive rivaroxaban as thromboprophylaxis. The secondary aim was to assess the non-inferiority of the reduction of blood loss of the short protocol versus the long protocol. PATIENTS AND METHODS: A multicentre, prospective, randomized, double-blind, placebo-controlled trial was undertaken involving 229 patients undergoing primary cementless THA using a posterior approach, whose extended rivaroxaban thromboprophylaxis started on the day of surgery. There were 98 male and 131 female patients, with a mean age of 65.5 years (32 to 91). The primary outcome, perioperative RBL, was evaluated at 72 hours postoperatively. The efficacy of short- and long-TXA protocols in the reduction of perioperative RBL was compared with a placebo group. RESULTS: TXA significantly reduced perioperative blood loss compared with placebo (p < 0.001); the mean differences were 525.3 ml (short-TXA vs placebo) and 550.1 ml (long-TXA vs placebo). No venous or arterial thromboembolic complications were reported. The upper boundary of the 95% confidence interval, when comparing short and long protocols, was below the pre-specified margin of non-inferiority (p = 0.027). CONCLUSION: In patients undergoing primary cementless THA, using a posterior approach, who are treated with rivaroxaban for thromboembolic prophylaxis, short- and long-TXA IV protocols are significantly more effective than placebo in reducing perioperative RBL, without any thromboembolic complications. Non-inferiority of a short- versus a long-TXA protocol in reducing perioperative RBL was supported in a secondary analysis.

Body mass index, a major confounder to insulin resistance association with unprovoked venous thromboembolism. Results from the EDITH case-control study.

Shared risk factors help explain the association between venous thromboembolism (VTE) and atherothrombosis. The potential association between insulin resistance and VTE has been poorly evaluated. Thus, we aimed to assess the association between insulin resistance and VTE in the EDITH hospital-based case-control study. Between May 2000 and December 2004, 677 patients with unprovoked VTE and their age- and sex-matched controls were included. Fasting glycaemia and insulinaemia were measured and insulin resistance was estimated with the homeostasis model assessment of insulin resistance (HOMA-IR) equation. The association between HOMA-IR and VTE was determined in non-diabetic patients in a quintile-based analysis. A total of 590 non-diabetic cases (median age 73.0 years, 255 men) and 581 non-diabetic controls (median age 72.0 years, 247 men) were analysed. There was a trend for a higher median level of HOMA-IR index in cases than in controls (1.21 [interquartile range 0.84-2.10] vs1.19 [interquartile range 0.72-2.02], p=0.08). The unadjusted analysis showed an increased risk of unprovoked VTE associated with increasing HOMA-IR (odds ratio [OR] 1.53; 95% confidence interval [CI] 1.00-2.34 for the highest quintile of HOMA-IR compared with the first quintile). Adjustment for lipid lowering drugs and antiplatelet agents use slightly modified the association (OR 1.51; 95% CI 0.97-2.34). When body mass index was added in the adjusted model, HOMA-IR was no longer associated with VTE (OR 1.08; 95% CI 0.67-1.73). Our results highlight the role of body mass index in the association between cardiovascular risk factors and VTE.

[Evaluation of preoperative non-invasive ventilation in thoracic surgery for lung cancer: the preOVNI study GFPC 12-01]. / Évaluation de la ventilation non invasive préopératoire avant chirurgie de résection pulmonaire. Étude préOVNI GFPC 12-01.

BACKGROUND: Surgical resection is the best treatment for stage I and II non-small cell lung cancer. Despite an improvement in the perioperative management of cancer patients and specialization of surgical teams, morbidity and mortality remains significant. Non-invasive ventilation (NIV) is an effective therapeutic option in hypercapnic respiratory failure. It also improves functional and gasometric parameters when undertaken before surgery. The objective of the preOVNI study is to demonstrate that preoperative non-invasive ventilation for 7 days, at home, reduces the postoperative respiratory and cardiovascular complications of lung resection surgery, in a high-risk population. METHODS: A prospective, randomized, controlled open-labelled multicentric French study, under the supervision of the Groupe Français de Pneumocancérologie (GFPC), comparing 7 days of preoperative non-invasive ventilation with standard treatment. Inclusion criteria are: patients suitable for lobectomy or segmentectomy for primary bronchial carcinoma and presenting with obstructive or restrictive lung disease, obesity or chronic cardiac insufficiency. The primary criterion is a composite one, including all respiratory and cardiac complications. The number of patients is 150 in each treatment arm, 300 in total. EXPECTED RESULTS: We think that preoperative NIV will be able to reduce the rate of postoperative complications. If this objective is achieved, the management of these patients could be changed.

[Epidemiology and risk factors of venous thromboembolism]. / Épidémiologie et facteurs de risque de la maladie veineuse thromboembolique.

INTRODUCTION: Venous thromboembolism (VTE) is a common disease. The incidence rises markedly with increasing age; over the age of 75, the annual incidence reaches 1 per 100. BACKGROUND: Besides major risk factors (surgery, trauma and acute medical illness), four risk factors have to be taken into account in the management of VTE: increasing age, cancer, previous history of VTE and pregnancy. To date, with the exception of the antiphospholipid syndrome and antithrombin deficiency, "thrombophilias" do not appear to change the management of VTE. VIEWPOINTS: "Thrombophilias" are useful tools for understanding the pathophysiology of VTE. Therefore, further studies are needed to identify new biological anomalies and their impact on the risk of VTE. Recently, links between VTE and atherosclerosis have been demonstrated, leading to new concept of pan-vascular disease and prevention. CONCLUSIONS: VTE is a major public health problem. The knowledge of VTE risk factors is of major importance in identifying high-risk patients and in reducing the incidence and mortality of VTE.

[Incidence, risk factors and skin manifestations of post-thrombotic syndrome: a four-year follow-up of patients included in the EDITH study]. / Incidence, facteurs de risque et signes cutanés de la maladie post-thrombotique : suivi à quatre ans des patients inclus dans l'étude EDITH.

PURPOSE: Despite appropriate therapy 10 to 100% of patients with deep vein thrombosis (DVT) of the lower limbs will develop post-thrombotic syndrome (PTS). The aim of this study was to evaluate the incidence of PTS in the EDITH cohort and to estimate the association between initial patients' characteristics and the risk of development of PTS. METHODS: One hundred and eighty patients included in the EDITH study for a first event of DVT of the lower limbs without clinical signs of venous insufficiency were recalled 4 years after their initial thrombotic event. PTS was diagnosed according to the Villalta score. RESULTS: Ninety-five patients (45 men, mean age 50.7 ± 16.9 years) were evaluated for PTS. Among them, 28.4% (95% CI 19.3-37.5) developed PTS but none had severe PTS. The most frequent clinical signs of PTS were varicose veins (59%), corona phlebectatica (48%), swelling leg (30%) and pigmented dermatitis (26%). No single risk factor was associated with PTS development (age, sex, BMI thrombophilia, etiology, localization, recurrence, symptomatic DVT and familial history of DVT). CONCLUSION: PTS is a frequent disease. However, lack of uniformity of diagnosis criteria in the different studies does not make possible the estimation of PTS risk factors.

Antihypertensive drugs and risk of venous thromboembolism: results from the EDITH case-control study.

Previous studies evaluating the association between arterial blood pressure and venous thromboembolism (VTE) reported conflicting results. The relationship between antihypertensive therapy and VTE has never been specifically evaluated. This report from a hospital-based case-control study included 785 cases with confirmed unprovoked VTE and their 785 age- and sex-matched controls. Cases and controls were asked for drug exposure in a one-to-one standardized interview using the same questionnaire. Drug exposure was defined as current use of drugs at admission with onset at least 1 week ago. Three hundred and eighty-four out of 785 cases (48.9%) and 379 out 785 controls (48.3%) reported that they were currently using at least one antihypertensive drug. Among all antihypertensive therapies, only angiotensin II receptor blockers were significantly associated with a reduced risk for VTE: adjusted conditional odds ratio (OR) 0.45 (95% CI, 0.29-0.70). In this hospital-based case-control study, a preventive role for angiotensin II receptor blockers as regards VTE risk was suggested. More studies are needed in order to further elucidate the biological mechanisms involved.

Inherited thrombophilias and unexplained pregnancy loss: an incident case-control study.

BACKGROUND: Despite an initial impressive impact, a critical appraisal of the link between pregnancy loss and inherited thrombophilias is currently growing. Furthermore, little is known about the paternal thrombophilic phenotype and pregnancy loss. OBJECTIVE: We sought an association between unexplained pregnancy loss and parental factor V Leiden (FVL) and Prothrombin G20210A (PTG) mutations. METHODS: Design - Incident case-control study. Setting- University Hospital of Brest (France). Patients - Women and their partners from the West Brittany area, consecutively referred for unexplained pregnancy losses (two or more consecutive losses at or before 21 weeks of gestation, or at least one later loss). Controls - Women and their partners with no history of pregnancy loss and at least one normal pregnancy, from the same geographic area, recruited using electoral lists. Statistical analysis - Comparison of FVL and PTG allele frequency between cases and controls using the chi-square test. Separate analyses were performed according to the type of pregnancy loss (early recurrent or later loss). RESULTS: 311 women (mean age: 32.8) and 284 of their partners were enrolled as cases while 599 women (mean age: 34.3) and 297 of their partners were recruited as controls. The prevalence of female, male or couple thrombophilic mutations was not statistically different between cases and controls whatever the definition of pregnancy loss retained. CONCLUSIONS: Presently, there is no clinical indication to routinely test for FVL and likely PTG mutations in women with early recurrent pregnancy loss. Moreover, our results did not reveal that paternal thrombophilic polymorphism should be further explored.

[Drugs and venous thromboembolism]. / Médicaments et maladie veineuse thromboembolique.

Among the many factors likely to favour the occurrence of venous thromboembolism (VTE), exposure to certain drugs has to be taken into account. Although hormone treatments, oral contraception and hormone replacement therapy (HRT) for menopause have been studied, these are not the only drugs associated with an increased risk of VTE. The antipsychotics have also been incriminated in the occurrence of venous thromboembolism. The association of thalidomide and dexamethasone, used in the treatment of multiple myeloma, is responsible for a major increase in the risk of VTE. The physiopathological mechanisms accounting for the possible prothrombotic effect of most of these drugs is still not fully understood. Further observational and interventional clinical studies should provide a better understanding of VTE, potentially associated with drugs. However, certain drugs may be associated with a reduced risk of VTE. Although several studies indicate that aspirin and statins may favourably influence the risk of VTE, it is still not possible to draw up any practical recommendations.

[Prolongation of anti vitamin K treatment for 18 months versus placebo after 6 months treatment of a first episode of ideopathic pulmonary embolism: a mutlicentre, randomised double blind trail. The PADIS-EP Trial]. / Prolongation d'un traitement par antivitamine K pendant dix-huit mois versus placebo au décours d'un premier épisode d'embolie pulmonaire idiopathique traité six mois: un essai randomisé multicentrique en double aveugle. Essai "PADIS-EP".

BACKGROUND: After stopping a 3 to 6 months course of oral anticoagulation for a first episode of idiopathic venous thromboembolism (VTE), the risk of recurrent VTE is high (10% per year). In this setting, international guidelines recommend at least 6 months treatment. However, this recommendation is not satisfactory for the following reasons: (1) no randomized trial has compared 6 months to extended duration (2 years) anticoagulation; and (2), even though the frequency of recurrent VTE is similar after pulmonary embolism (PE) and deep vein thrombosis (DVT), the fatality rate of recurrent VTE after PE is higher than that after DVT. METHODS: A French multicentre double blind randomized trial. The main objective is to demonstrate, after a first episode of symptomatic idiopathic PE treated for 6 months using a vitamin K antagonist, that extended anticoagulation for 18 months (INR between 2 and 3) is associated with an increased benefit / risk ratio (recurrent VTE and severe anticoagulant-related bleeding) compared to placebo. The double blind evaluation is ensured using by active warfarin and placebo, and blinded INR. The protocol was approved by the ethics board of the Brest Hospital on the 7th of March 2006. For an alpha risk of 5% and a beta risk of 20%, the estimated sample size is 374 patients. EXPECTED RESULTS: This study has the potential to: (1) demonstrate that the benefit / risk ratio of extended anticoagulation for 18 months is higher than that observed with placebo in patients with a first episode of idiopathic PE initially treated for 6 months, during and after the treatment period; and (2) to validate or invalidate the contribution of isotope lung scans, lower limb Doppler ultrasound and D-Dimer at 6 months of treatment as predictors of recurrent VTE (medico-economic analysis included).

Association between antipsychotic drugs, antidepressant drugs and venous thromboembolism: results from the EDITH case-control study.

Cohort studies suggest that exposure to antipsychotic agents may be associated with an increased risk of venous thromboembolism (VTE). Few data concerning antidepressant drugs are available. Using a different methodological approach, the aim of this study was to estimate the association between neuroleptic and antidepressant drug use and the risk of VTE. We report the results of a case-control study designed to evaluate interactions between acquired and inherited risk factors of VTE. We included 677 cases hospitalized with deep vein thrombosis and or pulmonary embolism with no major acquired risk factor for VTE, and 677 controls matched for gender and age. Drug exposure was defined as current use of drugs at admission. Neuroleptic exposure was associated with an increased risk of VTE (OR = 2.1, 95% CI 1.4-3.2). Among neuroleptics, antipsychotic agent use was associated with a 3.5-fold increased risk of VTE (OR = 3.5, 95% CI 2.0-6.2). No association was found between antidepressant drug exposure and the risk of VTE (OR = 1.1, 95% CI 0.9-1.5). In this hospital-based case-control study, exposure to antipsychotic drugs was associated with an increased risk of VTE. These results, added to previous results, suggest that clinicians should consider antipsychotic drug exposure as a potential risk factor of VTE. More studies are needed in order to further elucidate this adverse effect, and to determine the possible predisposing factors and the biological mechanisms involved.

Vitamin K epoxide reductase genetic polymorphism is associated with venous thromboembolism: results from the EDITH Study.

BACKGROUND: The vitamin K epoxide reductase complex subunit 1 (VKORC1) recycles endogenous vitamin K, a cofactor for vitamin K-dependent coagulation factor synthesis. Common polymorphisms in VKORC1, the gene coding for VKORC1, have been found to affect the dose response to vitamin K antagonists, and to confer an increased risk of vascular diseases in a Chinese population. The aim of this study was to evaluate the association between the VKORC1 1173C > T polymorphism and venous thromboembolism (VTE). METHODS: We report the results of a case-control study designed to evaluate interactions between acquired and inherited risk factors of VTE. We studied 439 cases hospitalized with a first venous thromboembolic event that was not related to a major acquired risk factor for VTE, and 439 matched controls. The VKORC1 1173C > T polymorphism was selected for genotyping as the tagging single-nucleotide polymorphism for previously identified VKORC1 haplotypes. RESULTS: The relationship between VTE and the VKORCI 1173C > T polymorphism was consistent with a recessive model. The frequency of the VKORCI TT genotype was lower in cases than in controls. The odds ratio (OR) (95% CI) was 0.62 (0.41-0.94) for the TT genotype as compared to CT/CC genotypes. Adjustment on cardiovascular diseases, body mass index, factor V (FV) and prothrombin gene mutations did not alter the results. CONCLUSIONS: In this case-control study, the frequency of the VKORCI TT genotype was lower in patients with VTE than in matched controls. The clinical consequence of these results remains to be determined, but gives new perspectives for exploration of the role of VKORCI polymorphism in the pathogenesis of VTE.

Strong evidence that skewed X-chromosome inactivation is not associated with recurrent pregnancy loss: an incident paired case control study.

BACKGROUND: Previous studies have reported conflicting results regarding recurrent pregnancy loss and skewed X-chromosome inactivation. Hence, we sought an association by carrying out a specifically designed incident paired case-control study with required statistical power. METHODS: Design incident 1:3 matched case-control study, from 2003 to 2007. SETTING: University Hospital of Brest. PATIENTS: Women, from the Brittany area, consecutively referred for at least two unexplained consecutive spontaneous abortions. CONTROLS: Women from the same geographic area, with no history of pregnancy loss and at least one normal pregnancy, recruited using electoral lists and then paired with cases, with respect to age, to within 1 year. INTERVENTION: Assessment of skewed X-chromosome inactivation. STATISTICAL ANALYSIS: Comparison of the ratio of >90% skewed X-chromosome inactivation by conditional logistic regression. RESULTS: Five hundred and forty-three controls (mean age: 34.3 years) were paired within 1 year to 200 cases. The cases (mean age: 33.6 years) had experienced between 2 and 14 consecutive losses (median 3). The rate of >90% skewed X-chromosome inactivation was not statistically different (P = 0.33, odds ratio: 0.58, 95% confidence interval: 0.19-1.77) between cases and paired controls, 2.27% versus 4.1%, respectively. CONCLUSIONS: We conclude that there is no association between skewed X-chromosome inactivation and recurrent pregnancy loss, defined as two or more unexplained consecutive spontaneous abortions.

[Clinical diagnosis of pulmonary embolism: a real challenge]. / La clinique de l'embolie pulmonaire: décidément difficile.

Clinical signs of pulmonary embolism are neither sensitive nor specific enough to rule in or out the diagnosis in suspected patients. As an example, a chest pain that is reproducible at palpation in suspected patients was recently shown not to be associated with a lower proportion of confirmed cases of pulmonary embolism. However, clinical evaluation of patients with suspected pulmonary embolism is important, because it allows the physician to assess the clinical probability of pulmonary embolism, a mandatory step in diagnostic strategies for this disease. In elderly patients, the diagnosis of pulmonary embolism is particularly challenging. Indeed, the diagnostic value of symptoms and clinical signs of pulmonary embolism is reduced, the evaluation of the clinical probability is more difficult, and performances of some diagnostic tests are diminished with increasing age. The diminution of the proportion of confirmed cases among suspected patients is a new challenge for physicians, and raises the question of what is a clinical suspicion of pulmonary embolism.

Hyperhomocysteinemia and low B vitamin levels are independently associated with venous thromboembolism: results from the EDITH study: a hospital-based case-control study.

BACKGROUND: Moderate hyperhomocysteinemia and B vitamins deficiency are thought to be risk factors for venous thromboembolism (VTE). The causality and independence of those associations are still questioned. METHODS: We measured fasting serum total homocysteine, folates, and vitamin B12 levels as well as 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T genotypes in 467 patients hospitalized with a first well-documented deep vein thrombosis and/or pulmonary embolism not related to a major acquired risk factor and 467 controls matched for gender and age. RESULTS: Mild hyperhomocysteinemia, low serum folates, and vitamin B12 were associated with VTE independently of each other. In multivariate analysis, odds ratios (OR) (95% CI) for VTE associated with mild hyperhomocysteinemia (>15 micromol L(-1)), low serum folates (< or = 4.9 nmol L(-1)), and vitamin B12 (< or = 253 pmol L(-1)) were 1.48 (1.05-2.08), 3.14 (1.35-7.32) and 1.42 (1.03-1.98), respectively. An MTHFRC677T genotype was not significantly associated with VTE; OR (95% CI): 1.13 (0.70-1.81) CONCLUSIONS: The current data provides further knowledge in the complex relationship between hyperhomocysteinemia, low vitamin levels, and VTE.