Céline Chapelle

Risk of venous and arterial thrombosis according to type of antiphospholipid antibodies in adults without systemic lupus erythematosus: a systematic review and meta-analysis.

AIM To evaluate the magnitude of venous and arterial thrombosis risk associated with antiphospholipid antibodies (APLs) in adults without systemic lupus erythematosus (SLE). METHODS Case-control and cohort studies were selected from the MEDLINE and Cochrane Library databases. Two investigators independently extracted data on study design, patient characteristics, venous and arterial events and exposure to APLs, including lupus anticoagulant (LA), anticardiolipin (aCL), anti-β2 Glycoprotein I (β2GpI), anti-prothrombin (aPT), anti-phosphatidyl serine (aPS), and anti-phosphatidyl ethanolamine (aPE). RESULTS 30 studies were included (16,441 patients). The odds ratio (OR) for venous thrombosis was 6.14 (95% confidence interval [CI] 2.74-13.8) in LA-positive patients (5 studies, 1650 patients) and 1.46 (CI 1.06-2.03) in aCL-positive patients (12 studies, 5375 patients). None of the associations with more recently identified APLs was significant, but fewer studies were available. For arterial thrombosis, the OR for LA and aCL was 3.58 (CI 1.29-9.92) and 2.65 (CI 1.75-4.00) respectively. The associations between β2GpI, aPT and aPS and the risk of arterial thrombosis were also significant, the OR being 3.12 (CI 1.51-6.44), 2.95 (CI 1.31-6.66) and 6.00 (CI 3.07-11.7), respectively. Owing to the heterogeneity of cut-off values for each APL assay, we were unable to perform any sensitivity analysis to determine the optimal value. The presence of low-quality studies may have led to overestimation of the magnitude of the associations. CONCLUSIONS LA and aCL were significantly associated with an increased risk of thrombosis, especially arterial, in patients without SLE. Systematic thromboprophylaxis in high-risk patients with APL should be evaluated.

Prevalence of poor biological response to clopidogrel: a systematic review.

The existence of poor biological response to clopidogrel has been shown in some patients. Despite the increasing number of studies, this phenomenon remains difficult to quantify. We performed a systematic review to estimate the prevalence of poor biological response to clopidogrel and investigate the factors known to modulate this. An exhaustive search was performed. Altogether 171 publications were identified, providing data for a total of 45,664 subjects. The estimated prevalence of poor biological response to clopidogrel ranged from 15.9% to 49.5% according to the platelet function assay employed. The assays most frequently used were light transmittance aggregometry (LTA), the vasodilator-stimulated phosphoprotein (VASP) assay and the Verifynow® assay. For all these assays, higher cut-off values were associated with a lower prevalence of poor biological response to clopidogrel. However, when choosing a fixed cut-off point for each assay, the prevalence of poor biological response to clopidogrel was highly variable suggesting that other factors could modulate poor biological response to clopidogrel. Finally, none of the studied factors could apparently explain the variability of poor biological response to clopidogrel. This meta-analysis shows that the prevalence of poor biological response depends on the assay employed, the cut-off value and on various unidentified additional factors.

Consistency of Safety and Efficacy of New Oral Anticoagulants across Subgroups of Patients with Atrial Fibrillation

Aims The well-known limitations of vitamin K antagonists (VKA) led to development of new oral anticoagulants (NOAC) in non-valvular atrial fibrillation (NVAF). The aim of this meta-analysis was to determine the consistency of treatment effects of NOAC irrespective of age, comorbidities, or prior VKA exposure. Methods and Results All randomized, controlled phase III trials comparing NOAC to VKA up to October 2012 were eligible provided their results (stroke/systemic embolism (SSE) and major bleeding (MB)) were reported according to age (≤ or >75 years), renal function, CHADS2 score, presence of diabetes mellitus or heart failure, prior VKA use or previous cerebrovascular events. Interactions were considered significant at p <0.05. Three studies (50,578 patients) were included, respectively evaluating apixaban, rivaroxaban, and dabigatran versus warfarin. A trend towards interaction with heart failure (p = 0.08) was observed with respect to SSE reduction, this being greater in patients not presenting heart failure (RR = 0.76 [0.67–0.86]) than in those with heart failure (RR = 0.90 [0.78–1.04]); Significant interaction (p = 0.01) with CHADS2 score was observed, NOAC achieving a greater reduction in bleeding risk in patients with a score of 0–1 (RR 0.67 CI 0.57–0.79) than in those with a score ≥2 (RR 0.85 CI 0.74–0.98). Comparison of MB in patients with (RR 0.97 CI 0.79–1.18) and without (RR 0.76 CI 0.65–0.88) diabetes mellitus showed a similar trend (p = 0.06). No other interactions were found. All subgroups derived benefit from NOA in terms of SSE or MB reduction. Conclusions NOAC appeared to be more effective and safer than VKA in reducing SSE or MB irrespective of patient comorbidities. Thromboembolism risk, evaluated by CHADS2 score and, to a lesser extent, diabetes mellitus modified the treatment effects of NOAC without complete loss of benefit with respect to MB reduction.

Thrombin generation and heparin‐induced thrombocytopenia

Summary.  Background: Heparin‐induced thrombocytopenia (HIT) is a severe complication of heparin therapy. IgG antibodies targeting the platelet factor 4‐heparin complex activate platelets and generate microparticles with procoagulant activity. Objectives: To determine whether the thrombin generation assay is capable of detecting procoagulant activity induced by patient platelet‐poor plasma (PPP) in donor platelet‐rich plasma (PRP). Patients and methods: We explored two groups of patients; group 1 (n = 23): patients with a positive clinical and biological diagnosis of HIT; group 2 (n = 25): patients with a negative clinical and biological diagnosis of HIT. Mixtures of donor PRP and patient PPP (1:1) were incubated either with unfractionated heparin 0.2 U mL−1 or with physiological saline. Thrombin generation was assessed by calibrated thrombinography. The effect of heparin on the mixtures was evaluated according to the ratio of the values with and without heparin (wH/woH) of the five thrombogram parameters. Results: With low heparin concentrations, plasma of group 1 activates donor platelets and generates procoagulant activity. A set of three ratios outside the cut‐off values corresponds to the ‘HIT thrombogram profile’, characterized by a highly specific aspect of the thrombogram wH in relation to the thrombogram woH. None of the group 2 patients presented a HIT thrombogram profile. The results of thrombinography correlate well with the results of the platelet aggregation test. Conclusion: Our studies illustrate the central paradox of HIT, namely enhancement of thrombin generation in the presence of heparin. The HIT thrombogram profile as it is defined in this study can detect the procoagulant activity of HIT IgG antibodies.

A randomized double-blind trial of upward progressive versus degressive compressive stockings in patients with moderate to severe chronic venous insufficiency

BACKGROUND The present randomized double-blind multicenter study was designed to assess the efficacy of a progressive compressive stocking (new concept with maximal pressure at calf), compared to a degressive compressive stocking graded 30 mm Hg, evaluating the improvement of lower leg symptoms of chronic venous insufficiency (CVI) in ambulatory patients with moderate to severe chronic venous disease. METHODS Both gender outpatients presenting symptomatic moderate to severe CVI were eligible for a treatment by compressive stockings. Patients were randomly assigned to receive either degressive compressive stockings (30 mm Hg at ankle, 21 mm Hg at upper calf) or progressive compressive stockings (10 mm Hg at ankle, 23 mm Hg at upper calf). The primary outcome, evaluated after 3 months, was a composite success outcome, including improvement of pain or heavy legs without onset of either ulcer, deep or superficial vein thrombosis of the lower limbs, or pulmonary embolism. The ease of application of the compressive stockings reported by patients was one of secondary outcome. RESULTS Overall, 401 patients (199 in the progressive compressive stocking group and 202 in the degressive compressive stocking group) were randomized by 44 angiologists in France. Among them, 66% were classified in the C3 CEAP category. The rate of success was significantly higher in the progressive compressive stocking group compared to the degressive compressive stocking group (70.0% vs 59.6%; relative risk, 1.18; 95% confidence interval, 1.02-1.37; P = .03). This was mainly due to more frequent symptom improvement in the progressive compressive stocking group. The compressive stockings were considered easy to apply by 81.3% of patients in the progressive compressive stocking group vs 49.7% of patients in the degressive compressive stocking group (P < .0001). The rate of related serious adverse events was low and similar in both groups. CONCLUSIONS This trial has demonstrated that progressive compressive stockings are more effective than usual degressive compressive stockings in the improvement of pain and lower leg symptoms in patients with CVI. Moreover, progressive compressive stockings were easier to apply, raising no safety concern at 3 months.

Individual patient data meta-analysis of enoxaparin vs. unfractionated heparin for venous thromboembolism prevention in medical patients.

Summary.  Background: Unfractionated heparin (UFH) and low‐molecular‐weight heparin (LMWH) are both recommended for venous thromboembolism (VTE) prophylaxis in hospitalized medical patients. Objective: To perform an individual patient data meta‐analysis to evaluate the relative efficacy and safety of the LMWH enoxaparin and UFH in preventing VTE in hospitalized medical patients. Methods: Randomized clinical trials comparing subcutaneous enoxaparin (4000 IU once‐daily) and UFH (5000 IU subcutaneous two‐ or three‐times daily) for VTE prevention were identified by a systematic search. Individual patient data were obtained from each eligible trial. Results: Overall, four trials were eligible, including 3600 patients randomized to receive enoxaparin (n = 1799) or UFH (n = 1801). Median patient age was 71 years, and 49.3% were female. Compared with UFH, enoxaparin was associated with risk reductions of 37% for total VTE [relative risk (RR) 0.63, 95% confidence interval (CI) 0.51–0.77] and 62% for symptomatic VTE (RR 0.38, 95% CI 0.17–0.85) at day 15. RR for total VTE in stroke and non‐stroke patients was 0.59 (95% CI 0.47–0.74) and 0.87 (95% CI 0.51–1.50), respectively. Major bleeding rates were consistently low and similar between treatment groups at day 15 (RR 1.13, 95% CI 0.53–2.44). There was a trend towards reduced risk for mortality in patients receiving enoxaparin (RR 0.83, 95% CI 0.64–1.08), compared with UFH. Conclusions: Enoxaparin significantly reduces VTE in hospitalized medical patients, compared with UFH, without increasing the risk for major bleeding, and was associated with a trend towards reduced all‐cause mortality.

Consistency of Effect of Docetaxel-Containing Adjuvant Chemotherapy in Patients with Early Stage Breast Cancer Independent of Nodal Status: Meta-Analysis of 12 Randomized Clinical Trials.

Background Up to now taxanes have been extensively evaluated in the treatment of node-positive early-stage breast cancers (ESBC). Recently, more data have become available in patients with node-negative as well as node-positive ESBC treated with docetaxel-based regimens. We conducted a meta-analysis of randomized ESBC trials in order to evaluate the efficacy of adjuvant docetaxel-based regimens in terms of disease-free survival (DFS), overall survival (OS), and whether treatment effects are maintained across different nodal status subpopulations. Methods Studies including at least 100 patients and presented or published before December 31, 2008 were retrieved by searching the MEDLINE, CANCERLIT, and Cochrane Library databases and the proceedings of major conferences. Outcomes recorded were DFS and OS. We extracted hazard ratios (HR) and 95% CIs for DFS and OS from each trial and obtained pooled estimates using an inverse-variance model in a random effect model. In trials including both node-positive and node-negative breast cancers, and with nodal status as a clear stratification factor at randomization, HR were extracted for each subpopulation separately. A HR less than 1 indicated that docetaxel was superior to the no-taxane regimen. Results Twelve randomized phase III studies were included in the meta-analysis (20 698 patients). Three subsets of trials/strata were used: node-positive (10 trials or strata, 14 787 patients), node-negative (4 trials/strata, 4 274 patients), or combination of both (2 trials, 1 637 patients). Overall, the pooled HR estimate [95% CI] for DFS was 0.81 [0.74;0.89] ( P ) in favor of docetaxel-based chemotherapy. The results are the same for node-positive (HR=0.84 [0.77;0.91]) and node-negative breast cancer (HR=0.84 [0.72;0.99]). The overall estimated HR for OS was 0.81 [0.72;0.91] ( P ). Results by nodal status subpopulations are awaited. Conclusion This meta-analysis of 12 recent randomized phase III trials shows that adjuvant docetaxel-based chemotherapy compared to regimens without taxanes is associated with an improvement in DFS and OS independent of nodal status. Other analyses will also be presented. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 605.

Impact of double‐blind vs. open study design on the observed treatment effects of new oral anticoagulants in atrial fibrillation: a meta‐analysis

The prospective, randomized, open, blinded endpoint evaluation (PROBE) design has been proposed as a valid alternative to the double‐blind (DB) design for trials comparing new oral anticoagulants (NOAs) with INR‐adjusted vitamin K antagonists in patients with non‐valvular atrial fibrillation (NVAF).

Intravenous Tranexamic Acid Bolus plus Infusion Is Not More Effective than a Single Bolus in Primary Hip Arthroplasty: A Randomized Controlled Trial

Background: Preoperative administration of the antifibrinolytic agent tranexamic acid reduces bleeding in patients undergoing hip arthroplasty. Increased fibrinolytic activity is maintained throughout the first day postoperation. The objective of the study was to determine whether additional perioperative administration of tranexamic acid would further reduce blood loss. Methods: This prospective, double-blind, parallel-arm, randomized, superiority study was conducted in 168 patients undergoing unilateral primary hip arthroplasty. Patients received a preoperative intravenous bolus of 1 g of tranexamic acid followed by a continuous infusion of either tranexamic acid 1 g (bolus-plus-infusion group) or placebo (bolus group) for 8 h. The primary outcome was calculated perioperative blood loss up to day 5. Erythrocyte transfusion was implemented according to a restrictive transfusion trigger strategy. Results: The mean perioperative blood loss was 919 ± 338 ml in the bolus-plus-infusion group (84 patients analyzed) and 888 ± 366 ml in the bolus group (83 patients analyzed); mean difference, 30 ml (95% CI, −77 to 137; P = 0.58). Within 6 weeks postsurgery, three patients in each group (3.6%) underwent erythrocyte transfusion and two patients in the bolus group experienced distal deep-vein thrombosis. A meta-analysis combining data from this study with those of five other trials showed no incremental efficacy of additional perioperative administration of tranexamic acid. Conclusions: A preoperative bolus of tranexamic acid, associated with a restrictive transfusion trigger strategy, resulted in low erythrocyte transfusion rates in patients undergoing hip arthroplasty. Supplementary perioperative administration of tranexamic acid did not achieve any further reduction in blood loss.

Prevention of Venous Thromboembolic Events With Low- Molecular-Weight Heparin in the Non-Major Orthopaedic Setting: Meta-Analysis of Randomized Controlled Trials

PURPOSE To assess the efficacy of low-molecular-weight heparin (LMWH) venous thromboprophylaxis in patients with transient reduced mobility in the non-major orthopaedic setting. METHODS A meta-analysis was conducted using data from all available randomized trials comparing LMWH with placebo or no prophylactic treatment in patients with leg immobilization for fracture or soft-tissue injury of the lower limb or in patients undergoing knee arthroscopy. The primary endpoint was the incidence of major venous thromboembolic events (VTEs), including asymptomatic proximal deep-vein thrombosis, symptomatic VTEs, and VTE-related death. The Mantel-Haenszel method was used to generate the summary statistics for the overall effect of LMWH. RESULTS Fourteen studies were included (4,726 patients). The weighted rate of major VTEs was estimated to be 2.9% (95% confidence interval [CI], 2.2% to 3.7%) without LMWH prophylaxis. Overall, a significant 68% reduction in the risk of major VTEs was observed with LMWH prophylaxis (relative risk [RR], 0.32; 95% CI, 0.20 to 0.51; P < .001). The treatment effect was not modified by the clinical setting, that is, distal lower limb injury (7 studies; 1,711 patients; RR, 0.42; 95% CI, 0.20 to 0.86) or knee arthroscopy (6 studies; 2,428 patients; RR, 0.27; 95% CI, 0.15 to 0.49). A nonsignificant 35% increase in the risk of major bleeding was observed in the LMWH prophylaxis group (RR, 1.35; 95% CI, 0.53 to 3.47). CONCLUSIONS This meta-analysis indicates potential efficacy of LMWH in preventing thromboembolic events in patients with reduced mobility in the non-major orthopaedic setting compared with placebo or no treatment. However, the decision of whether to implement LMWH prophylaxis in each specific setting should also take into account the risk of VTEs in the absence of prophylaxis, the potential adverse effects of LMWH, and the cost. LEVEL OF EVIDENCE Level II, meta-analysis of Level II studies or Level I studies with inconsistent results.