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Asciminib, the first BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), is approved worldwide for the treatment of adults with Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase (CML-CP) treated with ≥2 prior tyrosine kinase inhibitors (TKIs). In ASCEMBL, patients with CML-CP treated with ≥2 prior TKIs were randomized (stratified by baseline major cytogenetic response [MCyR]) 2:1 to asciminib 40 mg twice daily or bosutinib 500 mg once daily. Consistent with previously published primary analysis results, after a median follow-up of 2.3 years, asciminib continued to demonstrate superior efficacy and better safety and tolerability than bosutinib. The major molecular response (MMR) rate at week 96 (key secondary endpoint) was 37.6% with asciminib vs 15.8% with bosutinib; the MMR rate difference between the arms, after adjusting for baseline MCyR, was 21.7% (95% CI, 10.53–32.95; two-sided p = 0.001). Fewer grade ≥3 adverse events (AEs) (56.4% vs 68.4%) and AEs leading to treatment discontinuation (7.7% vs 26.3%) occurred with asciminib than with bosutinib. A higher proportion of patients on asciminib than bosutinib remained on treatment and continued to derive benefit over time, supporting asciminib as a standard of care for patients with CML-CP previously treated with ≥2 TKIs.

Patients with chronic myeloid leukemia in chronic phase (CML-CP) resistant/intolerant to ≥2 tyrosine kinase inhibitors (TKIs) are at high risk of experiencing poor outcomes because of disease biology and inadequate efficacy and/or safety of current therapies. Asciminib, a first-in-class BCR-ABL1 inhibitor Specifically Targeting the ABL Myristoyl Pocket (STAMP), has the potential to overcome resistance/intolerance to approved TKIs. In this phase 3, open-label study, patients with CML-CP previously treated with ≥2 TKIs were randomized (2:1) to receive asciminib 40 mg twice daily vs bosutinib 500 mg once daily. Randomization was stratified by major cytogenetic response (MCyR) status at baseline. The primary objective was to compare the major molecular response (MMR) rate at week 24 for asciminib vs bosutinib. A total of 233 patients were randomized to asciminib (n = 157) or bosutinib (n = 76). Median follow-up was 14.9 months. The MMR rate at week 24 was 25.5% with asciminib and 13.2% with bosutinib. The difference in MMR rate between treatment arms, after adjusting for MCyR at baseline, was 12.2% (95% confidence interval, 2.19-22.30; 2-sided P = .029). Fewer grade ≥3 adverse events (50.6% vs 60.5%) and adverse events leading to treatment discontinuation (5.8% vs 21.1%) occurred with asciminib than with bosutinib. The study showed a superior efficacy of asciminib compared with that of bosutinib, together with a favorable safety profile. These results support the use of asciminib as a new therapy in patients with CML-CP who are resistant/intolerant to ≥2 prior TKIs. This trial was registered at www.clinicaltrials.gov as #NCT03106779.

7004 Background: Asciminib is the first BCR::ABL1 inhibitor to specifically target the ABL Myristoyl Pocket (STAMP). In the ASCEMBL primary analysis, asciminib had superior efficacy and better safety/tolerability than BOS in pts with CML-CP after ≥2 prior TKIs. After a median follow-up of 2.3 years (16.5 months’ additional follow-up since primary analysis), we report efficacy and safety results (cutoff: October 6, 2021). Methods: Eligible pts were adults with CML-CP after ≥2 prior TKIs, with intolerance or lack of efficacy per 2013 European LeukemiaNet. Pts were randomized 2:1 to asciminib 40 mg twice daily or BOS 500 mg once daily, stratified by major cytogenetic response (MCyR) status (Ph+ metaphases ≤35%) at baseline. The key secondary endpoint was major molecular response (MMR) rate at wk 96. Results: 233 pts were randomized to asciminib (n=157) or BOS (n=76). At cutoff, treatment was ongoing in 84 (53.5%) and 15 (19.7%) pts, respectively; the most common reason for discontinuation was lack of efficacy in 38 (24.2%) and 27 (35.5%) pts, respectively. MMR rate at wk 96 (per ITT) was higher on asciminib (37.6%) than BOS (15.8%). The difference, adjusting for baseline MCyR, was 21.7% (95% CI, 10.5%-33.0%; 2-sided P=.001). More pts on asciminib than BOS, respectively, had BCR::ABL1IS ≤1% (45.1% vs 19.4%) at wk 96. The probability of maintaining MMR and BCR::ABL1IS ≤1% for ≥72 wk was 96.7% (95% CI, 87.4%-99.2%) and 94.6% (95% CI, 86.2%-97.9%), respectively, on asciminib and 92.9% (95% CI, 59.1%-99.0%) and 95.0% (95% CI, 69.5%-99.3%), respectively, on BOS. Median duration of exposure was 103.1 (range, 0.1-201.1) wk on asciminib and 30.5 (range, 1.0-188.3) wk on BOS. Despite the longer duration of asciminib exposure, safety/tolerability of asciminib continued to be better than that of BOS (Table). No new on-treatment deaths were reported since the primary analysis. Most frequent (>10%) grade ≥3 adverse events (AEs) on asciminib vs BOS were thrombocytopenia (22.4%, 9.2%), neutropenia (18.6%, 14.5%), diarrhea (0%, 10.5%), and increased alanine aminotransferase (0.6%, 14.5%). Conclusions: After >2 years of follow-up, asciminib continued to show superior efficacy and better safety/tolerability vs BOS. Responses were durable, with more pts on asciminib in MMR. Additionally, more pts on asciminib had BCR::ABL1IS ≤1%, a milestone response in later lines associated with improved survival. These results continue to support the use of asciminib as a new CML therapy, with the potential to transform standard of care. Clinical trial information: NCT03106779. [Table: see text]

Chronic myeloid leukemia (CML) is rare in children and accounts for £15% of all myeloid leukemia cases. When we initiated this study with nilotinib, imatinib was the only tyrosine kinase inhibitor indicated for pediatric patients with Philadelphia chromosome–positive (Ph1) CML in chronic phase (CP); alternative treatment options were needed, particularly for patients who developed resistance or intolerance (R/I) to imatinib. This phase 2 study enrolled pediatric patients with either Ph1 CML-CP R/I to imatinib or dasatinib or newly diagnosed Ph1 CML-CP. Data presented are from analyses with minimum follow-up of up to 24 cycles (1 cycle is 28 days). Fifty-nine patients with Ph1 CML-CP were enrolled, and 58 were treated (R/I, n 5 33; newly diagnosed, n 5 25). Major molecular response (MMR) rate at cycle 6 in the R/I cohort was 39.4% (primary end point); 57.6% of patients achieved or maintained MMR and 81.8% achieved or maintained complete cytogenetic response (CCyR) by 24 cycles. In patients with newly diagnosed disease, rates of MMR by cycle 12 and CCyR at cycle 12 were 64.0% each (primary end points); by cycle 24, cumulative MMR and CCyR rates were 68.0% and 84.0%, respectively. The safety profile of nilotinib in pediatric patients was generally comparable with the known safety profile in adults, although cardiovascular events were not observed in this study, and hepatic laboratory abnormalities were more frequent; no new safety signals were identified. In summary, nilotinib demonstrated efficacy and a manageable safety profile in pediatric patients with Ph1 CML-CP. This trial was registered at www.clinicaltrials.gov as #NCT01844765. (Blood. 2019;134(23):2036-2045).

To compare magnetic resonance imaging (MRI) brain feature in cryptogenic stroke patients with patent foramen ovale (PFO), cryptogenic stroke patients without PFO and patients with cardioembolic stroke.The ethics committee required neither institutional review board approval nor informed patient consent for retrospective analyses of the patients' medical records and imaging data. The patients' medical files were retrospectively reviewed in accordance with human subject research protocols. Ninety-two patients under 60 years of age were included: 15 with cardioembolic stroke, 32 with cryptogenic stroke with PFO and 45 with cryptogenic stroke without PFO. Diffusion-weighted imaging of brain MRI was performed by a radiologist blinded to clinical data. Univariate, Fischer's exact test for qualitative data and non-parametric Wilcoxon test for quantitative data were used.There was no statistically significant difference found between MRI features of patients with PFO and those with cardioembolic stroke (p.05). Patients without PFO present more corticosubcortical single lesions (p.05) than patients with PFO. Patients with PFO have more often subcortical single lesions larger than 15mm, involvement of posterior cerebral arterial territory and intracranial occlusion (p.05) than patients with cryptogenic stroke without PFO.Our study suggests a cardioembolic mechanism in ischemic stroke with PFO.

SummaryWhile laboratory monitoring is not required in patients treated with apixaban, a direct factor-Xa inhibitor, assessment of its concentration is useful in some critical situations. However, few data are available on its effect on coagulation tests and on the suitability of anti-Xa assays for its quantification. It was the objective of this study to identify laboratory tests suitable for apixaban concentration assessment. Coagulation tests – PT and aPTT- and anti-Xa assays were performed in apixaban-spiked plasma samples. To evaluate the sensitivity of PT and aPTT to apixaban, we conducted a first monocenter part, with a wide range of concentrations (50–1,000 ng/ml), a large panel of reagents (20 reagents), and two coagulometers (STAR®, Stago and ACL TOP®, IL), and a second multicenter part involving 13 laboratories using either a common PT reagent (RecombiPlastin2G®) or the local PT and aPTT reagents. In the multicentre part, five blinded apixaban-spiked plasma samples (0/100/200/400/800 ng/ml – checked by HPLC-MS/MS) were used; apixaban concentrations were measured with three anti-Xa assays, apixaban calibrators and controls (Stago). PT and aPTT tests using a large panel of reagents displayed a low sensitivity to a wide range of apixaban concentrations. The concentrations to double PT ranged from 400 to >1,000 ng/ml with the 10 reagents. With the three anti-Xa assays, interlaboratory precision and accuracy were below 11% and 12%, respectively. In conclusion, whereas PT and aPTT tests were not sensitive enough to detect apixaban, the three anti-Xa assays tested using lyophilised apixaban calibrators and controls allowed to reliably quantify a wide range of apixaban concentrations.

Introduction Management of pregnant women at increased risk of venous thromboembolism (VTE) remains complex in the absence of an easy-to-use tool allowing individualised, risk-adapted prophylaxis. Our objective was to assess whether treatment based on risk score is feasible in these women. Materials and methods A scoring system for VTE risk in pregnant women was developed, each score being associated with a specific treatment. This system was implemented in a prospective cohort of 2736 consecutive women delivered in our teaching hospital from July 2002 to June 2003. Thromboembolic and obstetrical outcomes during pregnancy and the early post-partum period were recorded. Results Treatment based on risk score was implemented in 2685 of the 2736 women included (98.1%). The scoring system identified 2431 women with no risk factor and 305 women (11%) with at least one risk factor. Eight women not at risk (0.3%, [95% CI: 0.1–0.5]) and one at risk (0.4%, [95% CI: 0–1.1]) experienced a VTE. This low event rate precluded estimation of the discriminatory power of the score. However, the benefit of the scoring system was evaluated indirectly by assessing VTE incidence in the 46 women at risk in whom it was not used (15.2%, [95% CI: 4.8–25.6]). Conclusions Our simple scoring system offers an easily implemented procedure for risk-based VTE prophylaxis of pregnant women and the proposed therapeutic strategy appears to be effective and safe in reducing VTE. The discriminatory power of the score is currently being evaluated in a randomized, controlled trial.

Venous thrombosis is a common and severe complication in patients with cancer. We reviewed studies assessing whether a state of acquired or congenital thrombophilia influenced the risk of thrombosis in patients with cancer. The results are equivocal. However, the majority of studies were of limited size. The influence of thrombophilia in patients with cancer may be more difficult to demonstrate than in the general population, the risk of thrombosis due to cancer per se possibly outweighing the contribution of thrombophilic factors. Moreover, the results may depend on the genetic background of the population, the type of cancer, the type of thrombosis, and the chemotherapeutic treatment. Nevertheless, it appears that factor V Leiden or G20210A prothrombin gene mutation increases the risk of venous thromboembolism about 2- to 4-fold, compared with patients with cancer without either of these mutations. Similar results were observed for the occurrence of central venous catheter-associated thrombosis. Antiphospholipid antibodies and acquired resistance to activated protein C were frequently observed in patients with cancer and appeared to favor the occurrence of thrombosis. The role of hyperhomocysteinemia deserves further investigation. Since the clinical implications of these findings remain to be clarified, routine screening of cancer patients for thrombophilia cannot yet be recommended on the basis of these studies. Studies designed to assess the value of thromboprophylaxis in high-risk patients, including thrombophilic patients, with long-term central venous catheters may be valuable.

Study objectives Low-molecular-weight heparins have been compared with unfractionated heparin (UFH) for treatment of deep vein thrombosis (DVT). However, a comparison of their efficacy in the presence or absence of pulmonary embolism (PE) has not been studied. We estimated the efficacy and safety of enoxaparin vs UFH in patients with proximal DVT with/without symptomatic PE using a meta-analysis of individual data from randomized controlled trials. Design and setting Randomized controlled trials were identified from MEDLINE, EMBASE, abstracts from international meetings on venous thromboembolism (VTE), previous meta-analyses, and trial data provided by the sponsor. Participants For inclusion, randomized controlled trials had to be properly randomized; include patients with objectively diagnosed DVT; compare enoxaparin twice daily with UFH; use objective methods to assess recurrent symptomatic VTE, major bleeding, and death at 3 months; and include blind evaluation of clinical events. Measurements A meta-analysis was performed using the logarithm of the relative risk (RR) method. Enoxaparin in DVT treatment with/without symptomatic PE was considered noninferior to UFH for preventing VTE at 3 months if the upper limit of the 95% confidence interval (CI) of the RR (enoxaparin/UFH) was lower than a prespecified noninferiority margin (1.61). No increase in major bleeding or mortality should be observed. Results The meta-analysis included individual data from three randomized controlled trials (749 patients and 754 patients in the enoxaparin and UFH groups, respectively). The observed RR (enoxaparin/UFH) of VTE was 0.81 (95% CI, 0.52 to 1.26) for the intention-to-treat population (RR, 0.70; 95% CI, 0.43 to 1.13; for per-protocol analysis). Results did not differ for patients with clinical PE (235 patients; RR, 0.84) and without clinical PE (1,268 patients; RR, 0.71), with a nonsignificant heterogeneity test between groups (p = 0.76). A trend in favor of enoxaparin was observed for reduced mortality and major bleeding. Conclusions The efficacy and safety of enoxaparin vs UFH for DVT treatment is not modified by the presence of symptomatic PE.

Superficial vein thrombosis (SVT) risk factors are close to those of venous thromboembolism (VTE). Diagnosis is made in a clinical setting but ultrasonography is useful to eliminate concomitant deep vein thrombosis (DVT). For SVT of the lower limbs, which is the main location, varicose veins represent the principal cause but underlying conditions (e.g.: autoimmune diseases, malignancy or thrombophilia) must be sought in idiopathic, migrant or recurrent SVT and in the absence of varicose veins. Concomitant DVT and pulmonary embolism can occur in approximately 15% and 5% respectively. Historical treatments consist of anti-inflammatory agents plus elastic stockings and, in case of varicose veins, thrombectomy and stripping. Other treatments (anticoagulants, vein ligation) were assessed to limit the VTE risk. A one-month prophylactic dose of low molecular weight heparin plus elastic stockings could be the appropriate strategy in most cases. Other studies are needed before definitive conclusions can be drawn.

Objective Superficial vein thrombosis may be complicated with venous thromboembolism. We examined factors predictive of venous thromboembolism in superficial vein thrombosis, which, to our knowledge, had not been prospectively studied before. Design and methods We performed post hoc analysis of the STENOX trial, a prospective randomized controlled trial that investigated various antithrombotic therapies in 427 hospitalized patients with objectively confirmed symptomatic isolated superficial vein thrombosis. The value of various baseline characteristics as predictive factors of venous thrombotic complications at 3 months was studied with logistic regression. Venous thrombotic complications were defined as deep vein thrombosis or pulmonary embolism, or recurrence or proximal extension of superficial vein thrombosis. Results Venous thrombotic complications occurred in 78 patients. Independent predictive factors for complications were superficial vein thrombosis of recent onset (odds ratio [OR], 3.01; 95% confidence interval [CI], 1.44-6.27), severe chronic venous insufficiency (OR, 2.75; CI, 1.10-6.89), male gender (OR, 2.17; CI, 1.28-3.68), and history of venous thromboembolism (OR, 2.07; CI 1.06-4.04). Deep vein thrombosis or pulmonary embolism occurred in 19 patients. Only severe chronic venous insufficiency was an independent predictor of this complication (OR, 4.50; CI, 1.30-15.61). Conclusions After symptomatic isolated superficial vein thrombosis, venous thrombotic complications are relatively frequent, and are more likely to occur in men, in patients with a history of venous thromboembolism or with severe chronic venous insufficiency, or in whom superficial vein thrombosis is recent. Knowledge of such predictive factors may be useful for determining appropriate treatment in patients with superficial vein thrombosis and for designing future phase III clinical trials.

SummaryThe aim of the study was to assess the respective roles of the half-life of elimination of oral anticoagulants and patient education as causes of instability of anticoagulation level in patients on oral anticoagulant therapy. Patients were randomised to receive either warfarin (long half-life) or acenocoumarol (short half-life) and either intensive or standard education, according to a factorial design. Instability of oral anticoagulant therapy was evaluated by the percentage of INRs and the time within the target range, and the variability between successive measurements. Compliance was assessed by means of electronic pill bottles. Eighty-six patients were included. Apart from the variability index, instability was similar between groups. Correlations between compliance and instability were observed only in the acenocoumarol group. No difference was found between the education groups. In patients starting oral anticoagulant therapy, dose determination may be the most important factor contributing to instability.

Journal Article; Multicenter Study; Research Support, Non-U.S. Gov't; BACKGROUND Patients with chronic obstructive pulmonary disease (COPD) have a modified clinical presentation of venous thromboembolism (VTE) but also a worse prognosis than non-COPD patients with VTE. As it may induce therapeutic modifications, we evaluated the influence of the initial VTE presentation on the 3-month outcomes in COPD patients. METHODS COPD patients included in the on-going world-wide RIETE Registry were studied. The rate of pulmonary embolism (PE), major bleeding and death during the first 3 months in COPD patients were compared according to their initial clinical presentation (acute PE or deep vein thrombosis (DVT)). RESULTS Of the 4036 COPD patients included, 2452 (61%; 95% CI: 59.2-62.3) initially presented with PE. PE as the first VTE recurrence occurred in 116 patients, major bleeding in 101 patients and mortality in 443 patients (Fatal PE: first cause of death). Multivariate analysis confirmed that presenting with PE was associated with higher risk of VTE recurrence as PE (OR, 2.04; 95% CI: 1.11-3.72) and higher risk of fatal PE (OR, 7.77; 95% CI: 2.92-15.7). CONCLUSIONS COPD patients presenting with PE have an increased risk for PE recurrences and fatal PE compared with those presenting with DVT alone. More efficient therapy is needed in this subtype of patients. Yes

International audience; In a meta-analysis of case-control studies, Zhang et al. (2011) found an increased risk of venous thromboembolic events (VTE) in patients exposed to antipsychotics (OR=2.39 [1.71-3.35]). Our updated meta-analysis including the 2 available cohort studies, recognized as a more relevant type of observational study, showed a weaker, but still strong association (OR=1.84 [1.39; 2.44]). In view of the lack of data on the confirmed risk factors for VTE in existing studies, prospective studies including adjustment for these risk factors are warranted to confirm this association and to assess the benefit/risk ratio of antipsychotics in high-risk patients.

Objectives To assess the efficiency of a systematically planned compression ultrasonography (SP-CUS) to detect venous thrombotic complications (VTCs) in patients with symptomatic isolated superficial vein thrombosis (SVT). Design Post hoc analysis of a prospective, multicentre, cohort study (POST). Patients As many as 537 patients with CUS-confirmed isolated SVT undergoing an SP-CUS 8–15 days after the initial CUS. Outcomes Asymptomatic VTC (extension or recurrence of SVT, deep-vein thrombosis (DVT) of the lower limbs) diagnosed by the SP-CUS and symptomatic thromboembolic complications (VTC and pulmonary embolism (PE)) up to 3 months. Results VTC was suspected before or on the day of the SP-CUS in 18 patients (3.0%). Among the 519 asymptomatic patients (97%) undergoing SP-CUS, this revealed asymptomatic VTC in 12 patients (2.3%; 4 DVT, 4 SVT recurrences, 4 SVT extensions), none of whom subsequently experienced symptomatic thromboembolic events up to 3 months. Among the 507 patients with a normal SP-CUS, 29 (5.7%) presented symptomatic thromboembolic events during follow-up: 2 PE, 7 DVT, 9 SVT recurrences and 11 SVT extensions. Conclusions In this study, the SP-CUS detected a few asymptomatic VTC, but failed to identify patients at risk of thromboembolic events during follow-up. Use of an SP-CUS was therefore neither efficient nor cost effective.

Background: The immediate and long-term clinical events associated with the placement and removal of a retrievable filter (ALN filter; ALN Implants Chirurgicaux; Ghisonaccia, France) remain largely unknown. Methods: This was a prospective cohort study with an 18-month follow-up. All consecutive patients scheduled for placement of an ALN filter between April 1999 and June 2005 in the Radiology Department of our hospital were included. Results: During the study period, placement of an ALN filter was indicated in 220 patients (mean age, 70.8 years), who were followed up for a median duration of 338.5 days (range, 1 to 561 days); 148 patients (67.3%) completed the 18-month follow-up. No patients were unavailable for follow-up. All patients had an acute or past venous thromboembolism. Main indications were recurrent venous thromboembolism despite adequate anticoagulation therapy (10.9%), transient bleeding event (21.8%), definitive contraindication for anticoagulant therapy (26.8%), or obligation to stop anticoagulant therapy due to major surgery, major trauma, or invasive procedure (37.7%). Filter insertion was successful in 98.6% of patients and resulted in an immediate complication in 11.8%. The median duration of filter implantation was 166 days (first to third quartiles, 34 to 478 days). Meanwhile, 17.0% (37 of 217 patients) had at least one venous thromboembolic event. Filter retrieval was attempted in 25.3% of patients after a median of 51 days (range, 6 to 352 days); removal was successful at the first attempt in 92.7% of patients. Conclusions: The filter could be easily inserted and successfully removed up to 1 year after insertion. Its safety and efficacy in preventing pulmonary embolism should be properly assessed in a randomized study. (CHEST 2007; 131:223–229)

Low-molecular-weight heparins have been compared with unfractionated heparin (UFH) for treatment of deep vein thrombosis (DVT). However, a comparison of their efficacy in the presence or absence of pulmonary embolism (PE) has not been studied. We estimated the efficacy and safety of enoxaparin vs UFH in patients with proximal DVT with/without symptomatic PE using a meta-analysis of individual data from randomized controlled trials.Randomized controlled trials were identified from MEDLINE, EMBASE, abstracts from international meetings on venous thromboembolism (VTE), previous meta-analyses, and trial data provided by the sponsor.For inclusion, randomized controlled trials had to be properly randomized; include patients with objectively diagnosed DVT; compare enoxaparin twice daily with UFH; use objective methods to assess recurrent symptomatic VTE, major bleeding, and death at 3 months; and include blind evaluation of clinical events.A meta-analysis was performed using the logarithm of the relative risk (RR) method. Enoxaparin in DVT treatment with/without symptomatic PE was considered noninferior to UFH for preventing VTE at 3 months if the upper limit of the 95% confidence interval (CI) of the RR (enoxaparin/UFH) was lower than a prespecified noninferiority margin (1.61). No increase in major bleeding or mortality should be observed.The meta-analysis included individual data from three randomized controlled trials (749 patients and 754 patients in the enoxaparin and UFH groups, respectively). The observed RR (enoxaparin/UFH) of VTE was 0.81 (95% CI, 0.52 to 1.26) for the intention-to-treat population (RR, 0.70; 95% CI, 0.43 to 1.13; for per-protocol analysis). Results did not differ for patients with clinical PE (235 patients; RR, 0.84) and without clinical PE (1,268 patients; RR, 0.71), with a nonsignificant heterogeneity test between groups (p = 0.76). A trend in favor of enoxaparin was observed for reduced mortality and major bleeding.The efficacy and safety of enoxaparin vs UFH for DVT treatment is not modified by the presence of symptomatic PE.

SummaryLow-molecular-weight heparins (LMWH) are routinely used for thromboprophylaxis in major lower limb orthopaedic surgery. However the optimal LMWH regimen, offering the greatest efficacy with an acceptable risk of bleeding, has not been clearly established with regard to dose and timing of treatment initiation. We performed a meta-analysis of all available randomised trials comparing LMWH to placebo. Relative risks (RR) and corresponding 95% confidence intervals (CI) were calculated. By means of subgroup analysis, we evaluated the consistency of the results according to the timing of treatment initiation (preoperative versus postoperative) and dose of LMWH used (low doses, i.e. 4000 anti-Xa IU or below versus high doses). The possibility of a dose-effect relationship of LMWH was also evaluated by meta-regression. Thirteen studies were included (1925 patients). In four studies, LMWH treatment was started postoperatively. Daily LMWH doses ranged from 3000 anti-Xa IU to over 6000 anti-Xa IU. Compared to placebo, LMWH significantly reduced the risk of asymptomatic deep-vein thrombosis (DVT) (RR=0.51, 95% CI=[0.45-0.59], p