Symptomatic Non-fatal Pulmonary Embolism Research Articles

Extended Thromboprophylaxis in Hospitalized Patients with Heart Failure: A Post Hoc Analysis of the MAGELLAN Study.

This post hoc subgroup analysis examined efficacy and safety outcomes with extended thromboprophylaxis rivaroxaban compared with in-hospital enoxaparin in 2,078 patients from the MAGELLAN study who had a hospitalization for heart failure or a history of heart failure and a lower risk of bleeding. A significant 36% reduction in the composite endpoint of asymptomatic proximal deep vein thrombosis (DVT) in the lower extremity, symptomatic DVT in the lower extremity (proximal or distal), symptomatic nonfatal pulmonary embolism, and venous thromboembolism-related death was observed with rivaroxaban. Major bleeding was low in both groups and not significantly increased with rivaroxaban.

Clinical and imaging outcomes of OptionELITE vena cava filter placement procedures

ObjectiveWe sought to determine the clinical and imaging outcomes after placement of the OptionELITE inferior vena cava (IVC) filter (Argon Medical Devices, Plano, TX). MethodsThe clinical characteristics and imaging findings of patients who had undergone OptionELITE filter placement at six affiliated hospitals between January 1, 2013 and April 19, 2019, were analyzed. Data were obtained from the Radiology Information System, imaging database, and electronic medical records. The patients were followed up until 1 month after filter removal, death, or the first clinic visit and imaging study after June 1, 2019. ResultsA total of 603 filter placement procedures in 594 patients were evaluated. Of the 603 procedures, 602 were technically successful (99.8%). Of the 594 patients, 356 had presented with acute pulmonary embolism and/or deep vein thrombosis. A total of 189 filters were retrieved from the 191 patients for whom retrieval had been attempted at 4.3 ± 6.3 months (median, 2.5 months) after placement. The 414 filters without removal procedures had been followed up for 14.8 ± 17.7 months (median, 6.9 months). During the follow-up period, 57 patients (9.5%) had developed new or worsening deep vein thrombosis caudal to the filter and 19 (3.2%) had experienced new symptomatic nonfatal pulmonary embolism after filter placement. One filter had migrated and fractured, and another filter had fractured and a strut was lost. Perforation was demonstrated equivocally in 12 (3%) and definitely in 17 (4.3%) of 399 patients with adequate imaging studies available, with penetration into surrounding structures in 13 patients (3.3%). Of 332 patients with adequate imaging studies, 12 (3.6%) had developed substantial IVC thrombosis and 4 (1.2%) had developed IVC occlusion. ConclusionsThe rates of symptomatic pulmonary embolism and filter-related complications were low after OptionELITE IVC filter placement, and filter retrieval, when attempted, was 99% successful.

Efficacy and Safety of Tinzaparin in CAT Patients with Hematological Malignancy

IntroductionIn patients with hematological cancers, the high risk of bleeding raises serious concerns when anticoagulant therapy is initiated for treatment of acute venous thromboembolism (VTE). In the CATCH trial, we showed that tinzaparin is associated with a significantly lower risk of clinically relevant bleeding (CRB) and clinically relevant non-major bleeding (CRNMB) compared with warfarin therapy in patients with a solid tumor or hematological cancer. Hence, we performed a post-hoc analysis to assess the risk of recurrent VTE (rVTE) and bleeding in the hematological cancer patient subgroup. Risk factors associated with rVTE and bleeding were also explored.MethodsCATCH (ClinicalTrials.govNCT01130025; Lee A et al. JAMA 2015) was a Phase III, multinational, randomized, active-controlled, open-label trial. Patients with solid tumors or hematological malignancies were randomized to receive therapeutic dosing of tinzaparin (175 IU/kg OD) vs warfarin (INR target 2.0 - 3.0) for treatment of acute VTE. Treatment was given for up to 6 months but was withheld during periods of severe thrombocytopenia (platelet count < 50 x 10 9/L). The primary efficacy outcome was the composite of symptomatic deep vein thrombosis (DVT), symptomatic nonfatal pulmonary embolism (PE), fatal PE, incidental proximal DVT and incidental proximal PE. All thrombosis and bleeding outcomes, including rPE, rDVT, major bleeding (MB), CRB, and CRNMB were objectively documented and centrally adjudicated in a treatment-blinded fashion. Patients with myeloma, lymphoma or leukemia were included in this sub-group analysis. Treatment effect was assessed by means of a cox-regression with time to first event as outcome and deaths not due to fatal PE as a competing risk factor. The cumulative incidence functions and the corresponding 95% CIs were estimated.Results94 of 900 subjects (10.4%) in CATCH had a hematological cancer. Of these patients, 44 and 50 received tinzaparin and warfarin, respectively. The most common hematological cancer was lymphoma (59.6%), followed by myeloma (30.9%), chronic leukemia (5.3%) and acute leukemia (4.3%). rVTE occurred in fewer patients assigned to tinzaparin versus warfarin (2.4% vs 6.4%) but this difference was not statistically significant (HR 0.36; 95%CI 0.04-3.14). All recurrent thrombotic events were PE; no rDVT occurred. Also, trends for less bleeding with tinzaparin were noted for MB (tinzaparin 0.0% versus warfarin 5.0%), CRB (tinzaparin 10.4% vs warfarin 23.5%; HR 0.53; 95%CI 0.15-1.83) and CRNMB (tinzaparin 10.4% vs warfarin 19.5%; HR 0.69; 95%CI 0.19-2.51). 3 patients in each treatment arm had a fatal bleeding event and there was no difference in overall mortality (tinzaparin 22.7% vs warfarin 22.0%). There were no risk factors associated with rVTE identified. Factors associated with CRB in patients with hematological cancer included the use of antiplatelet agents (HR 7.63; 95%CI 1.17-49.6; p=0.033) and renal insufficiency (HR 12.4; 95%CI 2.15-72.0; p=0.005).ConclusionIn this post-hoc subgroup analysis of patients with hematological cancers who received anticoagulation for acute VTE, tinzaparin may be a more effective and safer alternative to warfarin. Randomized controlled trials are warranted to test this hypothesis in this challenging population with a high risk of bleeding. [Display omitted] DisclosuresLee: Leo Pharma: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Servier: Consultancy, Honoraria. Bauersachs: Bayer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; LEO Pharma: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Janus: LEO Pharma: Current Employment. Leeder: LEO Pharma: Current Employment. Thoning: LEO Pharma: Current Employment. Khorana: Anthos: Consultancy, Honoraria; Halozyme: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria.

Efficacy and Safety of Tinzaparin in CAT Patients with Metastatic Disease

Introduction Venous thromboembolism (VTE) frequently complicates the course of active cancer with a significant impact on morbidity and mortality. The results of CATCH trial for treatment of cancer-associated thrombosis (CAT) have been reported and included patients with and without metastatic disease. As metastatic disease is known to be associated with a higher risk of recurrent VTE and bleeding, we performed these post hoc analyses to assess the recurrent VTE (rVTE), recurrent deep vein thrombosis (rDVT), and bleeding events (major bleeding (MB), clinically relevant (CRB) and clinically relevant non-major (CRNMB)) in patients with CAT with metastatic disease. Risk factors associated with rVTE, rDVT and CRB were also explored. Method CATCH (ClinicalTrials.govNCT01130025; Lee A et al. JAMA 2015) was a Phase III, multinational, randomized, active-controlled, open-label trial. Patients with solid tumor cancer and haematological malignancies were included. Patients were randomized to receive therapeutic dosing of tinzaparin (175 U/kg OD) vs warfarin (INR target 2.0 - 3.0). Treatment was given for up to 6 months. The primary efficacy outcome was the composite of symptomatic DVT, symptomatic nonfatal pulmonary embolism (PE), fatal PE, incidental proximal DVT and incidental proximal PE. All cumulative incidence VTE and MB outcome were objectively documented and centrally adjudicated in a treatment-blinded fashion. Patients who had known metastatic solid tumor at presentation were included in these analysis. The regression model compared the two treatment groups adjusting for competing risks and geographical region and history of VTE. Results Among the CATCH study population, 55% had metastatic disease. Of these patients, 247 and 245 received tinzaparin and warfarin, respectively, with no significant differences in patient characteristics between treatment groups. Patients with metastatic disease had a higher incidence of rVTE (10.2% vs 7.0%) and symptomatic non-fatal rDVT (5.5% vs 2.9%) compared to patients without metastatic disease. Patients with metastatic disease also had a higher incidence of MB (2.8% vs 1.9%), CRB (17.7%% vs 11.8%) and CRNMB (15.0% vs 10.5%) compared to patients without metastatic disease. rVTE occurred in significantly fewer patients assigned to tinzaparin (6.8%) versus warfarin (14.4%) (HR 0.45; 95%CI 0.25-0.80; p=0.007). rDVT also occurred significantly less frequently in patients assigned to tinzaparin (3.0%) versus warfarin (8.4%) (HR 0.34; 95%CI 0.15-0.81; p=0.015). 96% of rVTE were symptomatic. There was no significant difference in MB between tinzaparin- and warfarin-treated patients (4.0% vs 1.6%; HR 2.17; 95%CI 0.71-6.65; p=0.177), but tinzaparin was associated with significantly lower risk of CRB (15.8% vs 19.6%; HR 0.63; 95%CI 0.41-0.97; p=0.037) and CRNMB (12.1% vs 18.0%; HR 0.53; 95%CI 0.33-0.84; p=0.008). Factors associated with rVTE in patients with metastatic disease included central venous catheterization (HR 0.10; 95%CI 0.01-0.79; p=0.029), venous compression from mass or adenopathy (HR 3.99; 95%CI 2.14-7.43; p&amp;lt;0.001), and hepatobiliary cancer (HR 4.07; 95%CI 1.65-10.0; p=0.002). The latter two were also significant risk factors for rDVT. Age &amp;gt; 75 (HR 2.56; 95%CI 1.43-4.60; p=0.002) and known intracranial pathology (HR 2.24; 95%CI 1.07-4.66; p=0.031) were found to be significant risk factors for CRB. Conclusion CAT patients with metastatic diseases have higher risks of rVTE and bleeding compared with patients without metastases. Amongst CAT patients with metastatic solid tumors, treatment with tinzaparin was associated with significantly lower risk of rVTE and rDVT and significantly lower risk of CRB and CRNMB compared with warfarin. Tinzaparin offers a favourable risk-benefit profile in treatment of CAT in patients with metastatic solid tumors. Disclosures Lee: Pfizer: Consultancy, Honoraria; BMS: Research Funding; LEO Pharma A/S: Consultancy, Honoraria; Bayer: Consultancy, Honoraria, Other: Advisory board, steering committee. Bauersachs:Aspen: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; LEO Pharma A/S: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Turpin:LEO Pharma Canada: Current Employment. Hansen:LEO Pharma A/S: Current Employment. Khorana:Leo Pharma: Honoraria; Merck: Research Funding; Array: Other: Research funding (to institution); Leap: Research Funding; Seattle Genetics: Honoraria; Pharmacyte: Honoraria; Pharmacyclics: Honoraria; Janssen: Honoraria; Pfizer: Honoraria; Medscape: Honoraria; Bayer: Honoraria; BMS: Honoraria, Research Funding; Sanofi: Honoraria.

The safety and efficacy of full- versus reduced-dose betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention With Extended-Duration Betrixaban (APEX) trial

The APEX trial assessed the safety and efficacy of extended-duration thromboprophylaxis using betrixaban versus standard dosing of enoxaparin among hospitalized, acutely ill medical patients. The 80-mg betrixaban dose was halved to 40 mg among subjects with severe renal insufficiency and those receiving a concomitant strong P-glycoprotein inhibitor. This analysis assessed the pharmacokinetics, efficacy, and safety of full- (80 mg) and reduced-dose (40 mg) betrixaban relative to enoxaparin in the APEX trial. The median concentration of betrixaban among subjects administered the 80-mg dose was higher than that of the 40-mg dose (19 ng/mL vs 11 ng/mL, P<.001). In the primary analysis cohort 1 (d-dimer ≥2× upper limit of normal), the primary efficacy outcome (asymptomatic proximal deep vein thrombosis, symptomatic proximal or distal deep vein thrombosis, symptomatic nonfatal pulmonary embolism, or venous thromboembolism-related death) was significantly reduced among subjects treated with 80 mg of extended-duration betrixaban versus enoxaparin (6.27% [95/1516] vs 8.39% [130/1549], relative risk reduction=0.26 [0.04-0.42], P=.023), and similarly in the entire primary efficacy outcome population (4.87% [122/2506] vs 7.06% [181/2562], relative risk reduction=0.30 [0.13-0.44], P=.001). There was no difference in the primary outcome for subjects treated with 40 mg betrixaban vs enoxaparin across cohorts. In addition, there was no excess of major bleeding associated with either betrixaban dose compared with enoxaparin. The 80-mg betrixaban dose achieves higher plasma concentrations than the 40-mg dose and, in contrast to the 40-mg dose, is associated with improved efficacy across all cohorts relative to standard-dose enoxaparin without an excess risk of major bleeding in the management of medically ill subjects.

The Safety and Efficacy of Full Versus Reduced Dose Betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention with Extended Duration Betrixaban (APEX) Trial

Background: The exposure of all the currently licenced DOACs is increased in renal impairment and by certain drug interactions. The Acute Medically Ill VTE (Venous Thromboembolism) Prevention with Extended Duration Betrixaban (APEX) trial assessed the safety and efficacy of extended-duration thromboprophylaxis using betrixaban versus standard dosing of enoxaparin among acutely ill medical patients. The full 80 mg dose of betrixaban was halved to 40 mg among subjects with severe renal insufficiency (calculated creatinine clearance <30ml/min), or receiving a concomitant strong P-glycoprotein (P-gp) inhibitor.Objectives and Methods: The goal of this analysis is to assess the efficacy and safety of full (80 mg) and reduced dose (40 mg) betrixaban relative to enoxaparin in the APEX trial. Subjects were stratified into the two dose groups prior to randomization according to the pre-specified dosing criteria. The primary efficacy outcome was the composite of asymptomatic proximal and symptomatic venous thromboembolism (proximal or distal deep-vein thrombosis, symptomatic nonfatal pulmonary embolism, or death from venous thromboembolism). The principal safety outcome was major bleeding.Results: The median concentration of betrixaban among subjects administered the 80 mg dose was higher than that of the 40 mg dose (19 ng/ml vs 11 ng/ml, p<0.0001). In the primary analysis Cohort 1 (the elevated D-dimer +ve patients), the primary efficacy outcome was significantly reduced among subjects treated with 80 mg of extended dose betrixaban vs enoxaparin [6.3% (95/1516) vs 8.4% (130/1549), RRR = 0.26 (0.04-0.42), p=0.023]. A similar reduction was observed in the entire modified Intention to Treat (mITT) population [4.87% (122/2506) vs 7.06% (181/2562), RRR = 0.30 (0.13 - 0.44), p=0.001]. In contrast, among subjects receiving 40 mg of betrixaban there was no significant difference in the primary outcomes compared with enoxaparin across Cohorts 1, 2, and 3. There was no excess of major bleeding associated with administration of either the full 80 mg dose or the reduced 40 mg dose of betrixaban as compared with enoxaparin.Conclusion: For extended duration prophylaxis against VTE in hospitalized medically ill patients, the full 80 mg dose of extended duration betrixaban achieves higher serum concentrations than the 40 mg dose and is associated with improved efficacy across all cohorts relative to standard dose enoxaparin, without an excess risk of major bleeding. Based upon the approximate halving of plasma concentrations in this analysis and the lack of improvement in clinical outcomes, the reduced 40 mg dose may have been excessively downwardly adjusted. Conversely, the 80 mg dose was efficacious in all cohorts, including cohort 1. The inclusion of the 40 mg dose in the primary analysis may explain at least in part the marginal statistical result in the original report. DisclosuresCohen:Takeda: Consultancy; Medscape: Speakers Bureau; XO1: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Speakers Bureau; Portola: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; NHS: Membership on an entity’s Board of Directors or advisory committees; Lifeblood: Membership on an entity’s Board of Directors or advisory committees; Department of Health: Membership on an entity’s Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Janssen: Consultancy; Aspen: Consultancy, Speakers Bureau; Boehringer Ingelheim: Consultancy, Speakers Bureau; Colation to Prevent Venous Thromboembolism: Other: Founder; Leo Pharma: Consultancy; UK Government Health Select Committee: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Consultancy, Honoraria, Speakers Bureau; ONO: Consultancy, Honoraria. Goldhaber:Portola: Consultancy. Hull:Portola: Consultancy. Hernandez:Portola: Consultancy. Gold:Portola Pharmaceuticals: Employment. Wiens:Portola: Employment, Equity Ownership. Harrington:Portola: Consultancy. Gibson:Portola: Consultancy.

A Randomized Trial of Long-Term Tinzaparin, a Low Molecular Weight Heparin (LMWH), Versus Warfarin for Treatment of Acute Venous Thromboembolism (VTE) in Cancer Patients - the CATCH Study

BackgroundPatients with cancer and VTE have a substantial risk of recurrent VTE. LMWH reduces the risk of symptomatic, recurrent VTE compared with warfarin and is recommended as the preferred anticoagulant by consensus guidelines. However, the evidence is based largely on a single, open-label randomized trial (CLOT; Lee et al NEJM 2003). Warfarin is still often used for the treatment of VTE in cancer patients worldwide.MethodsThe primary objective of this randomized, open-label, multicenter, Phase III trial (CATCH; NCT01130025) was to assess the efficacy of tinzaparin in preventing recurrent VTE in patients with active cancer and acute, symptomatic proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE). Patients were randomized (stratified by geographic region, tumor characteristic [distant metastasis, no distant metastasis, hematological malignancy] and history of VTE) to receive tinzaparin 175 IU/kg once daily for 6 months or initial tinzaparin 175 IU/kg once daily for 5-10 days overlapped and followed by dose-adjusted warfarin (target INR 2.0-3.0) for 6 months. The primary efficacy outcome was time to recurrent VTE verified by objective, standard imaging and blinded central adjudication; this was a composite primary endpoint that included symptomatic DVT and/or PE, incidental proximal DVT and/or PE and fatal PE. The primary safety endpoint was incidence of major bleeding. All patients were followed up to 6 months or death, whichever came sooner. Blinded central adjudication was also performed for all bleeding events and causes of death. A proportional hazards model for competing risks was applied to all randomized patients, treating all non-VTE-related deaths as competing events. An independent Data Safety Monitoring Board reviewed safety data at regular intervals.ResultsNine hundred patients were included from 165 sites in 32 countries across 5 continents. Of these, 449 were randomized to tinzaparin and 451 to warfarin. Mean age was 59 years (range 18-89); 59% female. A total of 77% of patients had a baseline ECOG performance status (PS) of 0-1 and 23% had a PS of 2. The most common primary tumor sites were gynecologic (23%), colorectal (13%), lung (12%), breast (9%); 10% had hematological malignancies. At the time of randomization, metastatic disease was present in 55% of patients and 44% had received prior cancer treatment (chemotherapy, surgery and/or radiation). Time-in-therapeutic range was 47% in the warfarin arm, with 27% above and 26% below the range. Over the 6-month trial period, 31 patients (6.9%) in the tinzaparin arm experienced recurrent VTE compared with 45 (10%) in the warfarin arm (hazard ratio [HR] 0.65 [95% CI 0.41-1.03; P=0.07]) (see figure). There were 2 patients with incidental VTE, both were in the warfarin arm. Symptomatic non-fatal DVT occurred in 12 patients (2.7%) in the tinzaparin arm and 24 (5.3%) in the warfarin arm (HR 0.48 [95% CI 0.24-0.96]; P=0.04). Symptomatic non-fatal PE occurred in 3 patients in the tinzaparin arm and 2 in the warfarin arm; fatal PE occurred in 17 (3.8%) patients in each arm (HR 0.96 [95% CI 0.49-1.88]; P=0.90). There was no difference in the incidence of major bleeding events (n=13 [2.9%] in the tinzaparin arm and 12 [2.7%] in the warfarin arm), but significantly fewer patients experienced clinically relevant non-major bleeding with tinzaparin than warfarin (50 [11%] and 73 [16%] patients, respectively; P=0.03). No difference in mortality was seen with 6-month survival rates of 59% and 60%, respectively.ConclusionsIn cancer patients with symptomatic VTE, tinzaparin lowered the risk of recurrent VTE compared with warfarin, with a significant reduction in symptomatic DVT and clinically relevant non-major bleeding. No difference in major bleeding or overall mortality was observed. [Display omitted] DisclosuresLee:Bayer: Advisory Boards Other, Honoraria; Bristol-Myers Squibb: Advisory Boards, Advisory Boards Other, Research Funding; Boehringer Ingelheim: Honoraria; Daiichi-Sankyo: Advisory Boards, Advisory Boards Other; Eisai: Research Funding; LEO Pharma: Advisory Boards Other; Pfizer: Advisory Boards Other, Honoraria, Research Funding; Sanofi-Aventis: Advisory Boards, Advisory Boards Other; Avivia: Advisory Boards, Advisory Boards Other. Kamphuisen:LEO Pharma: Honoraria, Research Funding. Meyer:Bayer: Research Funding; Boehringer Ingelheim: Research Funding; LEO Pharma: Research Funding; Sanofi-Aventis: Research Funding. Janas:LEO Pharma: Employment. Jarner:LEO Pharma: Employment. Khorana:LEO Pharma: Honoraria, Research Funding.

Heparin for the prevention of venous thromboembolism in acutely ill medical patients (excluding stroke and myocardial infarction).

Venous thromboembolic disease has been extensively studied in surgical patients. The benefit of thromboprophylaxis is now generally accepted, but it is medical patients who make up the greater proportion of the hospital population. Medical patients differ from surgical patients with regard to their health and the pathogenesis of thromboembolism and the impact that preventative measures can have. The extensive experience from thromboprophylaxis studies in surgical patients is therefore not necessarily applicable to non-surgical patients. This is an update of a review first published in 2009. To determine the effectiveness and safety of heparin (unfractionated heparin or low molecular weight heparin) thromboprophylaxis in acutely ill medical patients admitted to hospital, excluding those admitted to hospital with an acute myocardial infarction or stroke (ischaemic or haemorrhagic) or those requiring admission to an intensive care unit. For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched November 2013) and CENTRAL (2013, Issue 10). Randomised controlled trials comparing unfractionated heparin (UFH) or low molecular weight heparin (LMWH) with placebo or no treatment, or comparing UFH with LMWH. One review author identified possible trials and a second review author confirmed their eligibility for inclusion in the review. Two review authors extracted the data. Disagreements were resolved by discussion. We performed the meta-analysis using a fixed-effect model with the results expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Sixteen studies with a combined total of 34,369 participants with an acute medical illness were included in this review. We identified 10 studies comparing heparin with placebo or no treatment and six studies comparing LMWH to UFH. Just under half of the studies had an open-label design, putting them at a risk of performance bias. Descriptions of random sequence generation and allocation concealment were missing in most of the studies. Heparin reduced the odds of deep vein thrombosis (DVT) (OR 0.38; 95% CI 0.29 to 0.51; P < 0.00001). The estimated reductions in symptomatic non-fatal pulmonary embolism (PE) (OR 0.46; 95% CI 0.19 to 1.10; P = 0.08), fatal PE (OR 0.71; 95% CI 0.43 to 1.15; P = 0.16) and in combined non-fatal PE and fatal PE (OR 0.65; 95% CI 0.42 to 1.00; P = 0.05) associated with heparin were imprecise. Heparin resulted in an increase in major haemorrhage (OR 1.81; 95% CI 1.10 to 2.98; P = 0.02). There was no clear evidence that heparin had an effect on all-cause mortality and thrombocytopaenia. Compared with UFH, LMWH reduced the risk of DVT (OR 0.77; 95% CI 0.62 to 0.96; P = 0.02) and major bleeding (OR 0.43; 95% CI 0.22 to 0.83; P = 0.01). There was no clear evidence that the effects of LMWH and UFH differed for the PE outcomes, all-cause mortality and thrombocytopaenia. The data from this review describe a reduction in the risk of DVT in patients presenting with an acute medical illness who receive heparin thromboprophylaxis. This needs to be balanced against an increase in the risk of bleeding associated with thromboprophylaxis. The analysis favoured LMWH compared with UFH, with a reduced risk of both DVT and bleeding.

Real-World Study of Dabigatran Etexilate for Thromboprophylaxis in Over 5000 Hip or Knee Replacement Patients: Favourable Safety Profile in Subgroups with Different BMI, Renal Function and Age

Real-World Study of Dabigatran Etexilate for Thromboprophylaxis in Over 5000 Hip or Knee Replacement Patients: Favourable Safety Profile in Subgroups with Different BMI, Renal Function and Age

Prevention of Venous Thromboembolism with New Oral Anticoagulants versus Standard Pharmacological Treatment in Acute Medically Ill Patients

Venous thromboembolism (VTE) is a common and potentially avoidable cause of morbidity and mortality in patients hospitalized for acute medical illness. Our objective was to conduct a systematic review of studies that assessed the efficacy and safety of new oral anticoagulant (OAC) drugs versus standard pharmacological drugs and/or placebo in prevention of VTE in acute medically ill patients. PubMed.org and ClinicalTrials.gov databases were searched to identify studies that evaluated the efficacy and safety of a new OAC versus the standard pharmacological treatment and/or placebo in the prevention of VTE in medically ill patients. Relative risks (RR), weighted means and 95% CIs were calculated. Statistical heterogeneity was evaluated using Chi2 and I2 statistics. Two studies were included in the meta-analysis. The primary outcome in both studies was the composite of VTE-related death, symptomatic non-fatal pulmonary embolism (PE), symptomatic deep venous thrombosis (DVT) and asymptomatic proximal DVT. Both studies compared a factor (F)Xa inhibitor with enoxaparin in standard short-term thromboprophylaxis followed by a period where the FXa inhibitor was compared with placebo as prolonged thromboprophylaxis in medically ill patients. The primary major safety outcome in both studies was a composite of treatment-related major bleeding and clinically relevant non-major bleeding. A total of 14 629 patients were randomized. Compared with subjects treated with enoxaparin followed by placebo, the RR of the primary outcome during the prolonged treatment period was 0.79 (95% CI 0.66, 0.94), the RR for the primary outcome during the first short-term treatment period was 1.03 (95% CI 0.81, 1.31). For major bleeding during the prolonged treatment period, the RR was 2.69 (95% CI 1.65, 4.39) for patients treated with an FXa inhibitor compared with enoxaparin/placebo. For major bleeding during the shorter treatment period, the RR was 2.01 (95% CI 1.10, 3.65) in favour of enoxaparin. In acute medically ill patients, prolonged thromboprophylaxis with an oral FXa inhibitor is more protective than regular short-term treatment with enoxaparin. However, treatment with FXa inhibitors is significantly associated with major bleeding, both in long- and short-term treatment compared with enoxaparin.

Extended-duration rivaroxaban thromboprophylaxis in acutely ill medical patients: MAGELLAN study protocol

Patients with acute medical illnesses are at increased risk of venous thromboembolism (VTE), a significant cause of morbidity and mortality. Thromboprophylaxis is recommended in these patients but questions remain regarding the optimal duration of therapy. The aim of this study is to determine whether oral rivaroxaban is non-inferior to standard-duration (approximately 10 days) subcutaneous (s.c.) enoxaparin for the prevention of VTE in acutely ill medical patients, and whether extended-duration (approximately 5 weeks) rivaroxaban is superior to standard-duration enoxaparin. Patients aged 40 years or older and hospitalized for various acute medical illnesses with risk factors for VTE randomly receive either s.c. enoxaparin 40 mg once daily (od) for 10 ± 4 days or oral rivaroxaban 10 mg od for 35 ± 4 days. The primary efficacy outcomes are the composite of asymptomatic proximal deep vein thrombosis (DVT), symptomatic DVT, symptomatic non-fatal pulmonary embolism (PE), and VTE-related death up to day 10 + 4 and up to day 35 + 4. The primary safety outcome is the composite of treatment-emergent major bleeding and clinically relevant non-major bleeding. As of July 2010, 8,101 patients from 52 countries have been randomized. These patients have a broad range of medical conditions: approximately one-third were diagnosed with acute heart failure, just under one-third were diagnosed with acute infectious disease, and just under one-quarter were diagnosed with acute respiratory insufficiency. MAGELLAN will determine the efficacy, safety, and pharmacological profile of oral rivaroxaban for the prevention of VTE in a diverse population of medically ill patients and the potential of extended-duration therapy to reduce incidence of VTE.

Certoparin versus unfractionated heparin to prevent venous thromboembolic events in patients hospitalized because of heart failure: A subgroup analysis of the randomized, controlled CERTIFY study

Despite the elevated risk for developing venous thromboembolic events in patients with heart failure, there are no randomized, double-blind, controlled trial data on the comparison of low-molecular-weight heparin with unfractionated heparin (UFH) in this patient population. This was a subgroup analysis of the CERTIFY trial, which included 3,239 nonsurgical, acutely ill medical patients 70 years or older. Patients were randomized to receive 3,000-U anti-Xa certoparin once daily or 5,000-IU UFH 3 times a day. The analysis was performed on a subgroup of 542 patients diagnosed with heart failure at hospital admission. Patients with heart failure differed from patients without heart failure in that they were more likely using antiplatelets (67.2% vs 48.9%; P < .0001) and had a lower glomerular filtration rate (8.0% vs 5.5%; ≤ 30 mL/min per 1.73 m²; P = .0232). Thromboembolic risk was comparable except for a higher incidence of distal deep venous thrombosis (DVT) in patients with heart failure (10.80% vs 7.26%; P = .0144). Within the heart failure population, patient characteristics were comparable between randomized treatment groups. The incidence of the primary end point (proximal DVT, symptomatic nonfatal pulmonary embolism, and venous thromboembolism-related death combined) was numerically, slightly smaller with certoparin (3.78% vs 4.74% with UFH; odds ratio 0.79, 95% CI 0.32-1.94), and the incidence of major bleeding was 0.72% with certoparin versus 0.38% with UFH. Patients hospitalized for heart failure are at high risk for developing distal DVT and bleeding complications compared with acutely ill medical patients without heart failure. Within the heart failure population, the observed differences in prophylactic efficacy between 3,000-U anti-Xa certoparin once daily and 5,000-IU UFH 3 times a day were similar to those observed in the overall study population; this suggests that certoparin might be at least as effective as UFH also in this subgroup. There were no relevant differences in bleeding risk or frequency of adverse events.

A randomized, double-blind study of certoparin vs. unfractionated heparin to prevent venous thromboembolic events in acutely ill, non-surgical patients: CERTIFY Study.

In medically ill patients, no contemporary double-blind head-to-head evaluation of low molecular weight heparin vs. unfractionated heparin (UFH) for the prevention of venous thromboembolic events is available. To compare the efficacy and safety of certoparin with those of UFH. In this double-blind, randomized, controlled trial, acutely ill, non-surgical patients aged > or = 70 years were randomized to certoparin (3000 U of anti-factor Xa once daily) or to UFH (5000 IU t.i.d.). The primary endpoint was the composite of proximal deep vein thrombosis as assessed by bilateral compression ultrasonography, symptomatic non-fatal pulmonary embolism and venous thromboembolism-related death, and was assessed by a blinded central adjudication committee. Non-inferiority margins were set at 1.8 for the odds ratio (OR) and 3.45% for the absolute difference. Three thousand two hundred and thirty-nine patients aged 78.8 + or - 6.3 years were treated for 9.1 + or - 3.4 days. The incidence of the primary endpoint was 3.94% in the certoparin group and 4.52% in the UFH group, with a difference in proportions of - 0.59% [95% confidence interval (CI) -2.09 to 0.92; P < 0.0001 for non-inferiority], and an OR of 0.87 (95% CI 0.60-1.26; P = 0.0001 for non-inferiority). Major bleeding occurred in 0.43% of certoparin-treated patients and 0.62% of UFH-treated patients (OR 0.69; 95% CI 0.26-1.83). Any bleeding occurred at 3.20% in certoparin-treated patients vs. 4.58% in UFH-treated patients (OR 0.69; 95% CI 0.48-0.99; P < 0.05), and 5.73% of certoparin-treated patients and 6.63% of UFH-treated patients experienced serious adverse events. All-cause mortality was 1.27% in certoparin-treated patients and 1.36% in UFH-treated patients. In acutely ill, non-surgical elderly patients, thromboprophylaxis with certoparin (3000 U of anti-FXa once daily) was non-inferior to 5000 IU of UFH t.i.d., with a favorable safety profile.

Incidence of ipsilateral postoperative deep venous thrombosis in the amputated lower extremity of patients with peripheral obstructive arterial disease

Patients undergoing amputation of the lower limb due to peripheral arterial disease (PAD) are at risk of developing deep venous thrombosis (DVT). Few studies in the research literature report the incidence of DVT during the early postoperative period or the risk factors for the development of DVT in the amputation stump. This prospective study evaluated the incidence of DVT during the first 35 postoperative days in patients who had undergone amputation of the lower extremity due to PAD and its relation to comorbidities and death. Between September 2004 and March 2006, 56 patients (29 men), with a mean age of 67.25 years, underwent 62 amputations, comprising 36 below knee amputations (BKA) and 26 above knee amputations (AKA). Echo-Doppler scanning was performed preoperatively and on postoperative days 7 and 31 (approximately). All patients received acetylsalicylic acid (100 mg daily) preoperatively and postoperatively, but none received prophylactic anticoagulation. DVT occurred in 25.8% of extremities with amputations (10 AKA and 6 BKA). The cumulative incidence in the 35-day postoperative period was 28% (Kaplan-Meier). There was a significant difference (P = .04) in the incidence of DVT between AKA (37.5%) and BKA (21.2%). Age >or=70 years (48.9% vs 16.8%, P = .021) was also a risk factor for DVT in the univariate analysis. Of the 16 cases, 14 (87.5%) were diagnosed during outpatient care. The time to discharge after amputation was averaged 6.11 days in-hospital stay (range, 1-56 days). One symptomatic nonfatal pulmonary embolism occurred in a patient already diagnosed with DVT. There was no relation between other comorbidities and DVT. The multivariate analysis showed no association between risk factors and the occurrence of DVT in the amputated extremity. DVT ipsilateral to the amputation did not influence the mortality rate (9.7%). The incidence of DVT in the early postoperative period (<or=35 days) was elevated principally in patients aged >or=70 years and for AKA. Patients with PAD who have recently undergone major amputations should be considered at high risk for DVT, even after hospital discharge. Given the high rate of postoperative DVT observed in this study, we now recommend prophylactic anticoagulation for these patients, but further study is needed to determine the optimal duration and efficacy of this treatment.

Dermatan Sulphate for the Prevention of Postoperative Venous Thromboembolism in Patients with Cancer

Patients undergoing surgery for cancer are at high risk for venous thromboembolism (VTE). Agents that selectively inhibit thrombin, such as dermatan sulphate, have potential for a favourable benefit-risk ratio in the prevention of this complication. Patients scheduled for elective abdominal, thoracic, gynecologic or urologic surgery for cancer resection, were randomised to dermatan sulphate (600 mg intramuscularly on the second day before surgery, then 300 mg once daily), or calcium heparin (5,000 IU subcutaneously t.i.d., starting 2 hours before operation). Both treatments were continued until postoperative day 7 or until adequate mobilisation was achieved. Bilateral venography was scheduled at the end of treatment. Venograms were centrally assessed in blind conditions. The study outcomes were VTE (venographically proven deep vein thrombosis IDVT] or symptomatic, objectively confirmed pulmonary embolism) and bleeding complications. At 27 centres, 842 patients were randomised and underwent surgery (418 dermatan sulphate, 424 heparin). Efficacy was assessed in 521 patients with adequate venography and/or confirmed pulmonary embolism. DVT was observed in a total of 96 patients; symptomatic non-fatal pulmonary embolism developed in 2 patients (one per group), who also had DVT at venography. Postoperative VTE occurred in 40 of 267 patients on dermatan sulphate, 15.0%, versus 56 of 254 patients on heparin. 22.0% (p = 0.033). Relative risk reduction was 32.7% (95% confidence interval, 3.1 to 53.2%). The rate of bleeding complications in all operated patients was 6.9% with dermatan sulphate and 7.5% with heparin (confidence interval for the absolute risk difference, -4.1 to 2.9%). The inhospital mortality rate was 1.2% and 1.4%, respectively. In oncologic surgery, dermatan sulphate prevents VTE more effectively than heparin without increasing bleeding complications.

Low Prevalence of Factor V:Q506 in 41 Patients with Isolated Pulmonary Embolism

In 70-80% of cases, pulmonary embolism is the consequence of lower extremity deep vein thrombosis. It has been demonstrated that the most common coagulation defect predisposing to venous thrombosis, resistance to activated protein C (APC), is not associated with an increased risk for pulmonary embolism, but the evidence was based on a functional assay to diagnose APC resistance and no information about concomitant deep vein thrombosis was provided. The aim of our study was to evaluate the prevalence of factor V:Q506, the gene mutation responsible for APC resistance, in patients with symptomatic non-fatal pulmonary embolism, whether or not associated with deep vein thrombosis. Patients with uncomplicated deep vein thrombosis and healthy controls were investigated as comparison groups. The overall prevalence of factor V:Q506 in 106 patients with pulmonary embolism was 12.3%, lower than that found in 106 patients with deep vein thrombosis (22.6%, OR 0.5, 95% CI 0.2-1.0) but significantly higher than that found in 212 healthy subjects taken as controls (2.8%, OR 4.8, 95% CI 1.8-13.0). In the 41 patients with isolated pulmonary embolism, i.e., without the presence of deep vein thrombosis, the prevalence was 4.9%, similar to that in controls (OR 1.8, 95% CI 0.3-9.6), while in the remaining 65 patients with pulmonary embolism associated with deep vein thrombosis the prevalence was significantly higher (16.9%, OR 5.5, 95% CI 2.0-15.8). In conclusion, the prevalence of factor V:Q506 is high in patients with pulmonary embolism associated with deep vein thrombosis, whereas in patients with isolated pulmonary embolism it is similar to that found in control subjects. This intriguing finding is of difficult interpretation and needs confirmation by further studies.

Subcutaneous Low Molecular Weight Heparin versus Subcutaneous Unfractionated Heparin in the Treatment of Deep Vein Thrombosis: a Polish Multicenter Trial

In a prospective multicenter trial, 149 consecutive patients with phlebographically proven proximal and/or distal deep vein thrombosis of the leg were randomly allocated to receive subcutaneously for 10 days either low molecular weight heparin CY 216 (Fraxiparine) in a fixed dose or unfractionated heparin (UFH) in doses adjusted according to the activated partial thromboplastin time. Pre- and post-treatment phlebograms were assessed blindly using the Arnesen's score system in 134 patients available for analysis of the treatment efficacy. The mean phlebographic score after 10 days of treatment was significantly decreased in both groups (p less than 0.001) in comparison with the baseline score but the difference in score changes between the two groups was not statistically significant. There was an improvement in 45/68 patients (66%) in the Fraxiparine group and in 32/66 patients (48%) in the UFH group, and an increase in the thrombus size in 10/68 (15%) and 12/66 (18%), respectively. One symptomatic non-fatal pulmonary embolism and one major bleeding episode were observed in the UFH group. During a follow-up period of 3 months, two rethromboses had occurred in the UFH group and none in the Fraxiparine group. It is concluded that subcutaneous fixed dose Fraxiparine is safe and at least as effective as subcutaneous adjusted UFH in the treatment of deep vein thrombosis.