Rivaroxaban for thromboprophylaxis among patients recently hospitalized for acute infectious diseases: a subgroup analysis of the MAGELLAN study

Essentials

• Net benefit of venous thromboprophylaxis (VTE) in patients hospitalized for infections is unknown.
• MAGELLAN trial subgroup analysis was performed for patients hospitalized for acute infectious diseases.
• At day 35, prolonged rivaroxaban prophylaxis reduced VTE compared to enoxaparin (4.2% vs. 6.6%).
• Rivaroxaban prophylaxis reduced VTE in patients hospitalized for active lung infections.

Summary

Background

Despite the well‐established association between infection and venous thromboembolism (VTE), there are few data specifically assessing the efficacy and safety of the VTE prophylaxis strategies for patients hospitalized for acute infectious diseases.

Objectives

To estimate the incidence of VTE and bleeding outcomes, comparing prolonged prophylaxis with rivaroxaban 10 mg daily for 35 days with enoxaparin 40 mg daily for 10 days.

Patients/Methods

A subgroup analysis of patients hospitalized for acute infectious diseases in the MAGELLAN trial was performed. The primary efficacy outcome was the composite of asymptomatic proximal or symptomatic VTE at days 10 and 35. The principal safety outcome was the composite of major or clinically relevant non‐major bleeding.

Results

Three thousand one hundred and seventy‐three patients with acute infectious diseases leading to hospitalization were randomized to either rivaroxaban (n = 1585) or enoxaparin/placebo (n = 1588), and received at least one dose of study medication. At day 10, primary composite efficacy outcomes did not differ between prophylaxis strategies (rivaroxaban, 2.7%; and enoxaparin, 3.7%). At day 35, there were fewer VTE events with rivaroxaban (4.2%) than with enoxaparin (6.6%) (relative risk [RR] 0.64; 95% confidence interval [CI] 0.45–0.92). Patients with pulmonary infections randomized to rivaroxaban had a lower incidence of VTE both at 10 days (RR 0.50, 95% CI 0.28–0.90) and at 35 days (RR 0.54, 95% CI 0.33–0.87). Primary safety outcome events were increased with rivaroxaban (RR 2.42, 95% CI 1.60–3.66).

Conclusions

Prolonged rivaroxaban prophylaxis reduced the incidence of VTE in patients hospitalized for acute infectious diseases, particularly those involving the lungs. Efficacy benefits were, in part, offset by bleeding outcomes. ClinicalTrials.gov Number: NCT 00571649.

     

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.     

Economic evaluation of dabigatran etexilate for the prevention of venous thromboembolism after total knee and hip replacement surgery

Objective: This was an evaluation of the cost-effectiveness of oral dabigatran etexilate compared with subcutaneous low-molecular-weight heparin (enoxaparin) for the prevention of venous thromboembolism (VTE) after total knee replacement (TKR) and total hip replacement (THR) surgery from the perspective of the UK National Health Service.Methods: Dabigatran etexilate (220 mg once daily) was compared with enoxaparin (40 mg once daily) in patients undergoing TKR (duration of prophylaxis, 6–10 days) and THR (duration of prophylaxis, 28–35 days). The 10-week acute postsurgical phase was modeled using a decision tree. A Markov process (1-year cycle length) was used to model long-term events (recurrent VTE, postthrombotic syndrome, and consequences of intracranial hemorrhage) for patients' remaining lifetimes. Relative risks for VTE and bleeding events were derived from 2 Phase III studies that compared dabigatran etexilate with enoxaparin 40 mg once daily. The probabilities of long-term events were estimated using data from published longitudinal studies.Results: Rates of VTE and bleeding events did not differ significantly between dabigatran etexilate and enoxaparin. Dabigatran etexilate was less costly than enoxaparin in TKR and substantially less costly in THR, primarily due to differences in administration costs. The cost of prophylaxis for THR patients, including drugs and administration costs, was estimated at £137 for dabigatran etexilate and £237 for enoxaparin (£7 for nursing time during the hospital stay, £91 for nurse home visits for administration after hospital discharge, and an additional £2 in drug costs). At a willingness-to-pay threshold of £20,000 per quality-adjusted life-year, the probability of cost-effectiveness for dabigatran etexilate was 75% in TKR and 97% in THR. These results were robust across a range of sensitivity analyses.Conclusion: From the perspective of the UK National Health Service, thromboprophylaxis with dabigatran etexilate was cost-saving compared with enoxaparin 40 mg once daily, with comparable efficacy and safety profiles.     

Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial

BACKGROUND: Oral anticoagulants, such as dabigatran etexilate, an oral, direct thrombin inhibitor, that do not require monitoring or dose adjustment offer potential for prophylaxis against venous thromboembolism (VTE) after total knee replacement surgery. METHODS: In this randomized, double-blind study, 2076 patients undergoing total knee replacement received dabigatran etexilate, 150 mg or 220 mg once-daily, starting with a half-dose 1-4 hours after surgery, or subcutaneous enoxaparin 40 mg once-daily, starting the evening before surgery, for 6-10 days. Patients were followed-up for 3 months. The primary efficacy outcome was a composite of total VTE (venographic or symptomatic) and mortality during treatment, and the primary safety outcome was the incidence of bleeding events. RESULTS: The primary efficacy outcome occurred in 37.7% (193 of 512) of the enoxaparin group versus 36.4% (183 of 503) of the dabigatran etexilate 220 mg group (absolute difference, -1.3%; 95% CI, -7.3 to 4.6) and 40.5% (213 of 526) of the 150 mg group (2.8%; 95% CI, -3.1 to 8.7). Both doses were noninferior to enoxaparin based on the pre-specified noninferiority criterion. The incidence of major bleeding did not differ significantly between the three groups (1.3% versus 1.5% and 1.3% respectively). No significant differences in the incidences of liver enzyme elevation and acute coronary events were observed during treatment or follow-up. CONCLUSIONS: Dabigatran etexilate (220 mg or 150 mg) was at least as effective and with a similar safety profile as enoxaparin for prevention of VTE after total knee-replacement surgery.     

Single intravenous administration of TB‐402 for the prophylaxis of venous thromboembolism after total knee replacement: a dose‐escalating,randomized, controlled trial

Summary. Background: TB‐402 is a novel anticoagulant monoclonal antibody with a prolonged antithrombotic effect resulting from its partial factor (F)VIII inhibition and long half‐life. We evaluated the efficacy and safety of a single administration of TB‐402 for the prevention of venous thromboembolism (VTE) after total knee replacement (TKR). Patients and methods: This was a phase II, dose‐escalating, randomized, enoxaparin‐controlled, open‐label study. Patients were post‐operatively assigned to a single dose of TB‐402 (0.3, 0.6 or 1.2 mg kg^?1) or enoxaparin 40 mg for at least 10 days (n = 75 per group; 3:1 TB‐402 to enoxaparin). The primary efficacy outcome was total VTE defined as asymptomatic deep vein thrombosis (DVT) detected by bilateral venography and symptomatic VTE by day 7 to 11. The principal safety outcome was the incidence of major bleeding and clinically relevant non‐major bleeding. Results: Total VTE was lower in all TB‐402 groups compared with enoxaparin: 16.7%(95% CI 9.8–26.9), 23.9%(95% CI 15.3–35.3), 24.1%(95% CI 16.0–34.5) and 39.0%(95% CI 28.8–50.1) for TB‐402 0.3, 0.6, 1.2 mg kg^?1 and enoxaparin, respectively (P = 0.003 for TB‐402 0.3 mg kg^?1 vs. enoxaparin). The incidence of total VTE in the pooled TB‐402 groups was 21.6% (95%CI 16.6–27.5), an absolute risk reduction vs. enoxaparin of 17.4% (95% CI 5.2–29.6). Major or clinically relevant non‐major bleeding was observed in 3/75(4.0%), 4/74(5.4%), 7/87(8.0%) and 3/79(3.8%) patients for TB‐402 0.3, 0.6, 1.2 mg kg^?1 and enoxaparin, respectively. Conclusions: TB‐402, as a single post‐operative administration, was associated with a lower rate of VTE in all doses tested, compared with enoxaparin. The incidence of major and clinically relevant non‐major bleeding was similar to enoxaparin 40 mg for TB‐402 0.3 and 0.6 mg kg^?1.     

A systematic review and Bayesian network meta‐analysis of risk of intracranial hemorrhage with direct oral anticoagulants

Essentials

• Risk of intracranial hemorrhage (ICH) may differ between direct oral anticoagulants (DOACs).
• We compared the risk of ICH between DOACs using network meta‐analysis.
• Dabigatran 110 mg and 150 mg were safer than rivaroxaban on Bayesian analysis.
• Dabigatran 110 mg ranked as the safest DOAC while rivaroxaban ranked last.

Summary

Background

The comparative risk of intracranial hemorrhage (ICH) among direct oral anticoagulants (DOACs) (dabigatran, rivaroxaban, apixaban and edoxaban) remains unclear.

Objective

To determine the difference in risk of ICH between DOACs

Methods

Seventeen randomized controlled trials (RCTs) were selected using PubMed/MEDLINE, EMBASE and CENTRAL (Inception, 31 December 2017). Estimates were reported as odds ratio (OR) with 95% credible interval (CR.I) in Bayesian network meta‐analysis (NMA), and OR with 95% confidence interval (CI) in traditional meta‐analyses. Relative ranking probability of each group was generated based on surface under the cumulative ranking curve (SUCRA).

Results

In NMA of 116 618 patients from 17 RCTs (apixaban = 19 495 patients, rivaroxaban = 14 157 patients, dabigatran = 16 074 patients, edoxaban = 11 652 patients, and comparator = 55 315 patients), all DOACs were safer than warfarin for risk of ICH. Dabigatran 110 mg ranked as the safest drug (SUCRA, 0.85) and reduced the risk of ICH by 56% compared to rivaroxaban (OR, 0.44; 95% Cr.I, 0.22–0.82). Pairwise meta‐analysis validated these findings, showing that DOACs were safer than warfarin (OR, 0.46; 95% CI, 0.35–0.59). Subgroup analysis showed that the benefit was present when DOACs were used in non‐valvular atrial fibrillation (NVAF) (OR, 0.51; 95% CI, 0.38–0.68) or venous thromboembolism (VTE) (OR, 0.32; 95% CI, 0.18–0.58).

Conclusion

Dabigatran 110 mg may be the safest choice among any anticoagulant regarding risk of ICH. Both dabigatran 110 mg and 150 mg were safer than rivaroxaban.

     

New oral anticoagulants to revolutionise venous thromboembolism (VTE) management

Warfarin, a vitamin K antagonist has been the mainstay of venous thromboembolism treatment for over 60 years. However, it has significant limitations in relation to achieving a safe and therapeutic efficacy. Evolution in the development of oral anticoagulants to offset the drawbacks of warfarin, has led to the introduction of two new oral anticoagulants, namely dabigatran, a direct thrombin inhibitor and rivaroxaban, a direct factor Xa inhibitor. This paper examines the potential of the two new oral anticoagulants to offer a safer therapeutic alternative to warfarin, as well as their clinical efficacy in relation to the prevention of venous thromboembolism in patients undergoing hip and knee replacement surgery. In seven randomized clinical trials, dabigatran has demonstrated noninferior efficacy to enoxaparin, with a similar safety profile. Following a single technology appraisal of dabigatran, The National Institute of Clinical Excellence (NICE) have now endorsed its clinical efficacy as a serious alternative to low molecular weight heparin and fondaparinux.Three randomized clinical trials have also concluded that rivaroxaban is as efficacious and safe as enoxaparin in the prevention of venous thromboembolism for patients undergoing major orthopaedic surgery of the lower limbs. In a single technology appraisal, rivaroxaban within its marketing authorisation was recommended by NICE in April 2009, as an option for the prevention of venous thromboembolism in adults having elective hip or knee replacement surgery.     

Interventions to reduce vasovagal reactions in blood donors: a systematic review and meta‐analysis

Vasovagal reactions (VVRs) in blood donors have significant implications for the welfare of donors, donor retention and the management of donor sessions. We present a systematic review of interventions designed to prevent or reduce VVRs in blood donors. Electronic databases were searched for eligible randomised trials to March 2015. Data on study design and outcomes were extracted and pooled using random effects meta‐analyses. Sixteen trials met the inclusion criteria: five trials (12 042 participants) of pre‐donation water, eight trials (3500 participants) of applied muscle tension (AMT) and one trial each of AMT combined with water, caffeine, audio‐visual distraction and/or social support. In donors receiving pre‐donation water, the relative risk (RR) compared with controls for VVRs was 0·79 [95% confidence interval (CI) 0·70–0·89, P < 0·0001] and the mean difference (MD) in severity of VVRs measured with the Blood Donation Reactions Inventory (BDRI) score was ?0·32 (95% CI ?0·51 to ?0·12, P < 0·0001). Excluding trials with a high risk of selection bias, the RR for VVRs was 0·70 (95% CI 0·45–1·11, P = 0·13). In donors who received AMT, there was no difference in the risk of chair recline in response to donor distress from controls (RR 0·76, 95% CI 0·53–1·10, P = 0·15), although the MD in BDRI score was ?0·07 (95% CI ?0·11 to ?0·03, P = 0·0005). There was insufficient data to perform meta‐analysis for other interventions. Current evidence on interventions to prevent or reduce VVRs in blood donors is indeed limited and does not provide strong support for the administration of pre‐donation water or AMT during donation. Further large trials are required to reliably evaluate the effect of these and other interventions in the prevention of VVRs.     

Naloxone in the management of hepatic encephalopathy

Background/aim: This study aimed to assess the effectiveness and safety of naloxone in the management of hepatic encephalopathy (HE). Methods: Cochrane collaboration methodology was used in a meta‐analysis of randomized controlled trials of naloxone therapy for HE. Results: Seventeen randomized trials were identified with 15 studies involving 1054 patients meeting criteria for inclusion. Naloxone use was associated with a significant improvement in HE [relative risk (RR) 1·46; 95% confidence interval (CI) 1·27–1·67; P = 0·0005]. This comparison showed statistical heterogeneity (P < 0·10, and χ² = 44·93). Subgroup analysis indicated naloxone administered parenterally by intermittent or continuous infusions to be effective (RR 1·34; 95% CI 1·17–1·53; P < 0·0001). A significant in trials by infusion route (RR 1·42; 95% CI 1·19–1·69; P < 0·0001) interaction was observed. Conclusions: Naloxone may improve HE. However, published data are limited.     

Less abnormal uterine bleeding with dabigatran than warfarin in women treated for acute venous thromboembolism

Essentials

• Factor Xa inhibitors cause more abnormal menstrual bleeding (AUB) than vitamin‐K antagonists (VKA).
• We analyzed data of AUB in women, evaluating dabigatran versus VKA.
• We observed a 41% lower risk of AUB in women on dabigatran compared to those on VKA.
• Our findings of lower AUB risk on dabigatran should be corroborated in future studies.

Summary

Introduction

Although direct oral anticoagulants (DOACs) are associated with a better safety profile than warfarin in patients with acute venous thromboembolism (VTE), direct factor Xa inhibitors involve a higher risk of abnormal uterine bleeding (AUB). We aimed to determine the risk of AUB during anticoagulation with dabigatran compared with warfarin.

Methods

Post‐hoc analysis of the pooled RE‐COVER studies and the RE‐MEDY trial. Incidences of AUB, based on a defined preferred terms search for adverse events, in female patients aged 18–50 years treated with dabigatran, were compared with those in women treated with warfarin.

Results

Of the 2964 women included in the above‐mentioned trials, 1280 women were in the relevant age category (18–50 years) and included in the current analysis. A total of 643 patients were randomized to treatment with dabigatran and 637 to treatment with warfarin. The overall rate of AUB was 8.1%, 5.9% for the women treated with dabigatran and 9.6% in those treated with warfarin, for an odds ratio for dabigatran‐treated patients of 0.59 (95% confidence interval [CI], 0.39–0.90; P = 0.015). In the dabigatran‐treated patients, three (0.5%) suffered major bleeding (MB) vs. five (0.8%) in the warfarin‐treated patients (HR, 0.65; 95% CI, 0.15–2.72). MB or non‐major relevant bleeding occurred in 30 (4.7%) patients randomized to receive dabigatran and 57 (8.9%) randomized to receive warfarin (HR, 0.53; 95% CI, 0.34–0.83). None of the bleeding events was fatal.

Conclusion

Dabigatran treatment was associated with a significantly (41%) lower risk of AUB than warfarin. Future studies in daily practice are needed to corroborate these findings.

     

Efficacy and safety of rivaroxaban or fondaparinux thromboprophylaxis in major orthopedic surgery: findings from the ORTHO‐TEP registry

Summary. Background: Thromboprophylaxis with rivaroxaban (R) is superior to enoxaparin in patients undergoing major orthopedic surgery (MOS). However, rivaroxaban has never been directly compared with fondaparinux (F), which also shows superior efficacy over enoxaparin. The clinical impact of switching from fondaparinux to rivaroxaban thromboprophylaxis is unclear. Objectives: To evaluate the efficacy and safety of rivaroxaban or fondaparinux thromboprophylaxis in unselected patients undergoing MOS. Patients/Methods: This is a monocentric, retrospective cohort study in 5061 consecutive patients undergoing MOS at our centre, comparing rates of symptomatic VTE, bleeding and surgical complications, length of hospital stay and risk factors for VTE. Results: Rates of symptomatic VTE were 5.6% (F) and 2.1% (R; P < 0.001), with rates for distal DVT being 3.9 vs. 1.1% (P < 0.001). Rates of major VTE were numerically higher with fondaparinux (1.8 vs. 1.1%), but not statistically significant. Rates of severe bleeding (bleeding leading to surgical revision or death, occurring in a critical site, or transfusion of at least two units of packed red blood cells) were statistically lower with rivaroxaban compared with fondaparinux (2.9 vs. 4.9%; P = 0.010). The mean length of hospital stay was significantly shorter in the rivaroxaban group (8.3 days, 95% CI 8.1–8.5 vs. 9.3 days, 9.1–9.5; P < 0.001). Conclusion: Based on an indirect comparison of two consecutive cohorts, our data suggest that thromboprophylaxis with rivaroxaban is associated with less VTE and bleeding events than fondaparinux in unselected patients undergoing MOS. Prospective comparisons are warranted to confirm our findings.     

Rivaroxaban and Apixaban for Initial Treatment of Acute Venous Thromboembolism of Atypical Location

Objectives

To assess the outcome of direct oral anticoagulants (DOACs), specifically Xa inhibitors: rivaroxaban and apixaban, for the treatment of venous thromboembolism (VTE) of atypical location (VTE-AL), portal, mesenteric, hepatic, splenic, gonadal, renal, and cerebral veins, prospectively collected data of Mayo Thrombophilia Clinic Registry were used.

Hormone replacement therapy and the risk of venous thromboembolism: a population‐based study

Summary. Background: Hormone replacement therapy (HRT) using oral estrogen alone or combined with a progestogen is associated with an increased risk of venous thromboembolism (VTE) in postmenopausal women. This risk may differ for tibolone and transdermal HRT. Methods: Among the United Kingdom’s General Practice Research Database, we identified the cohort of all women aged 50–79 between 1 January 1987 and 1 March 2008. Using a nested case–control approach, all incident cases of VTE occurring during the study period were identified and matched with up to 10 controls selected from the cohort members. Rate ratios (RR) of VTE with current use of tibolone, transdermal and oral HRT were estimated using conditional logistic regression. Results: The cohort of 955 582 postmenopausal women included 23 505 cases of VTE matched with 231 562 controls. The risk of VTE was not increased with current use of transdermal estrogen alone (RR 1.01; 95% CI, 0.89–1.16) or combined with a progestogen (RR 0.96; 95% CI, 0.77–1.20), or with current use of tibolone (RR 0.92; 95% CI: 0.77–1.10), relative to non‐use. On the other hand, the risk was increased with current use of oral estrogen (RR 1.49; 95% CI, 1.37–1.63) and oral estrogen–progestogen (RR 1.54; 95% CI, 1.44–1.65), and increased with estrogen dosage. The risks with oral formulations were particularly elevated during the first year of use but disappeared 4 months after discontinuation. Conclusion: Transdermal HRT and tibolone were not associated with an increased risk of VTE in postmenopausal women.     

Lack of clinically significant pharmacological interactions between ticagrelor and enoxaparin or unfractionated heparin in healthy subjects

What is known and Objective: Patients with acute coronary syndromes (ACS) receive several pharmacological therapies concomitantly, including antiplatelet and anticoagulant agents. As unfractionated heparin (UFH) activates platelets in vitro and in vivo, co‐administration with an antiplatelet agent may lead to decreased clinical effectiveness of the latter. The aim was therefore to determine any potential drug–drug interactions between the new oral antiplatelet agent ticagrelor, and UFH or enoxaparin. Methods: In two open‐label, three‐period, crossover trials, healthy subjects were randomized to receive ticagrelor alone or with enoxaparin (study 1) or UFH (study 2), or enoxaparin or UFH alone. Ticagrelor plasma concentrations, inhibition of platelet aggregation (IPA), anti‐factor Xa levels, activated partial thromboplastin time (aPTT) and activated coagulation time (ACT) were measured. Results: Thirty and 28 subjects completed studies 1 and 2, respectively. Study drugs were generally well tolerated, with no significant bleeding or serious adverse events. Co‐administration with enoxaparin or UFH had no significant effect on ticagrelor pharmacokinetics. The effect of ticagrelor on IPA was unimpaired by co‐administration of enoxaparin, except for a marginal (?2·9%; 908·7%.h, 881·9%.h) reduction in final extent area under the effect curve (AUEC)_2–12 (95% CI: ?51·6%.h, ?2·0%.h). Co‐administering UFH with ticagrelor caused small decreases in IPA_max (?3·8%; 94·6%, 91·0%) and AUEC_2–12 (?6·8%; 888·6%.h, 828·3%.h) vs. ticagrelor alone (95% CI: final extent IPA_max?5·7%, ?1·6%; AUEC_2–12?109·8%.h, ?10·8%.h). Ticagrelor had no clinically significant effects on enoxaparin as assessed by anti‐factor Xa (study 1), or UFH as assessed by aPTT or ACT (study 2). What is new and conclusions: Enoxaparin and UFH had no effect on the pharmacokinetics and no clinically significant effect on the pharmacodynamics of ticagrelor. Ticagrelor had no clinically significant effects on the pharmacodynamics of enoxaparin or UFH.     

A dose escalation study of YM150, an oral direct factor Xa inhibitor, in the prevention of venous thromboembolism in elective primary hip replacement surgery

BACKGROUND: YM150, a new oral direct factor Xa inhibitor is used as prophylaxis for venous thromboembolism (VTE), a well-known risk after orthopaedic surgery. OBJECTIVES: To assess the safety and efficacy of thromboprophylaxis with YM150 in a dose escalation study. PATIENTS/METHODS: Patients (174) undergoing hip replacement surgery were randomized per cohort to oral once daily YM150 or subcutaneous enoxaparin (40 mg daily) in a 4:1 ratio for 7-10 days treatment. The YM150 doses were 3, 10, 30 and 60 mg by sequential four-dose escalation cohorts. The primary endpoint was major and/or clinically relevant non-major bleeding. The incidence of VTE was defined as a composite of verified symptomatic events and/or positive findings at bilateral venography on the last treatment day. An independent adjudication committee evaluated blindly the outcomes of the open-label study. RESULTS: No major and three clinically relevant non-major bleeds were reported, 1 (2.9%; 95% CI, 0.1-15.1) in the 3 mg and 2 (5.7%; 95% CI, 1.0-18.8) in the 10 mg YM150 dose groups. Of 147 patients (84%) with an evaluable venogram, VTE was observed in 51.9% (95% CI, 31.9-71.4), 38.7% (95% CI, 22.6-57.0), 22.6% (95% CI, 9.7-39.4), and 18.5% (95% CI, 7.5-36.5) in the YM150 dose groups 3, 10, 30 and 60 mg, respectively. A significant YM150 dose-related trend in VTE incidence was found (P=0.006). VTE with enoxaparin was 38.7% (95% CI, 22.6-57.0). CONCLUSIONS: YM150, 10-60 mg daily, starting 6-10 h after primary hip replacement, was shown to be safe, well tolerated and effective.     

Apixaban and Rivaroxaban in Patients With Acute Venous Thromboembolism

ObjectiveTo compare the clinical efficacy and safety of apixaban with those of rivaroxaban for the treatment of acute venous thromboembolism (VTE).Patients and MethodsConsecutive patients enrolled in the Mayo Thrombophilia Clinic Registry (between March 1, 2013, and January 30, 2018) and treated with apixaban or rivaroxaban for acute VTE were followed forward in time. The primary efficacy outcome was VTE recurrence. The primary safety outcome was major bleeding; the second safety outcome was clinically relevant nonmajor bleeding (CRNMB); and the third was a composite of major bleeding or CRNMB.ResultsWithin the group of 1696 patients with VTE enrolled, 600 (38%) were treated either with apixaban (n=302, 50%) or rivaroxaban (n=298, 50%) within the first 14 days of VTE diagnosis and who completed at least 3 months of therapy or had a study event. Recurrent VTE was diagnosed in 7 patients (2.3%) treated with apixaban and in 6 (2%) treated with rivaroxaban (adjusted hazard ratio [aHR], 1.4; 95% CI, 0.5-3.8). Major bleeding occurred in 11 patients (3.6%) receiving apixaban and in 9 patients (3.0%) receiving rivaroxaban (aHR, 1.2; 95% CI, 0.5-3.2). Clinically relevant nonmajor bleeding was diagnosed in 7 patients (2.3%) receiving apixaban and in 20 (6.7%) receiving rivaroxaban (aHR, 0.4; 95% CI, 0.2-0.9). The rates of composite major bleeding or CRNMB were similar (aHR, 0.6; 95% CI, 0.3-1.2). Most study events occurred in patients with cancer.ConclusionIn the setting of a standardized, guideline-directed, patient-oriented clinical practice, the efficacy and safety of apixaban and rivaroxaban for the treatment of acute VTE were comparable.     

全髋关节置换后应用利伐沙班安全性的Meta分析

背景：利伐沙班预防全髋关节置换后静脉血栓的疗效已经得到诸多实验的证明,但有关其安全性实验结果并不一致。目的：系统评价利用伐沙班和依诺肝素预防全髋关节置换后静脉血栓的安全性。方法：全面检索国内外关于利伐沙班和依诺肝素预防全髋关节置换术后静脉血栓的随机对照研究文献,筛选出符合评价标准的文献,采用RevMan5.1软件进行Meta分析。结果与结论：纳入随机对照研究文献6篇,其中5篇英文和1篇中文,全部样本量合计9611例。荟萃分析结果显示：全髋关节置换后应用利伐沙班的大出血事件发生率高于依诺肝素,RR为1.75（95%CI,0.76-4.04）,Z=1.31（P=0.19）;临床非大出血事件发生率高于依诺肝素,RR为1.29（95%CI,0.99-1.68）,Z=1.85（P=0.06）;小出血事件发生率稍低于依诺肝素,RR为0.98（95%CI,0.76-1.25）,Z=0.20（P=0.84）;总出血事件发生率稍高于依诺肝素,RR为1.13（95%CI,0.95-1.35）,Z=1.38（P=0.17）。提示全髋关节置换后使用利伐沙班预防静脉血栓栓塞的安全性与依诺肝素相当,差异无显著性意义。     

Statins after recent stroke reduces recurrence and improves survival in an aging Mediterranean population without known coronary heart disease

What is known and Objective: The effect of a statin‐based medical intervention on prevention of fatal and non‐fatal stroke recurrence and the incidence of all‐causes mortality have been explored previously in aging populations within the scope of clinical trials research. However, such evidence needs to be explored under conditions of routine clinical practice. The objective of this study was to determine whether statin therapy in patients with a first stroke episode reduces the incidence of 6‐year recurrent fatal or non‐fatal stroke and all‐cause mortality in an aging Mediterranean population without known coronary heart disease followed in routine medical practice. Methods: A retrospective study was carried out using records on death, hospitalizations owing to stroke and history of statin therapy included in the Badalona Serveis Assistencials (BSA) database. The cohort studied consisted of consecutive patients covered by the BSA health provider plan with a first‐ever acute stroke episode during January 2003 until December 2008, for whom there was available information covering the 6‐year follow‐up period. Recurrence rate (RR) and incidence rate (IR) of fatal/non‐fatal stroke and all‐causes mortality were computed. Association with statin therapy was assessed by means of calculation of relative risk (RR) and hazard ratio (HR) using multivariate logistic regression and Cox proportional hazards models controlling for confounding covariates. Results and Discussion: The cohort comprised a series of 601 consecutive patients [57% men, 75·9 (12·4) years old (88% >60 years)]. Of these, 32% received statins, which were associated with lower fatal/non‐fatal recurrent stroke RR; 7% vs. 18% [adjusted RR = 0·32 (CI: 0·16–0·61), P = 0·001] and lower IR; 16·78 vs. 45·22 events/year‐1000 subjects [adjusted HR = 0·35 (0·19–0·64), P = 0·001]. Similarly, observed all‐causes mortality was lower in the cohort receiving statins; 11% vs. 16% [adjusted RR = 0·29 (CI: 0·08–1·12), P = 0·072], and also mortality rate; 26·09 vs. 36·25 deaths/year‐1000 subjects [adjusted HR = 0·23 (0·08–0·67), P = 0·007]. What is new and Conclusions:  Statin therapy in patients with first‐ever acute stroke lowers the risk of 6‐year stroke recurrence and improves survival in an aging Mediterranean cohort. These results add additional evidence in routine clinical practice to the observed effects of statins in clinical trials.     

A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial

BACKGROUND: Dabigatran etexilate is an oral direct thrombin inhibitor undergoing evaluation for the prevention of venous thromboembolism (VTE) following orthopedic surgery. METHODS: In a multicenter, parallel-group, double-blind study, 1973 patients undergoing total hip or knee replacement were randomized to 6-10 days of oral dabigatran etexilate (50, 150 mg twice daily, 300 mg once daily, 225 mg twice daily), starting 1-4 h after surgery, or subcutaneous enoxaparin (40 mg once daily) starting 12 h prior to surgery. The primary efficacy outcome was the incidence of VTE (detected by bilateral venography or symptomatic events) during treatment. RESULTS: Of the 1949 treated patients, 1464 (75%) patients were evaluable for the efficacy analysis. VTE occurred in 28.5%, 17.4%, 16.6%, 13.1% and 24% of patients assigned to dabigatran etexilate 50, 150 mg twice daily, 300 mg once daily, 225 mg twice daily and enoxaparin, respectively. A significant dose-dependent decrease in VTE occurred with increasing doses of dabigatran etexilate (P < 0.0001). Compared with enoxaparin, VTE was significantly lower in patients receiving 150 mg twice daily [odds ratio (OR) 0.65, P = 0.04], 300 mg once daily (OR 0.61, P = 0.02) and 225 mg twice daily (OR 0.47, P = 0.0007). Compared with enoxaparin, major bleeding was significantly lower with 50 mg twice daily (0.3% vs. 2.0%, P = 0.047) but elevated with higher doses, nearly reaching statistical significance with the 300 mg once-daily dose (4.7%, P = 0.051). CONCLUSIONS: Oral administration of dabigatran etexilate, commenced early in the postoperative period, was effective and safe across a range of doses. Further optimization of the efficacy/safety balance will be addressed in future studies.