Rivaroxaban reversal with prothrombin complex concentrate or tranexamic acid in healthy volunteers

Essentials

• Specific reversal agents for managing severe factor Xa inhibitor‐associated bleeding are lacking.
• We assessed 4‐factor‐prothrombin complex concentrate (4F‐PCC) and tranexamic acid (TXA).
• 4F‐PCC, but not TXA, reduced the prothrombin time and increased endogenous thrombin potential.
• These agents may be viable options for reversal of therapeutic doses of rivaroxaban.

Summary

Background

Oral activated factor X inhibitors such as rivaroxaban are widely used, but specific reversal agents are lacking. Although four‐factor prothrombin complex concentrate (4F‐PCC) and tranexamic acid (TXA) are sometimes used to manage serious bleeding, their efficacy is unknown. Prior studies in healthy subjects taking rivaroxaban revealed that 4F‐PCC partially reverses the prolonged prothrombin time (PT), and fully restores the endogenous thrombin potential (ETP). The effect of TXA has not been evaluated.

Methods

In this double‐blind, parallel‐group study, 147 healthy volunteers given rivaroxaban 20 mg twice daily for 3 days were randomized after their morning dose on day 4 to receive intravenous 4F‐PCC (50 IU kg^?1), TXA (1.0 g), or saline. Standardized punch biopsies were performed at baseline and after 4F‐PCC, TXA or saline administration. Reversal was assessed by measuring bleeding duration and bleeding volume at biopsy sites, and by determining the PT and ETP.

Results

As compared with saline, 4F‐PCC partially reversed the PT and completely reversed the ETP, whereas TXA had no effect. Neither 4F‐PCC nor TXA reduced bleeding duration or volume. All treatments were well tolerated, with no recorded adverse events.

Conclusions

Although 4F‐PCC reduced the PT and increased the ETP in volunteers given supratherapeutic doses of rivaroxaban, neither 4F‐PCC nor TXA influenced punch biopsy bleeding.

     

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.

     

Contribution of rivaroxaban to the international normalized ratio when switching to warfarin for anticoagulation as determined by simulation studies

Aim

This study evaluated the influence of rivaroxaban 20 mg once daily on international normalized ratio (INR) during the co-administration period when switching from rivaroxaban to warfarin.

Methods

We developed a calibrated coagulation model that was qualified with phase I clinical data. Prothrombin time and INR values were simulated by use of phospholipid concentrations that matched Neoplastin Plus® and Innovin® reagents. To simulate the combined effects of rivaroxaban and warfarin on INR during switching, warfarin initiation was simulated by adjusting the magnitude of the warfarin effect to reach the desired target INRs over the course of 21 days. The warfarin effect values (obtained every 6 h) and the desired rivaroxaban plasma concentrations were used. Nomograms were generated from rivaroxaban induced increases in INR.

Results

The simulation had good prediction quality. Rivaroxaban induced increases in the total INR from the warfarin attributed INR were seen, which increased with rivaroxaban plasma concentration. When the warfarin only INR was 2.0–3.0, the INR contribution of rivaroxaban with Neoplastin Plus® was 0.5–1.2, decreasing to 0.3–0.6 with Innovin® at median trough rivaroxaban plasma concentrations (38 μg l⁻¹).

Conclusions

The data indicate that measuring warfarin induced changes in INR are best performed at trough rivaroxaban concentrations (24 h after rivaroxaban dosing) during the co-administration period when switching from rivaroxaban to warfarin. Furthermore, Innovin® is preferable to Neoplastin Plus® because of its substantially lower sensitivity to rivaroxaban, thereby reducing the influence of rivaroxaban on the measured INR.     

骨科大手术中的静脉血栓的预防:口服抗凝药的系统回顾和间接比较

目的:基于有效的循证证据,以低分子肝素为对照组,分析达比加群、阿哌沙班和利伐沙班在骨科大手术后预防静脉血栓的有效性与安全性。方法:在Pub Med和Embase中系统地检索随机对照试验以及参考文献中关键的文章,这些文章评价了以低分子肝素为对照组,达比加群、阿哌沙班和利伐沙班在进行了骨科大手术的病人中的作用。结果:评价的结果包括总静脉血栓(total VTE)、深静脉血栓(DVT)、肺栓塞(PE)、死亡和主要出血事件(major bleeding)。笔者独立地评价了每1篇文章的方法质量同时独立地提取了文献数据。在总静脉血栓预防方面,利伐沙班和阿哌沙班优于达比加群,分别为[RR=0.37,95%CI(0.23,0.60)]和[RR=0.58,95%CI(0.35,0.96)]。利伐沙班和阿哌沙班之间没有区别[RR=0.64,95%CI(0.33,1.25)]。利伐沙班与阿哌沙班相比增加了出血风险[RR=1.57,95%CI(1.20,2.07)],利伐沙班与达比加群相比增加了出血风险[RR=1.25,95%CI(0.93,1.70)]。阿哌沙班和达比加群在出血方面没有差别[RR=0.78,95%CI(0.58,1.07)]。结论:在接受骨科大手术病人之中,利伐沙班和阿哌沙班2种药物与达比加群相比,预防静脉血栓的效果更好,出血风险相似。利伐沙班与阿哌沙班相比,预防静脉血栓的效果相似,但是增加了出血的风险。     

低分子肝素及利伐沙班预防全髋关节置换术后失血的观察

探讨人工全髋关节置换患者术后应用低分子肝素或利伐沙班对术后出血量的影响。回顾性分析2012年2月至2014年2月共240例行人工全髋关节置换患者,按术后是否应用低分子肝素或利伐沙班分为空白对照组、低分子肝素组及利伐沙班组。统计比较各组术后血红蛋白、血小板的变化及术后总失血量、显性失血量及隐性失血量。 低分子肝素组总失血量明显高于对照组（P＜0.01）,利伐沙班组总失血量明显高于对照组（P＜0.01）。低分子肝素组及利伐沙班组的显性失血量及隐性失血量也明显高于对照组。低分子肝素组与利伐沙班组出血量无明显差异。3组患者中隐性失血量占总失血量的比例无明显差异。髋骨关节置换术后应用低分子肝素及利伐沙班可增加失血量,包括隐性失血量的增加,2种抗凝药物的疗效相当,应密切关注血红蛋白及血小板的变化,充分认识隐性失血,对患者有效血容量的丢失作出正确评估。     

Direct Oral Anticoagulants: New Drugs and New Concepts

Direct oral anticoagulants (DOACs) are approved for multiple thromboembolic disorders and provide advantages over existing agents. As with all anticoagulants, management protocols for the eventuality of bleeding are important. Randomized phase III studies generally show that DOACs have a similar risk of clinically relevant bleeding compared with standard anticoagulants, with reductions in major bleeding in some cases. This may be particularly important in patients with atrial fibrillation, for whom the rate of intracranial hemorrhage was approximately halved with DOACs compared with warfarin. Conversely, the risk of gastrointestinal bleeding may be increased. Specific patient characteristics, such as renal impairment, comedications, and particular aspects of each drug, including the proportion eliminated by the kidneys, must be taken into account when assessing the risk of bleeding. Although routine coagulation monitoring of DOACs is not required, it may be useful under some circumstances. Of the traditional clotting assays, a sensitive and calibrated prothrombin time may be useful for detecting the presence or absence of clinically relevant factor Xa inhibitor concentrations (rivaroxaban or apixaban), but specific anti–factor Xa assays can measure drug levels quantitatively. For dabigatran, the results of an activated partial thromboplastin time test may exclude a clinically relevant pharmacodynamic effect, but a calibrated dilute thrombin time assay can be used for quantification of drug levels. In the event of mild or moderate bleeding, normal hemostatic support measures are recommended. For life-threatening bleeding, use of nonspecific prohemostatic agents may be considered, although clinical evidence is scarce. Specific antidotes are in development.