Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.

BACKGROUND: A fixed-dose regimen of rivaroxaban, an oral factor Xa inhibitor, has been shown to be as effective as standard anticoagulant therapy for the treatment of deep-vein thrombosis, without the need for laboratory monitoring. This approach may also simplify the treatment of pulmonary embolism. METHODS: In a randomized, open-label, event-driven, noninferiority trial involving 4832 patients who had acute symptomatic pulmonary embolism with or without deep-vein thrombosis, we compared rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with standard therapy with enoxaparin followed by an adjusted-dose vitamin K antagonist for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism. The principal safety outcome was major or clinically relevant nonmajor bleeding. RESULTS: Rivaroxaban was noninferior to standard therapy (noninferiority margin, 2.0; P=0.003) for the primary efficacy outcome, with 50 events in the rivaroxaban group (2.1%) versus 44 events in the standard-therapy group (1.8%) (hazard ratio, 1.12; 95% confidence interval [CI], 0.75 to 1.68). The principal safety outcome occurred in 10.3% of patients in the rivaroxaban group and 11.4% of those in the standard-therapy group (hazard ratio, 0.90; 95% CI, 0.76 to 1.07; P=0.23). Major bleeding was observed in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the standard-therapy group (hazard ratio, 0.49; 95% CI, 0.31 to 0.79; P=0.003). Rates of other adverse events were similar in the two groups. CONCLUSIONS: A fixed-dose regimen of rivaroxaban alone was noninferior to standard therapy for the initial and long-term treatment of pulmonary embolism and had a potentially improved benefit-risk profile. (Funded by Bayer HealthCare and Janssen Pharmaceuticals; EINSTEIN-PE ClinicalTrials.gov number, NCT00439777.).

Enoxaparin followed by once-weekly idrabiotaparinux versus enoxaparin plus warfarin for patients with acute symptomatic pulmonary embolism: a randomised, double-blind, double-dummy, non-inferiority trial.

BACKGROUND: Treatment of pulmonary embolism with low-molecular-weight heparin and vitamin K antagonists, such as warfarin, is not ideal. We aimed to assess non-inferiority of idrabiotaparinux, a reversible longlasting indirect inhibitor of activated factor X, to warfarin in patients with acute symptomatic pulmonary embolism. METHODS: In our randomised, double-blind, double-dummy, non-inferiority trial, we enrolled adults with objectively documented acute symptomatic pulmonary embolism attending 291 centres in 37 countries. We excluded patients who were pregnant, had active bleeding, kidney failure, or malignant hypertension, or were at high risk of death, bleeding, or adverse reactions to study drugs. We randomly allocated patients to receive 5-10 days' enoxaparin 1·0 mg/kg twice daily followed by subcutaneous idrabiotaparinux (starting dose 3·0 mg) or adjusted-dose warfarin (target international normalised ratio 2·0-3·0); regimens lasted 3 months or 6 months dependent on clinical presentation. Block randomisation was done with a central interactive computerised system, stratified by study centre and intended treatment duration. The primary efficacy outcome was recurrent venous thromboembolism at 99 days after randomisation. We estimated the odds ratio and 95% CI with a Mantel-Haenzsel χ(2) analysis (non-inferiority margin 2·0) in the intention-to-treat population. The main safety outcome was clinically relevant bleeding (major or non-major) in all patients at day 99. This study is registered with ClinicalTrials.gov, number NCT00345618. FINDINGS: Between Aug 1, 2006, and Jan 31, 2010, we enrolled 3202 patients aged 18-96 years. 34 (2%) of 1599 patients randomly allocated to receive enoxaparin-idrabiotaparinux and 43 (3%) of 1603 patients randomly allocated to receive enoxaparin-warfarin had recurrent venous thromboembolism (odds ratio 0·79, 95% CI 0·50-1·25; p(non-inferiority)=0·0001). 72 (5%) of 1599 patients in the enoxaparin-idrabiotaparinux group and 106 (7%) of 1603 patients in the enoxaparin-warfarin group had clinically relevant bleeding (0·67, 0·49-0·91; p(superiority)=0·0098). We noted similar differences in outcomes in those patients treated to 6 months. INTERPRETATION: Idrabiotaparinux could provide an attractive alternative to warfarin for the long-term treatment of pulmonary embolism, and seems to be associated with reduced bleeding. FUNDING: Sanofi-Aventis (Paris, France).

Oral rivaroxaban for symptomatic venous thromboembolism.

BACKGROUND: Rivaroxaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for treating acute deep-vein thrombosis (DVT) and for continued treatment, without the need for laboratory monitoring. METHODS: We conducted an open-label, randomized, event-driven, noninferiority study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. In parallel, we carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism. The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety outcome was major bleeding or clinically relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study. RESULTS: The study of rivaroxaban for acute DVT included 3449 patients: 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist. Rivaroxaban had noninferior efficacy with respect to the primary outcome (36 events [2.1%], vs. 51 events with enoxaparin-vitamin K antagonist [3.0%]; hazard ratio, 0.68; 95% confidence interval [CI], 0.44 to 1.04; P<0.001). The principal safety outcome occurred in 8.1% of the patients in each group. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11). CONCLUSIONS: Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation. (Funded by Bayer Schering Pharma and Ortho-McNeil; ClinicalTrials.gov numbers, NCT00440193 and NCT00439725.).

An update of consensus guidelines for warfarin reversal.

• Despite the associated bleeding risk, warfarin is the most commonly prescribed anticoagulant in Australia and New Zealand. Warfarin use will likely continue for anticoagulation indications for which novel agents have not been evaluated and among patients who are already stabilised on it or have severe renal impairment. • Strategies to manage over-warfarinisation and warfarin during invasive procedures can reduce the risk of haemorrhage. • For most warfarin indications, the target international normalised ratio (INR) is 2.0-3.0 (venous thromboembolism and single mechanical heart valve excluding mitral). For mechanical mitral valve or combined mitral and aortic valves, the target INR is 2.5-3.5. • Risk factors for bleeding with warfarin use include increasing age, history of bleeding and specific comorbidities. • For patients with elevated INR (4.5-10.0), no bleeding and no high risk of bleeding, withholding warfarin with careful subsequent monitoring seems safe. • Vitamin K1 can be given to reverse the anticoagulant effect of warfarin. When oral vitamin K1 is used for this purpose, the injectable formulation, which can be given orally or intravenously, is preferred. • For immediate reversal, prothrombin complex concentrates (PCC) are preferred over fresh frozen plasma (FFP). Prothrombinex-VF is the only PCC routinely used for warfarin reversal in Australia and New Zealand. It contains factors II, IX, X and low levels of factor VII. FFP is not routinely needed in combination with Prothrombinex-VF. FFP can be used when Prothrombinex-VF is unavailable. Vitamin K1 is essential for sustaining the reversal achieved by PCC or FFP. • Surgery can be conducted with minimal increased risk of bleeding if INR ≤ 1.5. For minor procedures where bleeding risk is low, warfarin may not need to be interrupted. If necessary, warfarin can be withheld for 5 days before surgery, or intravenous vitamin K1 can be given the night before surgery. Prothrombinex-VF use for warfarin reversal should be restricted to emergency settings. Perioperative management of anticoagulant therapy requires an evaluation of the risk of thrombosis if warfarin is temporarily stopped, relative to the risk of bleeding if it is continued or modified.

Idraparinux versus standard therapy for venous thromboembolic disease.

BACKGROUND: Venous thromboembolism is treated with unfractionated heparin or low-molecular-weight heparin, followed by a vitamin K antagonist. We investigated the potential use of idraparinux, a long-acting inhibitor of activated factor X, as a substitute for standard therapy. METHODS: We conducted two randomized, open-label noninferiority trials involving 2904 patients with deep-vein thrombosis and 2215 patients with pulmonary embolism to compare the efficacy and safety of idraparinux versus standard therapy. Patients received either subcutaneous idraparinux (2.5 mg once weekly) or a heparin followed by an adjusted-dose vitamin K antagonist for either 3 or 6 months. The primary efficacy outcome was the 3-month incidence of symptomatic recurrent venous thromboembolism (nonfatal or fatal). RESULTS: In the study of patients with deep venous thrombosis, the incidence of recurrence at day 92 was 2.9% in the idraparinux group as compared with 3.0% in the standard-therapy group (odds ratio, 0.98; 95% confidence interval [CI], 0.63 to 1.50), a result that satisfied the prespecified noninferiority requirement. At 6 months, the hazard ratio for idraparinux was 1.01. The rates of clinically relevant bleeding at day 92 were 4.5% in the idraparinux group and 7.0% in the standard-therapy group (P=0.004). At 6 months, bleeding rates were similar. In the study of patients with pulmonary embolism, the incidence of recurrence at day 92 was 3.4% in the idraparinux group and 1.6% in the standard-therapy group (odds ratio, 2.14; 95% CI, 1.21 to 3.78), a finding that did not meet the noninferiority requirement. CONCLUSIONS: In patients with deep venous thrombosis, once-weekly subcutaneous idraparinux for 3 or 6 months had an efficacy similar to that of heparin plus a vitamin K antagonist. However, in patients with pulmonary embolism, idraparinux was less efficacious than standard therapy. (ClinicalTrials.gov numbers, NCT00067093 [ClinicalTrials.gov] and NCT00062803 [ClinicalTrials.gov].).

Extended prophylaxis of venous thromboembolism with idraparinux.

BACKGROUND: The extended use of vitamin K antagonists for prophylaxis against venous thromboembolism is often constrained by risk-benefit limitations and inconvenience. We evaluated the efficacy and safety of a 6-month extension of prophylaxis against recurrent venous thromboembolism with idraparinux in patients who had initially received 6 months of prophylaxis with an anticoagulant. METHODS: We randomly assigned patients who had completed 6 months of prophylaxis with idraparinux or a vitamin K antagonist and in whom extended anticoagulation was warranted to receive once-weekly injections of 2.5 mg of idraparinux or placebo for 6 months without monitoring. The primary efficacy and safety outcomes were recurrent venous thromboembolism and major bleeding. RESULTS: Of 1215 patients, 6 of 594 (1.0%) in the idraparinux group and 23 of 621 (3.7%) in the placebo group had recurrent venous thromboembolism (P=0.002). Major bleeding occurred in 11 patients (1.9%) in the idraparinux group and in none in the placebo group (P<0.001). Of these 11 episodes, 3 were fatal intracranial hemorrhages. As compared with patients whose initial treatment was a vitamin K antagonist, patients whose initial treatment was idraparinux who were assigned to 6 months in the placebo group had a lower incidence of recurrent thromboembolism (0.7% vs. 5.9%); patients who received 6 additional months of idraparinux therapy had a higher incidence of major bleeding (3.1% vs. 0.9%). CONCLUSIONS: During a 6-month extension of thromboprophylaxis, idraparinux was effective in preventing recurrent thromboembolism but was associated with an increased risk of a major hemorrhage. (ClinicalTrials.gov number, NCT00071279 [ClinicalTrials.gov].).

Heparin-induced thrombocytopenia (HIT). A report of 1,478 clinical outcomes of patients treated with danaparoid (Orgaran) from 1982 to mid-2004.

Clinical outcomes of 1,478 danaparoid treatment case reports for HIT (involving 1,418 patients) treated between 1982 and mid-2004 are analysed. Treatment in 1,291 episodes was for current HIT. Thromboembolism due to HIT was present in 39.4%. The patients include 33 children and 32 pregnancies. Two hundred twenty-six patients required extra-corporeal circuit use for renal failure, 241 patients had a concomitant thrombophilic disorder, and 351 major operations were performed. Clinical outcomes were assessed during danaparoid treatment (range one day to 3.5 years) plus three months of follow-up. Of the danaparoid-treated patients 83.8% survived; 63.7% had no or minor adverse events and 20.1% suffered serious non-fatal adverse events. New thromboses occurred during 9.7% of treatment episodes, and 16.4% of treatment episodes had an inadequate treatment response (i. e. developed one or more of the following: new/extended thrombosis, persistent/new platelet count reduction, unplanned amputation during treatment and follow-up). Major bleeding was reported in 8.1% of treatment episodes. Clinical cross-reactivity of danaparoid (new/persistent platelet count reduction and/or new/extended thrombosis) was confirmed serologically in 23 of 36 patients with positive pretreatment serological danaparoid cross-reactivity and in 22 of 32 additional patients tested at the time of the new event, i.e. a total of 45 patients (3.2%). Clinical outcomes of these case reports of patients given danaparoid because of suspected or confirmed HIT appear to be comparable with those reported by others who used direct thrombin inhibitors, especially when a sufficient danaparoid dosing intensity was used in patients with isolated HIT. Post-operative bleeding limits danaparoid use for cardiopulmonary by-pass surgery. Routine clinical and platelet count monitoring are required to minimise adverse reactions due to cross-reactivity.

Early time courses of recurrent thromboembolism and bleeding during apixaban or enoxaparin/warfarin therapy. A sub-analysis of the AMPLIFY trial.

Risks of recurrence and bleeding are highest during the first weeks of anticoagulant therapy for venous thromboembolism (VTE). We therefore examined the early time course of recurrence and major bleeding in a pre-specified sub-analysis of the AMPLIFY trial, a randomised, double-blind, six-month comparison of oral apixaban with conventional therapy (enoxaparin followed by warfarin) in 5,395 patients with symptomatic proximal deep-vein thrombosis or pulmonary embolism. Early events were of particular interest because apixaban was given without initial heparin treatment. The primary efficacy and safety outcomes were the incidences of the adjudicated composite of recurrent symptomatic VTE or death related to VTE, and of adjudicated major bleeding, respectively. This analysis reports on recurrence and bleeding after 7, 21, and 90 days of therapy, in addition to the previously reported end-of-study results. These were the times specified before statistical analysis. Recurrent VTE after 7, 21, and 90 days, and six months had occurred in 18 (0.7%), 29 (1.1%), 46 (1.8%), and 59 patients (2.3%), respectively, given apixaban, and in 23 (0.9%), 35 (1.3%), 58 (2.2%), and 71 patients (2.7%), respectively, given conventional therapy. Major bleeding had occurred during these time intervals in 3 (0.1%), 5 (0.2%), 11 (0.4%), and 15 patients (0.6%), respectively, who received apixaban, and in 16 (0.6%), 26 (1.0%), 38 (1.4%), and 49 patients (1.8%), respectively, given conventional therapy. Efficacy of apixaban was non-inferior at each time point, with no excess of early recurrences. The reduced bleeding risk associated with apixaban began early during the course of treatment.

Clinical impact and course of major bleeding with edoxaban versus vitamin K antagonists.

Edoxaban is a once-daily direct oral anticoagulant (DOAC). The Hokusai-VTE study revealed that, after initial treatment with heparin, edoxaban was non-inferior to and safer than vitamin K antagonists (VKA) in the prevention of recurrent deep-vein thrombosis and pulmonary embolism. This is the first report on the clinical relevance and management of bleeding events with edoxaban. All major bleeding events were classified blindly by three study-independent adjudicators. Pre-defined criteria were used to classify severity of clinical presentation and, separately, the clinical course and outcome into four categories. Major bleeding occurred in 56 patients treated with edoxaban and 65 patients treated with VKA. The severest categories (3 or 4) of the clinical presentation were assigned to 46 % of the major bleeding episodes in edoxaban recipients versus 58 % of the major bleeds in VKA recipients (odds ratio [OR] 0.62, 95 % confidence interval [CI] 0.30-1.27, p = 0.19). Clinical course was classified as severe (category 3 or 4) in 23 % of the edoxaban and 29 % of the VKA associated bleeds (OR 0.73, 95 % CI 0.32-1.66, p = 0.46). In conclusion, edoxaban associated major bleeding events have a comparable clinical presentation and course to major bleeds with VKA in patients treated for venous thromboembolism in the Hokusai-VTE study. These results may assure physicians that it is safe to prescribe this medication. If a major bleeding during edoxaban treatment occurs, its clinical presentation and clinical course are not worse than in VKA-treated patients.

Rationale and Design of the Informing Fresh versus Old Red Cell Management (INFORM) Trial: An International Pragmatic Randomized Trial.

Although red blood cell transfusion is a potentially lifesaving intervention in severely anemic and acutely bleeding patients, some observational studies have suggested that prolonged red cell storage before transfusion is associated with harm. INFORM is a large, pragmatic, randomized controlled trial comparing the effect of the shorter storage with longer storage red blood cell transfusions on inhospital mortality in hospitalized patients who require a blood transfusion. The trial is being conducted in centers in Australia, Canada, Israel, and the United States and is expected to enroll 31497 patients. If the results of INFORM indicate that shorter storage red blood cell transfusion is associated with superior outcomes compared with standard issue red blood cell transfusion, consideration may be given to shortening blood storage times. If, in contrast, the INFORM trial provides no evidence of harm from longer storage red blood cells, clinicians and patients may be reassured that current blood inventory management strategies are appropriate.

Thromboprophylaxis for intensive care patients in Australia and New Zealand: a brief survey report.

PURPOSE: Internationally, there is practice variation concerning optimal thromboprophylaxis for patients in the intensive care unit (ICU). The current practice in Australia and New Zealand is unknown. METHOD: We conducted a self-administered e-mail survey of 22 Australian and New Zealand ICUs expressing interest in participating in a proposed international randomized trial (PROphylaxis for ThromboEmbolism in Critical Care Trial). RESULTS: Our response rate was 95.4% (95% CI, 77%-100%). Of participating ICUs, 90.5% (95% CI, 70%-99%) used subcutaneous unfractionated heparin for routine thromboprophylaxis in ICU patients. Low-molecular-weight heparin was reserved for specific high-risk patients in many units. CONCLUSION: Routine thromboprophylaxis for ICU patients in Australia and New Zealand is similar to Canada but different to France. Optimal thromboprophylaxis for ICU patients is currently unclear in the absence of randomized trial data.

Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis.

For most warfarin indications, the target maintenance international normalised ratio (INR) is 2-3. Risk factors for bleeding complications with warfarin use include age, history of past bleeding and specific comorbid conditions. To reverse the effects of warfarin, vitamin K(1) can be given. Immediate reversal is achieved with a prothrombin complex concentrate (PCC) and fresh frozen plasma (FFP). Vitamin K(1) is essential for sustaining the reversal achieved by PCC and FFP. When oral vitamin K(1) is used for warfarin reversal, the injectable formulation of vitamin K(1) is preferable to tablets because of its flexible dosing; this formulation can be given orally or injected. To temporarily reverse the effect of warfarin when there is a need to continue warfarin therapy, vitamin K(1) should be given in a dose that will quickly lower the INR to a safe, but not subtherapeutic, range and will not cause resistance once warfarin is reinstated. Prothrombinex-HT is the only PCC approved in Australia and New Zealand for warfarin reversal. It contains factors II, IX and X, and low levels of factor VII. FFP should be added to Prothrombinex-HT as a source of factor VII when used for warfarin reversal. Simple dental or dermatological procedures may not require interruption to warfarin therapy. If necessary, warfarin therapy can be withheld 5 days before elective surgery, when the INR usually falls to below 1.5 and surgery can be conducted safely. Bridging anticoagulation therapy for patients at high risk for thromboembolism should be undertaken in consultation with the relevant experts.

Assessment of an age-adjusted warfarin initiation protocol.

OBJECTIVE: To examine the time taken to reach a stable international normalized ratio (INR), as well as the incidence of overanticoagulation of an age-adjusted warfarin initiation protocol. METHODS: Inpatients and outpatients commencing warfarin therapy at 2 teaching hospitals were dosed according to the age-adjusted protocol. Data were collected prospectively. MAIN OUTCOME MEASURES: Time to reach a stable INR of 2-3 and the number of patients experiencing an INR > or =4 during the first week of warfarin therapy. RESULTS: Seventy-three patients were assessed; at the completion of the 4-day titration protocol, 63% had achieved a stable INR. After an additional 2 days of empiric dosage adjustment by the attending physician, 86% of the subjects demonstrated a stable INR. Five patients (7%) experienced an INR > or =4. These patients had a nonsignificant trend toward a lower plasma albumin level compared with other patients (p = 0.057, Student's t-test). The INR-driven dose adjustments on days 3 and 4 of this protocol coped with other variables that have been shown to affect maintenance warfarin dosing. These included weight, gender, pharmacologic factors affecting clearance, and the presence of certain predesignated risk factors. CONCLUSIONS: The age-adjusted dosing protocol rapidly achieved a stable INR with minimal overanticoagulation. Patients with low serum albumin levels (<3.0 g/dL) may be sensitive to the effects of warfarin during the loading phase.