Akos F. Pap

Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial

BACKGROUND The risk of venous thromboembolism is high after total hip arthroplasty and could persist after hospital discharge. Our aim was to compare the use of rivaroxaban for extended thromboprophylaxis with short-term thromboprophylaxis with enoxaparin. METHODS 2509 patients scheduled to undergo elective total hip arthroplasty were randomly assigned, stratified according to centre, with a computer-generated randomisation code, to receive oral rivaroxaban 10 mg once daily for 31-39 days (with placebo injection for 10-14 days; n=1252), or enoxaparin 40 mg once daily subcutaneously for 10-14 days (with placebo tablet for 31-39 days; n=1257). The primary efficacy outcome was the composite of deep-vein thrombosis (symptomatic or asymptomatic detected by mandatory, bilateral venography), non-fatal pulmonary embolism, and all-cause mortality up to day 30-42. Analyses were done in the modified intention-to-treat population, which consisted of all patients who had received at least one dose of study medication, had undergone planned surgery, and had adequate assessment of thromboembolism. This study is registered at ClinicalTrials.gov, number NCT00332020. FINDINGS The modified intention-to-treat population for the analysis of the primary efficacy outcome consisted of 864 patients in the rivaroxaban group and 869 in the enoxaparin group. The primary outcome occurred in 17 (2.0%) patients in the rivaroxaban group, compared with 81 (9.3%) in the enoxaparin group (absolute risk reduction 7.3%, 95% CI 5.2-9.4; p<0.0001). The incidence of any on-treatment bleeding was much the same in both groups (81 [6.6%] events in 1228 patients in the rivaroxaban safety population vs 68 [5.5%] of 1229 patients in the enoxaparin safety population; p=0.25). INTERPRETATION Extended thromboprophylaxis with rivaroxaban was significantly more effective than short-term enoxaparin plus placebo for the prevention of venous thromboembolism, including symptomatic events, in patients undergoing total hip arthroplasty.

Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial

BACKGROUND The role of adjuvant treatment in pancreatic cancer remains uncertain. The European Study Group for Pancreatic Cancer (ESPAC) assessed the roles of chemoradiotherapy and chemotherapy in a randomised study. METHODS After resection, patients were randomly assigned to adjuvant chemoradiotherapy (20 Gy in ten daily fractions over 2 weeks with 500 mg/m(2) fluorouracil intravenously on days 1-3, repeated after 2 weeks) or chemotherapy (intravenous fluorouracil 425 mg/m(2) and folinic acid 20 mg/m(2) daily for 5 days, monthly for 6 months). Clinicians could randomise patients into a two-by-two factorial design (observation, chemoradiotherapy alone, chemotherapy alone, or both) or into one of the main treatment comparisons (chemoradiotherapy versus no chemoradiotherapy or chemotherapy versus no chemotherapy). The primary endpoint was death, and all analyses were by intention to treat. Findings 541 eligible patients with pancreatic ductal adenocarcinoma were randomised: 285 in the two-by-two factorial design (70 chemoradiotherapy, 74 chemotherapy, 72 both, 69 observation); a further 68 patients were randomly assigned chemoradiotherapy or no chemoradiotherapy and 188 chemotherapy or no chemotherapy. Median follow-up of the 227 (42%) patients still alive was 10 months (range 0-62). Overall results showed no benefit for adjuvant chemoradiotherapy (median survival 15.5 months in 175 patients with chemoradiotherapy vs 16.1 months in 178 patients without; hazard ratio 1.18 [95% CI 0.90-1.55], p=0.24). There was evidence of a survival benefit for adjuvant chemotherapy (median survival 19.7 months in 238 patients with chemotherapy vs 14.0 months in 235 patients without; hazard ratio 0.66 [0.52-0.83], p=0.0005). Interpretation This study showed no survival benefit for adjuvant chemoradiotherapy but revealed a potential benefit for adjuvant chemotherapy, justifying further randomised controlled trials of adjuvant chemotherapy in pancreatic cancer.

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism

BACKGROUND Although many patients with venous thromboembolism require extended treatment, it is uncertain whether it is better to use full‐ or lower‐intensity anticoagulation therapy or aspirin. METHODS In this randomized, double‐blind, phase 3 study, we assigned 3396 patients with venous thromboembolism to receive either once‐daily rivaroxaban (at doses of 20 mg or 10 mg) or 100 mg of aspirin. All the study patients had completed 6 to 12 months of anticoagulation therapy and were in equipoise regarding the need for continued anticoagulation. Study drugs were administered for up to 12 months. The primary efficacy outcome was symptomatic recurrent fatal or nonfatal venous thromboembolism, and the principal safety outcome was major bleeding. RESULTS A total of 3365 patients were included in the intention‐to‐treat analyses (median treatment duration, 351 days). The primary efficacy outcome occurred in 17 of 1107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) receiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P<0.001 for both comparisons). Rates of major bleeding were 0.5% in the group receiving 20 mg of rivaroxaban, 0.4% in the group receiving 10 mg of rivaroxaban, and 0.3% in the aspirin group; the rates of clinically relevant nonmajor bleeding were 2.7%, 2.0%, and 1.8%, respectively. The incidence of adverse events was similar in all three groups. CONCLUSIONS Among patients with venous thromboembolism in equipoise for continued anticoagulation, the risk of a recurrent event was significantly lower with rivaroxaban at either a treatment dose (20 mg) or a prophylactic dose (10 mg) than with aspirin, without a significant increase in bleeding rates. (Funded by Bayer Pharmaceuticals; EINSTEIN CHOICE ClinicalTrials.gov number, NCT02064439.)

Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials

BACKGROUND Patients with venous thromboembolism and cancer have a substantial risk of recurrent venous thromboembolism and bleeding during anticoagulant therapy. Although monotherapy with low-molecular-weight heparin is recommended in these patients, in clinical practice many patients with venous thromboembolism and cancer do not receive this treatment. We aimed to assess the efficacy and safety of a single-drug regimen with oral rivaroxaban compared with enoxaparin followed by vitamin K antagonists, in the subgroup of patients with cancer enrolled in the EINSTEIN-DVT and EINSTEIN-PE randomised controlled trials. METHODS We did a subgroup analysis of patients with active cancer (either at baseline or diagnosed during the study), a history of cancer, or no cancer who were enrolled in the EINSTEIN-DVT and EINSTEIN-PE trials. Eligible patients with deep-vein thrombosis (EINSTEIN-DVT) or pulmonary embolism (EINSTEIN-PE) were randomly assigned in a 1:1 ratio to receive rivaroxaban (15 mg twice daily for 21 days, followed by 20 mg once daily) or standard therapy (enoxaparin 1·0 mg/kg twice daily and warfarin or acenocoumarol; international normalised ratio 2·0-3·0). Randomisation with a computerised voice-response system was stratified according to country and intended treatment duration (3, 6, or 12 months). The prespecified primary efficacy and safety outcomes of both the trials and this subanalysis were symptomatic recurrent venous thromboembolism and clinically relevant bleeding, respectively. We did efficacy and mortality analyses in the intention-to-treat population, and bleeding analyses for time spent receiving treatment plus 2 days in the safety population (all patients who received at least one dose of study drug). The EINSTEIN-DVT and EINSTEIN-PE studies are registered at ClinicalTrials.gov, numbers NCT00440193 and NCT00439777. FINDINGS In patients with active cancer (diagnosed at baseline or during treatment), recurrent venous thromboembolism occurred in 16 (5%) of 354 patients allocated to rivaroxaban and 20 (7%) of 301 patients allocated to enoxaparin and vitamin K antagonist (hazard ratio [HR] 0·67, 95% CI 0·35 to 1·30). Clinically relevant bleeding occurred in 48 (14%) of 353 patients receiving rivaroxaban and in 49 (16%) of 298 patients receiving standard therapy (HR 0·80, 95% CI 0·54 to 1·20). Major bleeding occurred in eight (2%) of 353 patients receiving rivaroxaban and in 15 (5%) of 298 patients receiving standard therapy (HR 0·42, 95% CI 0·18 to 0·99). The overall frequency of recurrent venous thromboembolism in patients with only a history of cancer (five [2%] of 233 patients in the rivaroxaban group vs five [2%] of 236 in the standard therapy group; HR 0·98, 95% CI 0·28-3·43) was similar to that of patients without cancer (65 [2%] of 3563 vs 70 [2%] of 3594, respectively; HR 0·93, 95% CI 0·66-1·30), but the frequency was increased in patients with active cancer at baseline (six [2%] of 258 vs eight [4%] of 204, respectively; HR 0·62, 95% CI 0·21-1·79) and most markedly increased in patients whose diagnosis of cancer was made during the study (ten [10%] of 96 vs 12 [12%] of 97, respectively; HR 0·80, 95% CI 0·34-1·88). The overall frequency of major bleeding in patients with only a history of cancer (one [<1%] patient in the rivaroxaban group vs four [2%] patients in the standard therapy group; HR 0·23, 95% CI 0·03-2·06) was similar to that of patients without cancer (31 [1%] vs 53 [1%], respectively; HR 0·58, 95% CI 0·37-0·91), but was increased in patients with active cancer at baseline (five [2%] vs eight [4%], respectively; HR 0·47, 95% CI 0·15-1·45) and was highest in those with cancer diagnosed during the study (three [3%] vs seven [7%], respectively; HR 0·33, 95% CI 0·08-1·31). INTERPRETATION In patients with active cancer and venous thromboembolism, rivaroxaban had similar efficacy to prevent recurrence of venous thromboembolism and reduced the number major bleeding events compared with treatment with enoxaparin and a vitamin K antagonist, although there was no difference between groups for clinically relevant bleeding. Based on these results, a head-to-head comparison of rivaroxaban with long-term low-molecular-weight heparin in patients with cancer is warranted. FUNDING Bayer HealthCare Pharmaceuticals and Janssen Research & Development.

Rivaroxaban versus enoxaparin/vitamin K antagonist therapy in patients with venous thromboembolism and renal impairment

BackgroundPatients with renal impairment receiving classical anticoagulation for venous thromboembolism (VTE) are at increased risk of bleeding and possibly pulmonary embolism. We examined the efficacy and safety of oral rivaroxaban in patients with VTE with and without renal impairment.MethodsPrespecified subgroup analysis of the EINSTEIN DVT and EINSTEIN PE studies comparing fixed-dose rivaroxaban with enoxaparin/a vitamin K antagonist (VKA), performed in 8246 patients enrolled from 2007 to 2011 in 314 hospitals.ResultsOutcomes were recurrent VTE and major or clinically relevant nonmajor bleeding in patients with normal renal function (n = 5569; 67.3%) or mild (n = 2037; 24.6%), moderate (n = 636; 7.7%), or severe (n = 21; 0.3%) renal impairment. Rates of recurrent VTE were 1.8%, 2.8%, 3.3%, and 4.8% in patients with normal renal function and mild, moderate, and severe renal impairment, respectively (ptrend = 0.001). Hazard ratios for recurrent VTE were similar between treatment groups across renal function categories (pinteraction = 0.72). Major bleeding in rivaroxaban recipients occurred in 0.8%, 1.4%, 0.9%, and 0%, respectively (ptrend = 0.50). Respective rates in enoxaparin/VKA recipients were 1.0%, 3.0%, 3.9%, and 9.1% (ptrend < 0.001). Rivaroxaban–enoxaparin/VKA hazard ratios were 0.79 (95% confidence interval [CI] 0.46–1.36) for normal renal function, 0.44 (95% CI 0.24–0.84) for mild renal impairment, and 0.23 (95% CI 0.06–0.81) for moderate renal impairment (pinteraction = 0.034).ConclusionsPatients with symptomatic VTE and renal impairment are at increased risk of recurrent VTE. Renal impairment increased the risk of major bleeding in enoxaparin/VKA-treated patients but not in rivaroxaban-treated patients.Trial registrationNCT00440193 and NCT00439777.

Post-thrombotic syndrome in patients treated with rivaroxaban or enoxaparin/vitamin K antagonists for acute deep-vein thrombosis A post-hoc analysis

Post-thrombotic syndrome (PTS) is a common complication of deep-vein thrombosis (DVT). Poor quality treatment with vitamin K antagonists (VKA) is a risk factor for PTS. We hypothesised that treatment with the direct oral anticoagulant (DOAC) rivaroxaban may lower PTS incidence as compared to enoxaparin/VKA, as DOACs have a more stable pharmacologic profile than VKA. We performed a post-hoc subgroup analysis of the Einstein DVT trial (n=3449). Kaplan-Meier survival analysis was performed to compare the cumulative incidence of PTS between the rivaroxaban and enoxaparin/VKA groups. Hazard ratios (HR) and 95 % confidence intervals (CI) were calculated using Cox proportional hazards models. We included 336 patients with a mean age of 58 ± 16 years and a median follow-up after index DVT of 57 months (interquartile range 48-64). Of these, 162 (48 %) had been treated with rivaroxaban and 174 (52 %) with enoxaparin/VKA. The cumulative PTS incidence at 60 months follow-up was 29 % in the rivaroxaban group and 40 % in the enoxaparin/VKA group. After adjusting for age, gender, body mass index, previous VTE, ipsilateral recurrent DVT, extent of DVT, idiopathic DVT, duration of anticoagulant treatment, compliance to assigned study medication, elastic compression stocking use and active malignancy, the HR of PTS development for rivaroxaban was 0.76 (95 % CI: 0.51-1.13). In conclusion, treatment of acute DVT with rivaroxaban was associated with a numerically lower but statistically non-significant risk of PTS compared to enoxaparin/VKA treatment. The potential effect on reducing PTS deserves evaluation in a large randomised trial.

Treatment of Pulmonary Embolism With Rivaroxaban: Outcomes by Simplified Pulmonary Embolism Severity Index Score from a Post Hoc Analysis of the EINSTEIN PE Study

Objectives The objective was to assess adverse outcomes in relation to the simplified Pulmonary Embolism Severity Index (PESI) score in patients treated with rivaroxaban or standard therapy in the phase III EINSTEIN PE study and to evaluate the utility of the simplified PESI score to identify low-risk pulmonary embolism (PE) patients. Methods A post hoc analysis of EINSTEIN PE data was performed to assess the efficacy and safety of rivaroxaban in patients with a range of simplified PESI scores. Recurrent venous thromboembolism, fatal PE, all-cause mortality, and major bleeding were stratified by simplified PESI scores of 0, 1, or ≥2 and according to treatment period at 7, 14, 30, and 90 days and at the end of the full intended treatment period. Results Simplified PESI scores could be calculated in 4,831 of the 4,832 randomized patients; of those, 53.6, 36.7, and 9.7% had PESI scores of 0, 1, and ≥2, respectively. Among patients with simplified PESI scores of 0 or 1, fatal PE, all-cause mortality, and other adverse outcomes were uncommon within the first 7, 14, and 30 days. Patients with simplified PESI scores of ≥2 had more frequent adverse outcomes. Major bleeding was lower in the rivaroxaban group, particularly in those with simplified PESI scores of 1 or ≥2. Conclusions The findings support using risk stratification with the simplified PESI score to identify low-risk patients with PE.

Use of Prestudy Heparin Did Not Influence the Efficacy and Safety of Rivaroxaban in Patients Treated for Symptomatic Venous Thromboem-bolism in the EINSTEIN DVT and EINSTEIN PE Studies

Abstract Objectives In the EINSTEIN DVT and EINSTEIN PE studies, the majority of patients received heparins to bridge the period during venous thromboembolism (VTE) diagnosis confirmation and the start of the study. In contrast to vitamin K antagonists (VKAs), rivaroxaban may not require initial heparin treatment. Methods To evaluate the effect of prestudy heparin on the efficacy and safety of rivaroxaban relative to enoxaparin/VKA, the 3‐month incidence of recurrent VTE, and the 14‐day incidence of major and nonmajor clinically relevant bleeding were compared in patients who did and did not receive prestudy heparin. Results Of the 8,281 patients randomized, 6,937 (83.8%) received prestudy heparin (mean ± SD duration = rivaroxaban: 1.04 [± 0.74] days; enoxaparin 1.03 [± 0.42] days), and 1,344 (16.2%) did not. In patients who did not receive prestudy heparin, the incidences of recurrent VTE were similar in rivaroxaban (15 of 649, 2.3%) and enoxaparin/VKA (13 of 695, 1.9%) patients (adjusted hazard ratio [HR] = 1.11; 95% confidence interval [CI] = 0.52 to 2.37). The incidences of recurrent VTE were also similar in rivaroxaban (54 of 3,501, 1.5%) and enoxaparin/VKA (69 of 3,436, 2.0%) patients who did receive prestudy heparin (adjusted HR = 0.74; 95% CI = 0.52 to 1.06; pinteraction = 0.32). The incidences of major or nonmajor clinically relevant bleeding with rivaroxaban were not significantly different from those with enoxaparin/VKA, either with (105 of 3,485, 3.0% vs. 104 of 3,428, 3.0%; adjusted HR = 0.98; 95% CI = 0.75 to 1.29) or without (24 of 645, 3.7% vs. 30 of 688, 4.4%; adjusted HR = 0.81; 95% CI = 0.46 to 1.40; pinteraction = 0.68) prestudy heparin. Conclusions Although the majority of patients in the EINSTEIN studies received prestudy heparin, there were no notable differences in treatment effect of rivaroxaban versus enoxaparin/VKA in those who did and did not receive it.

Risk of major bleeding in patients with venous thromboembolism treated with rivaroxaban or with heparin and vitamin K antagonists

The study aim was to identify predictive factors for major bleeding in patients receiving the novel oral factor Xa inhibitor rivaroxaban or enoxaparin-vitamin K antagonists (VKAs) for the treatment of acute symptomatic venous thromboembolism. We analysed data from patients included in the phase III EINSTEIN DVT and EINSTEIN PE studies. Factors associated with major bleeding events were assessed with best subset variable selection using Cox proportional hazards regression model. Three time windows were considered, i.e. the initial three weeks, after the third week onwards, and the entire duration of the anticoagulant treatment. Model discrimination was estimated using the C-statistic and validated internally by bootstrap techniques. Major bleeding occurred in 40 (1.0%) of 4130 patients receiving rivaroxaban and in 72 (1.7%) of 4116 receiving enoxaparin/VKAs, with 44% of the major bleeding events occurring in the first three weeks of treatment. Significant risk factors for major bleeding were older age, black race, low haemoglobin concentrations, active cancer, and antiplatelet or non-steroidal anti-inflammatory drug therapy. The discrimination of the model for major bleeding was high for the first three weeks (C-statistic 0.73), from the fourth week onwards (C-statistic 0.68), and the entire period of anticoagulant treatment (C-statistic 0.74). This analysis identified risk factors for major bleeding in patients receiving the novel oral anticoagulant rivaroxaban or enoxaparin/VKAs for the treatment of acute venous thromboembolism. The prognostic model based on the combination of identified risk factors may be informative to estimate the risk of major bleeding both during the initial and later phases of anticoagulation.

Choosing wisely: The impact of patient selection on efficacy and safety outcomes in the EINSTEIN-DVT/PE and AMPLIFY trials

BACKGROUND The results of the EINSTEIN-DVT/PE and AMPLIFY trials, which compared rivaroxaban and apixaban with conventional anticoagulation therapy for acute venous thromboembolism (VTE), respectively, are often compared. However, the trials differed in duration of therapy (3-12 and 6months, respectively) and in patient selection (few exclusion criteria and more stringent exclusion criteria, respectively). METHODS To determine the effect of these methodological differences on outcomes, the patients enrolled in EINSTEIN-DVT/PE were divided into 2 cohorts; the 5253 patients that matched the exclusion criteria for AMPLIFY and were treated for at least 6months (cohort 1) and the 2368 patients who would have been ineligible for AMPLIFY (cohort 2). RESULTS Compared with patients in cohort 2, those in cohort 1 were older and more often male and there were more with unprovoked VTE, prior VTE, cancer and known thrombophilia. In cohort 1, rivaroxaban would have significantly reduced recurrent VTE (relative risk [RR], 0.64; 95% confidence interval [CI], 0.43-0.95) and major bleeding (RR, 0.50; 95% CI, 0.30-0.82) compared with conventional therapy, whereas the two treatments would have had similar effects on recurrent VTE (RR, 1.08; 95% CI, 0.65-1.79) and major bleeding (RR, 1.03; 95% CI, 0.48-2.18) in cohort 2. CONCLUSIONS This analysis illustrates the influence of patient selection and treatments duration on outcome results and highlights the limitations of cross-trial comparisons.