Scott D. Berkowitz

Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies

BackgroundStandard treatment for venous thromboembolism (VTE) consists of a heparin combined with vitamin K antagonists. Direct oral anticoagulants have been investigated for acute and extended treatment of symptomatic VTE; their use could avoid parenteral treatment and/or laboratory monitoring of anticoagulant effects.MethodsA prespecified pooled analysis of the EINSTEIN-DVT and EINSTEIN-PE studies compared the efficacy and safety of rivaroxaban (15xa0mg twice-daily for 21xa0days, followed by 20xa0mg once-daily) with standard-therapy (enoxaparin 1.0xa0mg/kg twice-daily and warfarin or acenocoumarol). Patients were treated for 3, 6, or 12xa0months and followed for suspected recurrent VTE and bleeding. The prespecified noninferiority margin was 1.75.ResultsA total of 8282 patients were enrolled; 4151 received rivaroxaban and 4131 received standard-therapy. The primary efficacy outcome occurred in 86 (2.1%) rivaroxaban-treated patients compared with 95 (2.3%) standard-therapy-treated patients (hazard ratio, 0.89; 95% confidence interval [CI], 0.66–1.19; pnoninferiorityu2009<u20090.001). Major bleeding was observed in 40 (1.0%) and 72 (1.7%) patients in the rivaroxaban and standard-therapy groups, respectively (hazard ratio, 0.54; 95% CI, 0.37–0.79; pu2009=u20090.002). In key subgroups, including fragile patients, cancer patients, patients presenting with large clots, and those with a history of recurrent VTE, the efficacy and safety of rivaroxaban were similar compared with standard-therapy.ConclusionThe single-drug approach with rivaroxaban resulted in similar efficacy to standard-therapy and was associated with a significantly lower rate of major bleeding. Efficacy and safety results were consistent among key patient subgroups.Trial registrationEINSTEIN-PE: ClinicalTrials.gov, NCT00439777; EINSTEIN-DVT: ClinicalTrials.gov, NCT00440193.

Factors Associated With Major Bleeding Events: Insights From the ROCKET AF Trial (Rivaroxaban Once-daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation)

OBJECTIVESnThis study sought to report additional safety results from the ROCKET AF (Rivaroxaban Once-daily oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation).nnnBACKGROUNDnThe ROCKET AF trial demonstrated similar risks of stroke/systemic embolism and major/nonmajor clinically relevant bleeding (principal safety endpoint) with rivaroxaban and warfarin.nnnMETHODSnThe risk of the principal safety and component bleeding endpoints with rivaroxaban versus warfarin were compared, and factors associated with major bleeding were examined in a multivariable model.nnnRESULTSnThe principal safety endpoint was similar in the rivaroxaban and warfarin groups (14.9 vs. 14.5 events/100 patient-years; hazard ratio: 1.03; 95% confidence interval: 0.96 to 1.11). Major bleeding risk increased with age, but there were no differences between treatments in each age category (<65, 65 to 74,xa0≥75 years; pinteractionxa0= 0.59). Compared with those without (nxa0= 13,455), patients with a major bleed (nxa0= 781) were more likely to be older, current/prior smokers, have prior gastrointestinal (GI) bleeding, mild anemia, and a lower calculated creatinine clearance and less likely to be female or have a prior stroke/transient ischemic attack. Increasing age, baseline diastolic blood pressure (DBP)xa0≥90 mm Hg, history of chronic obstructive pulmonary disease or GI bleeding, prior acetylsalicylic acid use, and anemia were independently associated with major bleeding risk; female sex and DBPxa0<90 mm Hg were associated with a decreased risk.nnnCONCLUSIONSnRivaroxaban and warfarin had similar risk for major/nonmajor clinically relevant bleeding. Age, sex, DBP, prior GI bleeding, prior acetylsalicylic acid use, and anemia were associated with the risk of major bleeding. (An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation: NCT00403767).

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.)

Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers

Four‐factor prothrombin complex concentrates (PCCs), which contain factor II, FVII, FIX, and FX, have shown the potential to reverse the anticoagulant effect of rivaroxaban in healthy volunteers. The purpose of this study was to determine whether a three‐factor PCC, which contains little FVII, has a similar effect.

Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation: results from the ROCKET-AF Trial.

Aim Anticoagulation prophylaxis for stroke is recommended for at-risk patients with either persistent or paroxysmal atrial fibrillation (AF). We compared outcomes in patients with persistent vs. paroxysmal AF receiving oral anticoagulation. Methods and results Patients randomized in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial (n = 14 264) were grouped by baseline AF category: paroxysmal or persistent. Multivariable adjustment was performed to compare thrombo-embolic events, bleeding, and death between groups, in high-risk subgroups, and across treatment assignment (rivaroxaban or warfarin). Of 14 062 patients, 11 548 (82%) had persistent AF and 2514 (18%) had paroxysmal AF. Patients with persistent AF were marginally older (73 vs. 72, P = 0.03), less likely female (39 vs. 45%, P < 0.0001), and more likely to have previously used vitamin K antagonists (64 vs. 56%, P < 0.0001) compared with patients with paroxysmal AF. In patients randomized to warfarin, time in therapeutic range was similar (58 vs. 57%, P = 0.94). Patients with persistent AF had higher adjusted rates of stroke or systemic embolism (2.18 vs. 1.73 events per 100-patient-years, P = 0.048) and all-cause mortality (4.78 vs. 3.52, P = 0.006). Rates of major bleeding were similar (3.55 vs. 3.31, P = 0.77). Rates of stroke or systemic embolism in both types of AF did not differ by treatment assignment (rivaroxaban vs. warfarin, Pinteraction = 0.6). Conclusion In patients with AF at moderate-to-high risk of stroke receiving anticoagulation, those with persistent AF have a higher risk of thrombo-embolic events and worse survival compared with paroxysmal AF.

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

BACKGROUNDnPatients 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.nnnMETHODSnWe 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.nnnFINDINGSnIn 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).nnnINTERPRETATIONnIn 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.nnnFUNDINGnBayer HealthCare Pharmaceuticals and Janssen Research & Development.

Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial

AIMSnThere are no data regarding management and outcomes of major bleeding events in patients treated with oral factor Xa inhibitors.nnnMETHODS AND RESULTSnUsing data from ROCKET AF, we analysed the management and outcomes of major bleeding overall and according to the randomized treatment. During a median follow-up of 1.9 years, 779 (5.5%) patients experienced major bleeding at a rate of 3.52 events/100 patient-years with a similar event rate in each arm (n = 395 rivaroxaban vs. n = 384 warfarin). The median number of transfused packed red blood cells (PRBC) per episode was similar in both arms [2 (25th, 75th: 2, 4) units]. Overall, few transfusions of whole blood (n = 14), platelets (n = 10), or cryoprecipitate (n = 2) were used. Transfusion of fresh frozen plasma (FFP) was significantly less in the rivaroxaban arm (n = 45 vs. n = 81 units) after adjustment for covariates [odds ratio (OR) 0.43 (95% CI 0.29-0.66); P < 0.0001]. Prothrombin complex concentrates (PCC) were administered less in the rivaroxaban arm (n = 4 vs. n = 9). Outcomes after major bleeding, including stroke or non-central nervous system embolism (4.7% rivaroxaban vs. 5.4% warfarin; HR 0.89; 95% CI 0.42-1.88) and all-cause death (20.4% rivaroxaban vs. 26.1% warfarin; HR 0.69, 95% CI 0.46-1.04) were similar in patients treated with rivaroxaban and warfarin (interaction P = 0.51 and 0.11).nnnCONCLUSIONnAmong high-risk patients with atrial fibrillation who experienced major bleeding in ROCKET AF, the use of FFP and PCC was less among those allocated rivaroxaban compared with warfarin. However, use of PRBCs and outcomes after bleeding were similar among patients randomized to rivaroxaban or to warfarin.

Complication rates after hip or knee arthroplasty in morbidly obese patients.

BackgroundMorbid obesity has been shown to be a risk factor for increased complications after THA and TKA; however, large studies that would determine the effect size are lacking.Questions/purposesThe purposes of this study were to determine whether morbid obesity increased the risk of: (1) venous thromboembolism (VTE), (2) bleeding, (3) other adverse events, and (4) infections during the early postoperative period (up to 6 to 8xa0weeks) after THA or TKA?MethodsData from the REgulation of Coagulation in ORthopaedic surgery to prevent Deep vein thrombosis and pulmonary embolism (RECORD) clinical trial program of rivaroxaban for prevention of VTE after THA or TKA were analyzed retrospectively. Data for 12,355 patients were reviewed to identify complication rates in morbidly obese patients (BMIxa0≥xa040xa0kg/m2) compared with patients with a BMI less thanxa040xa0kg/m2. Explorative analyses compared the rates of asymptomatic deep vein thrombosis (DVT), symptomatic DVT, symptomatic pulmonary embolism, bleeding, and other adverse events by BMI group.ResultsThere were no significant differences in asymptomatic DVT, symptomatic DVT, symptomatic pulmonary embolism, or bleeding, but there were increases in other adverse events (including receipt of blood transfusion, erythema, peripheral edema, diarrhea, gastrointestinal or abdominal pain) and infections (including respiratory tract or lung infections, wound inflammation or infection, and extrasurgical-site infections), in patients with a BMI of 40xa0kg/m2 or greater compared with patients with a BMI less thanxa040xa0kg/m2.ConclusionsAfter THA or TKA, morbid obesity is not associated with an increased risk of VTE or bleeding but is associated with increased early postoperative complications, including erythema, peripheral edema, diarrhea and gastrointestinal or abdominal pain, wound inflammation or infection, extrasurgical-site infections, and respiratory tract or lung infections.Level of EvidenceLevel III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Allogeneic Blood Transfusions and Postoperative Infections After Total Hip or Knee Arthroplasty

BACKGROUNDnUp to 70% of patients who undergo total hip or total knee arthroplasty receive blood transfusions. Using data from more than 12,000 patients assessed in the Phase-III RECORD (Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism) studies, we investigated whether allogeneic blood transfusion increases the risk of postoperative infection compared with autologous blood transfusion or no transfusion.nnnMETHODSnA post hoc analysis of the pooled RECORD data stratified patients into three groups according to the type of blood transfusion that they received: no transfusion (n = 6313), autologous blood transfusion (n = 1902), and allogeneic blood transfusion with or without autologous blood transfusion (n = 3962). The types of postoperative infection were recorded and included lower or upper respiratory tract and lung infection, bone and joint infection, wound inflammation or infection, urinary tract infection, and other infections.nnnRESULTSnThe rates of infection in patients receiving no transfusion or autologous blood transfusion were similar; therefore, data from these two groups were combined. The rate of any infection was 9.9% (392 of 3962) in patients receiving allogeneic blood transfusion and 7.9% (646 of 8215) in patients not receiving allogeneic blood transfusion with or without autologous blood transfusion (p = 0.003). The rates of lower or upper respiratory tract and lung infection (2.1% [eighty-five of 3962] versus 1.3% [109 of 8215]; p = 0.002) and of wound inflammation or infection (2.4% [ninety-four of 3962] versus 1.7% [138 of 8215]; p = 0.046) were significantly higher in patients receiving allogeneic blood transfusion compared with patients not receiving allogeneic blood transfusion. When comparing patients who had received allogeneic blood transfusion with those who had not received allogeneic blood transfusion, the rates of bone and joint infection (0.4% [fourteen of 3962] versus 0.2% [eighteen of 8215]; p = 0.056), of urinary tract infection (3.1% [123 of 3962] versus 2.5% [209 of 8215]; p = 0.551), and of other infections (3.0% [120 of 3962] versus 2.7% [225 of 8215]; p = 0.308) were not significantly different.nnnCONCLUSIONSnThe rates of any infection, lower or upper respiratory tract and lung infection, and wound inflammation or infection were significantly increased after elective total hip or total knee arthroplasty in patients receiving allogeneic blood transfusion compared with those receiving autologous blood transfusion or no blood transfusion.

Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation but underlying native mitral and aortic valve disease participating in the ROCKET AF trial

Aims We investigated clinical characteristics and outcomes of patients with significant valvular disease (SVD) in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial. Methods and results ROCKET AF excluded patients with mitral stenosis or artificial valve prostheses. We used Cox regression to adjust comparisons for potential confounders. Among 14 171 patients, 2003 (14.1%) had SVD; they were older and had more comorbidities than patients without SVD. The rate of stroke or systemic embolism with rivaroxaban vs. warfarin was consistent among patients with SVD [2.01 vs. 2.43%; hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.55–1.27] and without SVD (1.96 vs. 2.22%; HR 0.89, 95% CI 0.75–1.07; interaction P = 0.76). However, rates of major and non-major clinically relevant bleeding with rivaroxaban vs. warfarin were higher in patients with SVD (19.8% rivaroxaban vs. 16.8% warfarin; HR 1.25, 95% CI 1.05–1.49) vs. those without (14.2% rivaroxaban vs. 14.1% warfarin; HR 1.01, 95% CI 0.94–1.10; interaction P = 0.034), even when controlling for risk factors and potential confounders. In intracranial haemorrhage, there was no interaction between patients with and without SVD where the overall rate was lower among those randomized to rivaroxaban. Conclusions Many patients with ‘non-valvular atrial fibrillation’ have significant valve lesions. Their risk of stroke is similar to that of patients without SVD after controlling for stroke risk factors. Efficacy of rivaroxaban vs. warfarin was similar in patients with and without SVD; however, the observed risk of bleeding was higher with rivaroxaban in patients with SVD but was the same among those without SVD. Atrial fibrillation patients with and without SVD experience the same stroke-preventive benefit of oral anticoagulants.