Menno V. Huisman

Rivaroxaban versus Enoxaparin for Thromboprophylaxis after Hip Arthroplasty

BACKGROUND This phase 3 trial compared the efficacy and safety of rivaroxaban, an oral direct inhibitor of factor Xa, with those of enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty. METHODS In this randomized, double-blind study, we assigned 4541 patients to receive either 10 mg of oral rivaroxaban once daily, beginning after surgery, or 40 mg of enoxaparin subcutaneously once daily, beginning the evening before surgery, plus a placebo tablet or injection. The primary efficacy outcome was the composite of deep-vein thrombosis (either symptomatic or detected by bilateral venography if the patient was asymptomatic), nonfatal pulmonary embolism, or death from any cause at 36 days (range, 30 to 42). The main secondary efficacy outcome was major venous thromboembolism (proximal deep-vein thrombosis, nonfatal pulmonary embolism, or death from venous thromboembolism). The primary safety outcome was major bleeding. RESULTS A total of 3153 patients were included in the superiority analysis (after 1388 exclusions), and 4433 were included in the safety analysis (after 108 exclusions). The primary efficacy outcome occurred in 18 of 1595 patients (1.1%) in the rivaroxaban group and in 58 of 1558 patients (3.7%) in the enoxaparin group (absolute risk reduction, 2.6%; 95% confidence interval [CI], 1.5 to 3.7; P<0.001). Major venous thromboembolism occurred in 4 of 1686 patients (0.2%) in the rivaroxaban group and in 33 of 1678 patients (2.0%) in the enoxaparin group (absolute risk reduction, 1.7%; 95% CI, 1.0 to 2.5; P<0.001). Major bleeding occurred in 6 of 2209 patients (0.3%) in the rivaroxaban group and in 2 of 2224 patients (0.1%) in the enoxaparin group (P=0.18). CONCLUSIONS A once-daily, 10-mg oral dose of rivaroxaban was significantly more effective for extended thromboprophylaxis than a once-daily, 40-mg subcutaneous dose of enoxaparin in patients undergoing elective total hip arthroplasty. The two drugs had similar safety profiles. (ClinicalTrials.gov number, NCT00329628.)

Idarucizumab for Dabigatran Reversal

BACKGROUND Specific reversal agents for non-vitamin K antagonist oral anticoagulants are lacking. Idarucizumab, an antibody fragment, was developed to reverse the anticoagulant effects of dabigatran. METHODS We undertook this prospective cohort study to determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients who had serious bleeding (group A) or required an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the determination at a central laboratory of the dilute thrombin time or ecarin clotting time. A key secondary end point was the restoration of hemostasis. RESULTS This interim analysis included 90 patients who received idarucizumab (51 patients in group A and 39 in group B). Among 68 patients with an elevated dilute thrombin time and 81 with an elevated ecarin clotting time at baseline, the median maximum percentage reversal was 100% (95% confidence interval, 100 to 100). Idarucizumab normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes. Concentrations of unbound dabigatran remained below 20 ng per milliliter at 24 hours in 79% of the patients. Among 35 patients in group A who could be assessed, hemostasis, as determined by local investigators, was restored at a median of 11.4 hours. Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively. One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated. CONCLUSIONS Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947.).

Detection of Deep-Vein Thrombosis by Real-Time B-Mode Ultrasonography

In 220 consecutive outpatients with clinically suspected deep-vein thrombosis of the leg, we compared contrast venography with real-time B-mode ultrasonography, using the single criterion of vein compressibility with the ultrasound transducer probe. The common femoral and popliteal veins were evaluated for full compressibility (no thrombosis) and noncompressibility (thrombosis). Both veins were fully compressible in 142 of the 143 patients with normal venograms (specificity, 99 percent; 95 percent confidence interval, 97 to 100). All 66 patients with proximal-vein thrombosis had noncompressible femoral veins, popliteal veins, or both (sensitivity, 100 percent; 95 percent confidence interval, 95 to 100). For all patients (including 11 with calf-vein thrombi), sensitivity and specificity were 91 (95 percent confidence interval, 82 to 96) and 99 percent, respectively. The sensitivity for isolated calf-vein thrombosis was only 36 percent. The compression ultrasound test was repeated in a subset of 45 consecutive patients by a second examiner, unaware of the results of the first test, whose results agreed in all patients with those of the first examiner (kappa = 1). We conclude that ultrasonography with the single criterion of vein compressibility is a highly accurate, simple, objective, and reproducible noninvasive method for detecting proximal-vein thrombosis in outpatients with clinically suspected deep-venous thrombosis.

Prognostic value of right ventricular dysfunction in patients with haemodynamically stable pulmonary embolism: a systematic review

AIMS To determine the prognostic value of right ventricular (RV) dysfunction assessed by echocardiography or spiral computed tomography (CT), or by increased levels of cardiac biomarkers [troponin, brain natriuretic peptide (BNP) and pro-BNP] in patients with haemodynamically stable pulmonary embolism (PE). METHODS AND RESULTS We included all studies published between January 1985 and October 2007 estimating the relationship between echocardiography, CT or cardiac biomarkers and the risk of death in patients with haemodynamically stable PE. Twelve of 722 potentially relevant studies met inclusion criteria. The unadjusted risk ratio of RV dysfunction as assessed by echocardiography (five studies) or by CT (two studies) for predicting death was 2.4 [95% confidence interval (CI) 1.3-4.4]. The unadjusted risk ratio for predicting death was 9.5 (95% CI 3.2-28.6) for BNP (five studies), 5.7 (95% CI 2.2-15.1) for pro-BNP (two studies) and 8.3 (95% CI 3.6-19.3) for cardiac troponin (three studies). Threshold values differed substantially between studies for all markers. CONCLUSION RV dysfunction assessed by CT, echocardiography, or by cardiac biomarkers are all associated with an increased risk of mortality in patients with haemodynamically stable PE. These findings should be interpreted with caution because of the clinical and methodological diversity of studies.

Serial impedance plethysmography for suspected deep venous thrombosis in outpatients. The Amsterdam General Practitioner Study

Diagnosis of deep venous thrombosis by clinical signs and symptoms is unreliable, but contrast venography is relatively expensive and invasive. We therefore evaluated the use of impedance plethysmography as a noninvasive alternative in 426 consecutive outpatients with clinically suspected acute deep venous thrombosis. Four sequential impedance plethysmograms were obtained on days 1, 2, 5, and 10 of the study. In 289 patients (68 percent), the results of all four studies were normal, and these patients were not treated with anticoagulants. One of these patients may have had a minor pulmonary embolus during the 10-day study period. During a six-month follow-up of all patients, none of the 289 patients whose plethysmograms were normal died of venous thromboembolism or presented with suspected pulmonary embolism. In 137 patients (32 percent), the impedance plethysmograms were abnormal; 117 (85 percent) had the abnormal results on their first test, and 20 (15 percent) had them on subsequent tests. All patients with abnormal plethysmograms also underwent contrast venography, which confirmed the diagnosis of deep venous thrombosis in 92 percent. We conclude that the diagnostic accuracy of repeated impedance plethysmography compares favorably with that of venography and that the technique is a safe and effective noninvasive approach to the diagnosis and care of outpatients with clinically suspected acute deep venous thrombosis.

Treatment of Proximal Deep-Vein Thrombosis with the Oral Direct Factor Xa Inhibitor Rivaroxaban (BAY 59-7939): The ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in Patients with Acute Symptomatic Deep-Vein Thrombosis) Study

Background— An effective and safe oral anticoagulant that needs no monitoring for dose adjustment is urgently needed for the treatment of diseases that require long-term anticoagulation. Rivaroxaban (BAY 59-7939) is an oral direct factor Xa inhibitor currently under clinical development. Methods and Results— This randomized, parallel-group phase II trial in patients with proximal deep-vein thrombosis explored the efficacy and safety of rivaroxaban 10, 20, or 30 mg BID or 40 mg once daily compared with enoxaparin 1 mg/kg BID followed by vitamin K antagonist. Each treatment was administered for 12 weeks. The primary efficacy end point was an improvement in thrombotic burden at day 21 (assessed by quantitative compression ultrasonography; ≥4-point improvement in thrombus score) without recurrent symptomatic venous thromboembolism or venous thromboembolism–related death. The primary safety end point was major bleeding during 12 weeks of treatment. Outcomes were adjudicated centrally without knowledge of treatment allocation. The primary efficacy end point was achieved in 53 (53.0%) of 100, 58 (59.2%) of 98, 62 (56.9%) of 109, and 49 (43.8%) of 112 patients receiving rivaroxaban 10, 20, or 30 mg BID or 40 mg once daily, respectively, compared with 50 (45.9%) of 109 patients treated with enoxaparin/vitamin K antagonist. There was no significant trend in the dose–response relationship between rivaroxaban BID and the primary efficacy end point (P=0.67). Major bleeding was observed in 1.7%, 1.7%, 3.3%, and 1.7% of patients receiving rivaroxaban 10, 20, or 30 mg BID or 40 mg once daily, respectively. There were no major bleeding events with enoxaparin/vitamin K antagonist. Conclusions— Results of this proof-of-concept and dose-finding study support phase III evaluation of the orally active direct factor Xa inhibitor rivaroxaban, because efficacy and safety were apparent in the treatment of proximal deep-vein thrombosis across a 3-fold range of fixed daily dosing.

Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study.

IMPORTANCE D-dimer measurement is an important step in the diagnostic strategy of clinically suspected acute pulmonary embolism (PE), but its clinical usefulness is limited in elderly patients. OBJECTIVE To prospectively validate whether an age-adjusted D-dimer cutoff, defined as age × 10 in patients 50 years or older, is associated with an increased diagnostic yield of D-dimer in elderly patients with suspected PE. DESIGN, SETTINGS, AND PATIENTS A multicenter, multinational, prospective management outcome study in 19 centers in Belgium, France, the Netherlands, and Switzerland between January 1, 2010, and February 28, 2013. INTERVENTIONS All consecutive outpatients who presented to the emergency department with clinically suspected PE were assessed by a sequential diagnostic strategy based on the clinical probability assessed using either the simplified, revised Geneva score or the 2-level Wells score for PE; highly sensitive D-dimer measurement; and computed tomography pulmonary angiography (CTPA). Patients with a D-dimer value between the conventional cutoff of 500 µg/L and their age-adjusted cutoff did not undergo CTPA and were left untreated and formally followed-up for a 3-month period. MAIN OUTCOMES AND MEASURES The primary outcome was the failure rate of the diagnostic strategy, defined as adjudicated thromboembolic events during the 3-month follow-up period among patients not treated with anticoagulants on the basis of a negative age-adjusted D-dimer cutoff result. RESULTS Of the 3346 patients with suspected PE included, the prevalence of PE was 19%. Among the 2898 patients with a nonhigh or an unlikely clinical probability, 817 patients (28.2%) had a D-dimer level lower than 500 µg/L (95% CI, 26.6%-29.9%) and 337 patients (11.6%) had a D-dimer between 500 µg/L and their age-adjusted cutoff (95% CI, 10.5%-12.9%). The 3-month failure rate in patients with a D-dimer level higher than 500 µg/L but below the age-adjusted cutoff was 1 of 331 patients (0.3% [95% CI, 0.1%-1.7%]). Among the 766 patients 75 years or older, of whom 673 had a nonhigh clinical probability, using the age-adjusted cutoff instead of the 500 µg/L cutoff increased the proportion of patients in whom PE could be excluded on the basis of D-dimer from 43 of 673 patients (6.4% [95% CI, 4.8%-8.5%) to 200 of 673 patients (29.7% [95% CI, 26.4%-33.3%), without any additional false-negative findings. CONCLUSIONS AND RELEVANCE Compared with a fixed D-dimer cutoff of 500 µg/L, the combination of pretest clinical probability assessment with age-adjusted D-dimer cutoff was associated with a larger number of patients in whom PE could be considered ruled out with a low likelihood of subsequent clinical venous thromboembolism. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01134068.

A Once-Daily, Oral, Direct Factor Xa Inhibitor, Rivaroxaban (BAY 59-7939), for Thromboprophylaxis After Total Hip Replacement

Background— Rivaroxaban (BAY 59-7939)—an oral, direct Factor Xa inhibitor—could be an alternative to heparins and warfarin for the prevention and treatment of thromboembolic disorders. Methods and Results— This randomized, double-blind, double-dummy, active-comparator–controlled, multinational, dose-ranging study assessed the efficacy and safety of once-daily rivaroxaban relative to enoxaparin for prevention of venous thromboembolism in patients undergoing elective total hip replacement. Patients (n=873) were randomized to once-daily oral rivaroxaban doses of 5, 10, 20, 30, or 40 mg (initiated 6 to 8 hours after surgery) or a once-daily subcutaneous enoxaparin dose of 40 mg (given the evening before and ≥6 hours after surgery). Study drugs were continued for an additional 5 to 9 days; mandatory bilateral venography was performed the following day. The primary end point (composite of any deep vein thrombosis, objectively confirmed pulmonary embolism, and all-cause mortality) was observed in 14.9%, 10.6%, 8.5%, 13.5%, 6.4%, and 25.2% of patients receiving 5, 10, 20, 30, and 40 mg rivaroxaban, and 40 mg enoxaparin, respectively (n=618, per-protocol population). No significant dose–response relationship was found for efficacy (P=0.0852). Major postoperative bleeding was observed in 2.3%, 0.7%, 4.3%, 4.9%, 5.1%, and 1.9% of patients receiving 5, 10, 20, 30, and 40 mg rivaroxaban, and 40 mg enoxaparin, respectively (n=845, safety population), representing a significant dose–response relationship (P=0.0391). Conclusions— Rivaroxaban showed efficacy and safety similar to enoxaparin for thromboprophylaxis after total hip replacement, with the convenience of once-daily oral dosing and without the need for coagulation monitoring. When both efficacy and safety are considered, these results suggest that 10 mg rivaroxaban once daily should be investigated in phase III studies.

Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement.

Summary.  Background: Joint replacement surgery is an appropriate model for dose‐ranging studies investigating new anticoagulants. Objectives: To assess the efficacy and safety of a novel, oral, direct factor Xa (FXa) inhibitor – BAY 59‐7939 – relative to enoxaparin in patients undergoing elective total hip replacement. Methods: In this double‐blind, double‐dummy, dose‐ranging study, patients were randomized to oral BAY 59‐7939 (2.5, 5, 10, 20, or 30 mg b.i.d.), starting 6–8 h after surgery, or s.c. enoxaparin 40 mg once daily, starting on the evening before surgery. Treatment was continued until mandatory bilateral venography was performed 5–9 days after surgery. Results: Of 706 patients treated, 548 were eligible for the primary efficacy analysis. The primary efficacy endpoint was the incidence of any deep vein thrombosis, non‐fatal pulmonary embolism, and all‐cause mortality; rates were 15%, 14%, 12%, 18%, and 7% for BAY 59‐7939 2.5, 5, 10, 20, and 30 mg b.i.d., respectively, compared with 17% for enoxaparin. The primary efficacy analysis did not demonstrate any significant trend in dose–response relationship for BAY 59‐7939. The primary safety endpoint was major, postoperative bleeding; there was a significant increase in the frequency of events with increasing doses of BAY 59‐7939 (P = 0.045), but no significant differences between individual BAY 59‐7939 doses and enoxaparin. Conclusions: When efficacy and safety were considered together, the oral, direct FXa inhibitor BAY 59‐7939, at 2.5–10 mg b.i.d., compared favorably with enoxaparin for the prevention of venous thromboembolism in patients undergoing elective total hip replacement.

Brain-type natriuretic peptide levels in the prediction of adverse outcome in patients with pulmonary embolism: a systematic review and meta-analysis.

RATIONALE The potential role of elevated brain-type natriuretic peptides (BNP) in the differentiation of patients suffering from acute pulmonary embolism at risk for adverse clinical outcome has not been fully established. OBJECTIVES We evaluated the relation between elevated BNP or N-terminal-pro-BNP (NT-pro-BNP) levels and clinical outcome in patients with pulmonary embolism. METHODS Articles reporting on studies that evaluated the risk of adverse outcome in patients with pulmonary embolism and elevated BNP or NT-pro-BNP levels were abstracted from Medline and EMBASE. Information on study design, patient and assay characteristics, and clinical outcome was extracted. Primary endpoints were overall mortality and predefined composite outcome of adverse clinical events. MEASUREMENTS AND MAIN RESULTS Data from 13 studies were included. In 51% (576/1,132) of the patients, BNP or NT-pro-BNP levels were increased. The different analyses were performed in subpopulations. Elevated levels of BNP or NT-pro-BNP were significantly associated with right ventricular dysfunction (P < 0.001). Patients with high BNP or NT-pro-BNP concentration were at higher risk of complicated in-hospital course (odds ratio [OR], 6.8; 95% confidence interval [CI], 4.4-10) and 30-day mortality (OR, 7.6; 95% CI, 3.4-17). Patients with a high NT-pro-BNP had a 10% risk of dying (68/671; 95% CI, 8.0-13%), whereas 23% (209/909; 95% CI, 20-26%) had an adverse clinical outcome. CONCLUSIONS High concentrations of BNP distinguish patients with pulmonary embolism at higher risk of complicated in-hospital course and death from those with low BNP levels. Increased BNP or NT-pro-BNP concentrations alone, however, do not justify more invasive treatment regimens.