Edoxaban for treatment of venous thromboembolism in patient groups with different types of cancer: Results from the Hokusai VTE Cancer study.

BACKGROUND: The safety and efficacy of edoxaban and dalteparin is unclear for several cancer groups. METHODS: We evaluated the occurrence of the primary outcome in large cancer groups. The primary outcome was the composite of recurrent VTE or major bleeding over 12 months. RESULTS: In patients with gastrointestinal cancer, the primary outcome occurred in 19.4% patients given edoxaban and in 15.0% given dalteparin (risk difference [RD], 4.4%; 95%-CI, -4.1% to 12.8%). The corresponding rates for edoxaban and dalteparin were 10.4% and 10.7% for lung cancer (RD, -0.3%; 95%-CI, -10.0% to 9.5%), 13.6% and 12.5% for urogenital cancer (RD, 1.1; 95%-CI, -10.1-12.4), 3.1% and 11.7% for breast cancer (RD, -8.6; 95%-CI, -19.3-2.2), 8.9% and 10.9% for hematological malignancies (RD, -2.0; 95%-CI, -13.1-9.1), and 10.4% and 17.4% for gynecological cancer (RD, -7.0; 95%-CI, -19.8-5.7). In the subgroup of gastrointestinal cancer, edoxaban was associated with a 3.5% lower absolute risk of recurrent VTE and a 7.9% higher risk of major bleeding. CONCLUSION: Edoxaban has a similar risk-benefit ratio to dalteparin in most cancer groups. In those with gastrointestinal cancer, the lower risk of recurrent VTE and the advantages of oral therapy need to be balanced against the increased risk of major bleeding.

Efficacy and safety of edoxaban for treatment of venous thromboembolism: a subanalysis of East Asian patients in the Hokusai-VTE trial.

BACKGROUND: Direct oral anticoagulants have been evaluated for their efficacy and safety in the treatment of venous thromboembolism (VTE), which comprises deep vein thrombosis and pulmonary embolism. The randomized, double-blind Hokusai-VTE trial demonstrated that 60 mg of edoxaban once daily following initial heparin treatment is non-inferior to heparin overlapped with and followed by warfarin for the treatment of VTE, and is associated with significantly fewer bleeding events. OBJECTIVES: To assess the efficacy and safety of edoxaban versus warfarin among East Asian patients enrolled in the Hokusai-VTE trial. PATIENTS/METHODS: The Hokusai-VTE trial enrolled 8292 patients from 439 centers worldwide, including 1109 patients from Japan, China, Korea, and Taiwan. The primary efficacy and safety outcomes were symptomatic recurrent VTE and clinically relevant bleeding, respectively. RESULTS: In the overall East Asian population, the primary efficacy outcome of symptomatic recurrent VTE occurred in 16 of 563 (2.8%) patients in the edoxaban group versus 24 of 538 (4.5%) patients in the warfarin group (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.34-1.19; P = 0.1601). The primary safety outcome of clinically relevant bleeding occurred in 56 of 563 (9.9%) patients in the edoxaban group versus 93 of 538 (17.3%) patients in the warfarin group (HR 0.56; 95% CI 0.40-0.78; P < 0.001). CONCLUSIONS: Edoxaban is an effective and safer alternative to warfarin in East Asian patients with acute VTE who require anticoagulant therapy, consistent with overall study findings from the Hokusai-VTE trial.

Edoxaban for the long-term treatment of venous thromboembolism: rationale and design of the Hokusai-venous thromboembolism study--methodological implications for clinical trials.

BACKGROUND: New oral anticoagulants may simplify long-term therapy by eliminating the need for laboratory monitoring. Edoxaban is an oral, direct inhibitor of factor Xa that is given in a fixed dose once daily. OBJECTIVE AND METHODS: The Hokusai-VTE study is a randomized, double-blind trial to evaluate whether initial low molecular weight heparin (LMWH) followed by edoxaban (60 mg once daily) is non-inferior to LMWH followed by warfarin (International Normalized Ratio of 2.0-3.0) for the prevention of recurrent thromboembolism in patients with acute symptomatic venous thromboembolism (VTE). The primary efficacy outcome is symptomatic recurrent VTE during the 12-month study period. The principal safety outcome is clinically relevant bleeding (major or non-major) occurring during or within 3 days of stopping study treatment. A clinical events committee adjudicates all suspected outcome events. A unique study design feature is the flexible treatment duration of between 3 and 12 months to simulate usual clinical practice, and enabled by: (i) double-blinding to minimize bias that could occur if knowledge of the patient's treatment influenced the duration of therapy; and (ii) follow-up for 12 months of all patients and inclusion in the primary efficacy analysis, regardless of the duration of therapy received. A second innovative design feature is the strategy for achieving an appropriate time in therapeutic range in the warfarin group, with central tracking for each participating center and feedback to the investigators. CONCLUSION: The standard methods combined with innovative design features should achieve study results that are both scientifically valid and relevant to clinical practice.

Effects of gender and age on paediatric headache.

The aim of this study was to evaluate the impact of gender and age on headache characteristics and disability. Headache characteristics were assessed at an initial visit to a paediatric specialty care centre and five follow-up visits. A total number of 4121 patients were evaluated. Fifty-eight per cent of the sample was female. Boys were younger at their first headache and initial visit. They more frequently described headache pain as squeezing and location as top of the head. Girls reported more frequent and longer headaches. Girls more often described headache pain as sharp and location as back of the head. Age accounted for more variance than gender in headache severity, duration, frequency and disability. Gender differences exist in headache characteristics. Age is also an important factor in the variability in characteristics and disability. Longitudinal studies are needed to describe further the natural history of headaches in childhood and compare outcome between genders.

Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study.

BACKGROUND: Apixaban, an oral potent reversible direct inhibitor of activated factor X, has shown promise in the prevention of venous thromboembolism following major orthopedic surgery. We conducted a dose-ranging study in patients with deep vein thrombosis. METHODS: Consecutive patients with symptomatic deep vein thrombosis were included and randomized to receive 84-91 days of apixaban 5 mg twice-daily, 10 mg twice-daily, or 20 mg once-daily, or low molecular weight heparin (LMWH) followed by a vitamin K antagonist (VKA). The primary efficacy outcome was the composite of symptomatic recurrent venous thromboembolism and asymptomatic deterioration of bilateral compression ultrasound or perfusion lung scan. The principal safety outcome was the composite of major and clinically relevant, non-major bleeding. RESULTS: The mean age of the 520 included patients was 59 years, and 62% were male. The primary outcome occurred in 17 of the 358 apixaban-treated patients [4.7%, 95% confidence interval (CI) 2.8-7.5%] and in five of the 118 LMWH/VKA-treated patients (4.2%, 95% CI 1.4-9.6%) who were evaluable. The incidence in all three apixaban groups was low and comparable without evidence of a dose response. The principal safety outcome occurred in 28 (7.3%) of the 385 apixaban-treated patients and in 10 (7.9%) of the 126 LMWH/VKA-treated patients. No dose response for apixaban was observed. CONCLUSION: These observations warrant further evaluation of apixaban in phase III studies. The attractive fixed-dose regimen of this compound may meet the demand to simplify anticoagulant treatment in patients with established venous thromboembolism.

Effect of obesity on outcomes after fondaparinux, enoxaparin, or heparin treatment for acute venous thromboembolism in the Matisse trials.

BACKGROUND: Selecting initial anticoagulant dose by patient weight for acute pulmonary embolism and deep vein thrombosis has clinical credibility; however, uncertainty remains regarding how to dose obese patients with newer anticoagulants because outcome data are sparse. OBJECTIVES: To use the Matisse trials' comparison of sc fondaparinux once daily with control heparin therapies (intravenous unfractionated heparin for pulmonary embolism, sc enoxaparin 1 mg/kg b.i.d. for deep vein thrombosis) for initial treatment in order to compare primary outcomes (venous thromboembolism recurrence and major bleeding) in obese patients. PATIENTS AND METHODS: Primary outcomes were compared in subsets composed of patients weighing < or = and > 100 kg and with body mass index (BMI) < 30 and > or = 30 kg/m(2). Medians and ranges for weight and BMI were compared for patients suffering either recurrence or major bleeding. RESULTS: Twenty-two thousand and one patients received fondaparinux and 2217 received enoxaparin or unfractionated heparin. Four hundred and ninety-six patients (11%) weighed > 100 kg and 1216 (28%) had a BMI > or = 30. Treatment groups had similar characteristics. The upper limit in subject weight for recurrence was 166 kg (BMI 58), and for major bleeding 120 kg (BMI 39). The incidences of recurrence and major bleeding were similar for each patient subset of weight and BMI for both fondaparinux and heparin treatment groups. Among patients with a primary outcome, median weights and BMIs were also similar. CONCLUSIONS: The current recommended doses of fondaparinux and heparins for the treatment of venous thromboembolism appear to provide similar protection against recurrence and major bleeding to one another and to obese and non-obese patients.

Development of a patient-based grading scale for PedMIDAS.

The objective was to develop and validate a patient-based grading scale for PedMIDAS. PedMIDAS was administered to 329 children, who rated their overall disability based on the adult MIDAS grades. This patient-based rating and PedMIDAS scores were compared to develop the grading scale. Headache disability was rated little to none, 49.5%; mild, 26.7%; moderate, 15.8%; and severe, 7.9%, with PedMIDAS raw scores of 4.9 +/- 6.3, 17.8 +/- 14.9, 40.6 +/- 34.2, and 91.4 +/- 69.8. Convergence of these results yielded an empirically derived grading system: Grade I, 0-10; II, 11-30; III, 31-50 and IV, > 50. Higher grades corresponded to an increased need for prophylactic treatment. A patient-based grading scale further increases the utility of PedMIDAS in assessing migraine disability in children, so that it can be widely used in routine clinical evaluation and management.

Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism.

BACKGROUND: The standard initial treatment of hemodynamically stable patients with pulmonary embolism is intravenous unfractionated heparin, requiring laboratory monitoring and hospitalization. METHODS: We conducted a randomized, open-label trial involving 2213 patients with acute symptomatic pulmonary embolism to compare the efficacy and safety of the synthetic antithrombotic agent fondaparinux with those of unfractionated heparin and to document noninferiority in terms of efficacy. Patients received either fondaparinux (5.0, 7.5, or 10.0 mg in patients weighing less than 50, 50 to 100, or more than 100 kg, respectively) subcutaneously once daily or a continuous intravenous infusion of unfractionated heparin (ratio of the activated partial-thromboplastin time to a control value, 1.5 to 2.5), both given for at least five days and until the use of vitamin K antagonists resulted in an international normalized ratio above 2.0. The primary efficacy outcome was the three-month incidence of the composite end point of symptomatic, recurrent pulmonary embolism (nonfatal or fatal) and new or recurrent deep-vein thrombosis. RESULTS: Forty-two of the 1103 patients randomly assigned to receive fondaparinux (3.8 percent) had recurrent thromboembolic events, as compared with 56 of the 1110 patients randomly assigned to receive unfractionated heparin (5.0 percent), for an absolute difference of -1.2 percent in favor of fondaparinux (95 percent confidence interval, -3.0 to 0.5). Major bleeding occurred in 1.3 percent of the patients treated with fondaparinux and 1.1 percent of those treated with unfractionated heparin. Mortality rates at three months were similar in the two groups. Of the patients in the fondaparinux group, 14.5 percent received the drug in part on an outpatient basis. CONCLUSIONS: Once-daily, subcutaneous administration of fondaparinux without monitoring is at least as effective and is as safe as adjusted-dose, intravenous administration of unfractionated heparin in the initial treatment of hemodynamically stable patients with pulmonary embolism.

Rufloxacin once daily versus ciprofloxacin twice daily in the treatment of patients with acute uncomplicated pyelonephritis.

PURPOSE: We compare the bacteriological and clinical efficacy of rufloxacin and ciprofloxacin in patients with acute uncomplicated pyelonephritis. MATERIALS AND METHODS: A total of 110 outpatients was enrolled in a randomized, double-blind multicenter study and treated for 10 days with 200 mg. rufloxacin daily (after a loading dose of 400 mg. on day 1) or 500 mg. ciprofloxacin twice daily. Bacteriological and clinical efficacy was based on the accumulated outcomes assessed at the end of treatment, and at 2 and 4 to 6 weeks. RESULTS: The bacteriological and clinical success rates of rufloxacin and ciprofloxacin were comparable: 55.6% versus 58.8% and 74% versus 71%, respectively (95% confidence interval -28% to +22% and -20% to +25%, respectively). Both study medications were well tolerated. CONCLUSIONS: Rufloxacin once daily is a good alternative in the outpatient treatment of acute uncomplicated pyelonephritis.

Homo- and heteronuclear two-dimensional NMR studies of the globular domain of histone H1: full assignment, tertiary structure, and comparison with the globular domain of histone H5.

The globular domain of chicken histone H1 (GH1) has been studied by 1H homonuclear and 1H-15N heteronuclear 2D NMR spectroscopy. After the full assignment of the proton and 15N resonances, the tertiary structure of GH1 was determined by an iterative procedure using distance geometry and restrained simulated annealing. The secondary structure elements of GH1, three helices (S5-A16, S24-A34, N42-K56) followed by a beta-hairpin (L59-L73), are folded in a manner very similar to the corresponding parts of the globular domain of chicken histone H5 (GH5) [Clore et al. (1987) EMBO J. 6, 1833-1842; Ramakrishnan et al. (1993) Nature 362, 219-223]. However, subtle differences are detected between the two structures and between the electrostatic potentials surrounding the molecules. The most important differences are located in the loop between the second and third helices, a region that could be responsible for the different affinity for DNA. The most positively charged regions are not found in exactly the same position in GH1 and GH5. Nevertheless, their location seems to agree with the model where nucleosome binding takes place through contact points located at one DNA terminus and close to the dyad axis of the nucleosome [Schwabe & Travers (1993) Curr. Biol. 3, 628-630].

Homo- and heteronuclear two-dimensional NMR studies of the globular domain of histone H1: sequential assignment and secondary structure.

A recombinant 75 amino acid polypeptide corresponding to the globular domain of the chicken histone H1 (GH1) has been studied by 1H homonuclear and 1H-15N heteronuclear 2D NMR spectroscopy. Sequential assignment of the backbone and beta-proton resonances has enabled us to determine the secondary structure of GH1. It was found to consist of three helical regions (T7-S17, L25-Y37, E40-K56) and probably a beta-hairpin (L59-L73). This structure is similar to the structure of the globular domain of histone H5 (GH5) obtained both by NMR spectroscopy [Zarbock et al. (1986) Proc. Natl. Acad. Sci. U.S.A. 83, 7628-7632; Clore et al. (1987) EMBO J. 6, 1833-1842] and by X-ray crystallography [Ramakrishnan et al. (1993) Nature 362, 219-223]. The beta-hairpin as suggested for GH1 is also present in the X-ray structure of GH5 but has not been reported for the NMR structure of GH5.

Bactericidal effect of propolis in vitro against agents causing upper respiratory tract infections.

Propolis is a natural product of bees which exhibits an antimicrobial effect. In the study the existence of a bactericidal effect against several strains isolated from patients with infections in their upper respiratory tracts is demonstrated. In light of the use of propolis as a therapeutic agent in natural medicine for common colds and inflammatory processes this effect is discussed.

Involvement of 19q13 in follicular thyroid adenoma.

Cytogenetic investigation of a follicular thyroid adenoma from a 31-year-old woman showed a t(16;19)(q12;q13), as the sole chromosome abnormality. As five more cases with 19q13 involvement have been described, we suggest that the terminal region of the long arm of chromosome 19 is important for the development of follicular thyroid adenoma.

[Myotomy of the cricopharyngeal muscle]. / Myotomie van de musculus cricopharyngeus.

Eleven patients who underwent cricopharyngeal myotomy from 1980 to 1990 at the Department of ENT, Head and Neck Surgery, KUL are reviewed. This procedure has been performed for swallowing and/or aspiration disorders due to dysfunction of varied etiology of m. cricopharyngeus. Our results indicate that only patients with a satisfactory pharyngeal motion and coordination and no cricopharyngeal relaxation are proven candidates for cricopharyngeal myotomy. Patients with Zenker's diverticulum were not taken into account. Nine out of 11 patients improved after cricopharyngeal myotomy. Careful interpretation of cineradiographic examination allows refinement of case selection.

Epiglottoplasty for reconstruction of posttraumatic laryngeal stenosis.

Laryngeal stenosis secondary to blunt laryngeal trauma is mostly localized at the supraglottic and glottic levels. The epiglottis is ideally suited to reconstruct the defect after excision of supraglottic and glottic scar tissue and anterior thyroid cartilage. It is the conclusion of the authors that epiglottic reconstruction is an effective procedure for repair of laryngeal stenosis at the supracricoid level. Two case reports are given.

The interaction of histone H5 and its globular domain with core particles, depleted chromatosomes, polynucleosomes, and a DNA decamer.

Certain features of linker histone behavior were analyzed using a precipitation and a nitrocellulose filter binding assay. Chromatosomes, depleted of the linker histones, present one unique binding site to the globular domain of histone H5 (GH5) which involves the two 10-base pair DNA ends of the chromatosome. Additional binding to lower affinity sites is intrinsically different and results in aggregation as does all binding to core particles. These findings, as well as the binding study on a synthetic DNA decamer, lend support to earlier hypotheses of more than one DNA binding site on the globular domain. Our studies provide a deeper insight into the long standing question of H5/nucleosome stoichiometry. A salt dependence analysis of GH5 binding to H5-depleted chromatosomes indicates that GH5 displaces a number of ions similar to the total H1 linker histone, suggesting a delocalized binding of the carboxyl- and amino-terminal tails.