Effectiveness and safety of betrixaban extended prophylaxis for venous thromboembolism compared with standard-duration prophylaxis intervention in acute medically ill patients: a systematic literature review and network meta-analysis.

Aims: To determine the clinical effectiveness and safety of venous thromboembolism (VTE) prophylaxis using US- and Europe-approved anticoagulants relative to extended-duration VTE prophylaxis with betrixaban. Low molecular weight heparins (LMWHs), unfractionated heparin (UFH), fondaparinux sodium and placebo were each compared to betrixaban, as standard-duration VTE prophylaxis for hospitalized, non-surgical patients with acute medical illness at risk of VTE. Materials and methods: A systematic literature review was conducted up to June 2019 to identify randomized controlled trials (RCTs) of VTE prophylaxis in hospitalized, non-surgical patients with acute medical illness at risk of VTE. Studies that reported the occurrence of VTE events (including death) and, where possible, major bleeding, from treatment initiation to 20-50 days thereafter were retrieved and extracted. A Bayesian fixed effect network meta-analysis was used to estimate efficacy and safety of betrixaban compared with standard-duration VTE prophylaxis. Results: Seven RCTs were analyzed which compared betrixaban, LMWHs, UFH, fondaparinux sodium, or placebo. There were significantly higher odds (median odds [95% credible interval]) of VTE with LMWHs (1.38 [1.12-1.70]), UFH (1.60 [1.05-2.46]), and placebo (2.37 [1.55-3.66]) compared with betrixaban. There were significantly higher odds of VTE-related death with placebo (7.76 [2.14-34.40]) compared with betrixaban. No significant differences were observed for the odds of major bleeding with all comparators, VTE-related death with any active standard-duration VTE prophylaxis, or of VTE with fondaparinux sodium, compared with betrixaban. Limitations and conclusions: In this indirect comparison, betrixaban was shown to be an effective regimen with relative benefits compared with LMWHs and UFH. This indicates that betrixaban could reduce the burden of VTE in at-risk hospitalized patients with acute medical illness who need extended prophylaxis, though without direct comparative evidence, stronger conclusions cannot be drawn.

Frequency of hospital readmissions for venous thromboembolism and associated hospital costs and length of stay among acute medically ill patients in the US.

Objectives: This study evaluated the frequency of hospital readmissions for venous thromboembolism (VTE) and the associated costs and length of stay (LOS) among acute medically ill patients in the US using a real-world claims database analysis. Methods: Patients (≥40 years of age) at risk of VTE due to hospitalization for acute medical illnesses, based on primary hospital discharge diagnosis codes, were identified from the MarketScan databases between July 1, 2011 and March 31, 2015. Patients were required to have continuous insurance enrollment in the 6 months prior to initial (index) hospitalizations (baseline period) and in the 6 months after hospital discharge (follow-up period). The proportions of patients with VTE-related (diagnosis at any position) and VTE as primary diagnosis hospital readmissions during the follow-up period were evaluated. The associated costs and LOS for such readmissions were also determined, as well as time to VTE-related readmissions. Results: Of the study population (n = 12,785; mean age = 68.3 years), most were hospitalized primarily for infectious diseases (35.2%), followed by respiratory diseases (27.9%), cancer (15.7%), heart failure (11.8%), ischemic stroke (8.1%), and rheumatic diseases (1.4%). Of the overall study population, 2.1% (n = 268) had a VTE-related hospital readmission in the 6 months following discharge of their index hospitalization, of which 36.6% (n = 98) were for a primary diagnosis of VTE. Approximately 25.4% of the VTE-related hospital readmissions occurred within the first 30 days of discharge and 58.2% within 90 days. The mean cost for a hospital readmission with a primary diagnosis of VTE was $18,681 (mean LOS = 5.0 days); for readmissions with a primary diagnosis of DVT and PE, mean costs were $14,719 and $23,305, respectively. Conclusions: Among this study population of patients hospitalized for acute medical illnesses, some experienced a VTE event requiring re-hospitalization, with 25% occurring within the first 30 days after hospital discharge.

Venous Thromboembolism Prophylaxis and Risk for Acutely Medically Ill Patients Stratified by Different Ages and Renal Disease Status.

The objectives of this study were to examine venous thromboembolism (VTE) prophylaxis patterns and risk for VTE events during hospitalization and in the outpatient continuum of care among patients hospitalized for acute illnesses in the United States with stratification by different age groups and renal disease status. Acutely ill hospitalized patients were identified from the MarketScan databases (January 1, 2012-June 30, 2015) and grouped by age (<65, 65-74, ≥75 years old) and whether or not they had a baseline diagnosis of renal disease, separately. Of acutely ill hospitalized patients, 60.1% (n = 10 748) were <65 years old, 15.7% (n = 2803) were 65 to 74 years old, and 24.3% (n = 4344) were ≥75 years old; 32.9% (n = 5892) had baseline renal disease. Among the study cohorts, the majority of patients received no VTE prophylaxis regardless of age or baseline renal status (52.1%-63.6%). Rates of VTE during hospitalization and in the 6 months postdischarge were 4.7%, 4.6%, and 4.5% for patients <65, 65 to 74, and ≥75 years old, respectively, and 6.3% and 3.8% for patients with and without baseline renal disease. The risk for VTE was elevated for 30 to 40 days after index admission regardless of age and renal disease status.

Influence of the duration of hospital length of stay on frequency of prophylaxis and risk for venous thromboembolism among patients hospitalized for acute medical illnesses in the USA.

BACKGROUND: We evaluated whether the duration of hospital stay influences venous thromboembolism (VTE) prophylaxis patterns and VTE risk during hospitalization and post-discharge among patients hospitalized for acute illnesses in the USA. METHODS: Patients hospitalized for acute illnesses were identified from the US MarketScan Commercial and Medicare databases (January 1, 2012-June 30, 2015). Patients were stratified by index hospital length of stay (LOS), with study groups with 1-3 day, 4-6 day, and ≥7 day LOSs. Use of VTE prophylaxis and VTE event rates during and after hospitalization (6-month follow-up) were evaluated. RESULTS: Of the overall population, 8647 had a 1-3 day LOS, 5551 had a 4-6 day LOS, and 3697 had a ≥7 day LOS. A greater proportion of patients with a 1-3 day LOS (66.2%) did not receive any VTE prophylaxis in comparison to patients with a 4-6 day LOS (55.0%) and ≥7 day LOS (48.8%; p<0.001). Proportions of patients with VTE events during the index hospitalization increased with longer hospital LOS (1-3 day LOS: 0.5%; 4-6 day LOS: 1.3%; ≥7 day LOS: 5.4%), as did proportions of patients with VTE events during the 6-month follow-up (1-3 day LOS: 2.4%; 4-6 day LOS: 2.7%; ≥7 day LOS: 4.2%). CONCLUSION: Among this study population of hospitalized acutely ill patients in the USA, VTE pharmacologic prophylaxis was underutilized, regardless of the duration of hospital stay. However, the risk for VTE events was substantial, with nearly 10% of those with a ≥7 day LOS having suffered a VTE event within 6 months.

Cost-Effectiveness of Betrixaban Compared with Enoxaparin for Venous Thromboembolism Prophylaxis in Nonsurgical Patients with Acute Medical Illness in the United States.

BACKGROUND: Studies show that the risk of venous thromboembolism (VTE) continues post-discharge in nonsurgical patients with acute medical illness. Betrixaban is the first anticoagulant approved in the United States (US) for VTE prophylaxis extending beyond hospitalization. OBJECTIVE: The aim was to establish whether betrixaban for VTE prophylaxis in nonsurgical patients with acute medical illness at risk of VTE in the US is cost-effective compared with enoxaparin. METHODS: A cost-effectiveness analysis was conducted, estimating the cost per quality-adjusted life-year (QALY) gained with betrixaban (35-42 days) compared with enoxaparin (6-14 days) from a US payer perspective over a lifetime horizon. A decision tree (DT) estimated primary VTE events, thrombotic events, and treatment complications in the first 3 months based on data from the phase III Acute Medically Ill VTE Prevention with Extended Duration Betrixaban study. A Markov model estimated recurrent events and long-term complication risks from published literature. EuroQoL-5 Dimensions utility data and costs inflated to 2017 US dollars (US$) were from published literature. Results were discounted at 3.0% per annum. Deterministic and probabilistic sensitivity analyses explored uncertainty. RESULTS: Betrixaban dominated enoxaparin, with savings of US$784 and increased QALYs of 0.017 per patient. In addition, betrixaban dominated enoxaparin across all sensitivity analyses, but was most sensitive to utilities and DT probabilities. Furthermore, probabilistic sensitivity analysis found that betrixaban was more cost-effective than enoxaparin at all willingness-to-pay thresholds. CONCLUSION: Betrixaban can be considered cost-effective for nonsurgical patients with acute medical illness at risk of VTE, requiring longer VTE prophylaxis from hospitalization through post-discharge.

Venous Thromboembolism Prophylaxis and Risk in the Inpatient and Outpatient Continuum of Care Among Hospitalized Acutely Ill Patients in the US: A Retrospective Analysis.

INTRODUCTION: Venous thromboembolism (VTE) is a leading cause of preventable morbidity and mortality among hospitalized patients in the US. The objectives of this study were to examine VTE prophylaxis patterns and risk for VTE events during hospitalization and post-discharge among patients hospitalized for acute illnesses in the US. METHODS: Acutely ill hospitalized patients were identified from the MarketScan databases (January 1, 2012-June 30, 2015). Proportions of patients that received inpatient and/or outpatient VTE prophylaxis were determined. VTE rates were calculated for the overall study population and for each subpopulation with each acute illness type. Risk for VTE events after the index admission was determined by Kaplan-Meier analysis. RESULTS: Of the acutely ill patients (n = 17,895, mean age: 58.4 years), most were hospitalized for infectious diseases (40.6%), followed by respiratory diseases (31.0%), cancer (10.7%), heart failure (10.4%), ischemic stroke (6.4%), and rheumatic diseases (0.9%). Among the entire study population, 59.1% did not receive any VTE prophylaxis, and only 7.1% received both inpatient and outpatient prophylaxis. Among the overall study population, cumulative VTE rate, including during index admission and within 6 months post-discharge, was 4.6%. VTE risk in the inpatient and outpatient continuum of care remained elevated up to 30-40 days after hospital admission, with 60.1% of VTEs occurring within 40 days of hospital admission. CONCLUSION: In this retrospective analysis of nearly 18,000 patients hospitalized for acute illnesses, 59.1% did not receive any VTE prophylaxis and only 7.1% received VTE prophylaxis in both the inpatient and outpatient continuum of care, despite significant VTE risk extending from hospitalization into the post-discharge period. FUNDING: Portola Pharmaceuticals.

Incremental economic burden associated with major bleeding among atrial fibrillation patients treated with factor Xa inhibitors.

OBJECTIVE: To evaluate healthcare resource use and costs incurred during, as well as following hospitalization for major bleeding (MB), among atrial fibrillation (AF) patients treated with factor Xa inhibitors Methods: Patients with an AF diagnosis and MB hospitalization (index event) were identified from the MarketScan Commercial and Medicare databases (January 1, 2011-December 31, 2014). Patients were required to have ≥1 prescription for rivaroxaban or apixaban within 3 months prior to MB hospitalization. AF patients treated with Xa inhibitors, but who did not have any diagnosis of MB during the study period were identified. Hospital resource use and costs were evaluated for index MB hospitalizations. Healthcare resource use and associated costs were also evaluated for up to 12 months and compared between AF patients with and without MB. RESULTS: Of the overall patient population with AF treated with factor Xa inhibitors (n = 92,949), 3,081 (3.3%) were identified as patients with MB and 89,868 without MB. The mean hospital length of stay and hospital cost for index MB hospitalizations were 5.3 days and $28,059, respectively. Total all-cause healthcare costs were higher during the 12 months of follow-up for AF patients with MB vs without ($63,866 vs $37,916, p < .001). After adjusting for differences in patient characteristics, mean total healthcare costs were estimated at $58,169 for patients with MB vs $41,241 for patients without MB. LIMITATIONS: Since this was an observational study using a claims database analysis, a causal relationship between factor Xa inhibitor treatment and MB events cannot be inferred from the results of this study. CONCLUSION: In the real-world setting, the cost of initial hospitalizations for MB was substantial, and the incremental burden of total healthcare costs within 1 year following MB hospitalization was high. Approaches to better manage the continuum of care of AF patients with factor Xa inhibitor-associated MB may reduce the healthcare economic burden.

A retrospective study to describe the incidence of moderate to severe allergic reactions to factor IX in subjects with haemophilia B.

Using a patient chart review process, we conducted a retrospective study to describe the frequency of allergic reactions in individuals with haemophilia B receiving factor IX (FIX) replacement therapy. The number of allergic reactions in individuals receiving a recombinant FIX (rFIX) product (BeneFix(®)) was then compared with the number of reactions in patients receiving plasma-derived FIX (pdFIX) products. Of the 180 subjects in the study, 163 received rFIX, 88 received pdFIX; 71 received both product types. A total of seven (3.89%) subjects had a moderate or severe allergic reaction to a FIX product (95% confidence interval [CI], 1.06-6.71%). Among those receiving rFIX, four subjects (2.45%) had an allergic reaction (95% CI, 0.08-4.83%). Of individuals taking pdFIX products, three (3.41%) developed an allergic reaction (95% CI, 0-7.20%). It was noted that three (1.84%) of those taking rFIX developed an inhibitor to FIX (95% CI, 0-3.90%), while four (4.55%) of those receiving a pdFIX product developed an inhibitor (95% CI, 0.19-8.90%). Inhibitor development was frequently associated with allergic reaction. These results provide evidence that there is no difference in the frequency of allergic reactions or inhibitor development in individuals receiving rFIX compared with those receiving pdFIX concentrates. The current study and a previous study of similar design have now compared the rate of allergic reactions associated with rFIX and pdFIX concentrates has now been compared in a total of 414 subjects; this represents the largest collection of data to date on this rare complication of haemophilia B therapy.

Epidemiology of migraine among students from randomly selected secondary schools in Lodz.

The purpose of the present study was to determine the prevalence of migraine among 2351 secondary school students aged 15 to 19 years. Six hundred fifty-nine students (120 males and 539 females) complained of migraine, including 148 with additional tension-type headache (mixed headache). Migraine with aura was diagnosed in 213 students (49 with mixed headache). The remaining 446 students (99 with mixed headache) had migraine without aura. In 83 students (16 with mixed headache), headaches were developing into migrainous states. In 237 students (56 with mixed headache), headaches were accompanied by dizziness. In 128 females (25 with mixed headache), interrelation between migraine and menstruation was found. Familial factors affecting the occurrence of migraine were noted in 536 students (127 with mixed headache). It was found that 28% of secondary school students aged 15 to 19 years suffer from migraine. Nine percent of them have migraine with aura and 19%, migraine without aura. The prevalence of migraine among secondary school students is about three times higher in females than in males. Migraine with tension-type headache differs from pure migraine in respect of more numerous attacks within 1 year among females, and of more frequent occurrence of migraine with sensory aura among males.

[Spontaneous headaches among secondary school students]. / Samoistne bóle glowy wsród mlodziezy szkolnej.

The aim of the work was to evaluate the prevalence of headache in secondary school students. The methods of the study were based on the inquiry investigations of the students of 5 schools recruited randomly from 44 secondary schools in Lódz, following informed consent given by the School Supervision Authorities of the Lódz province, head-masters of the schools, parents, and by the students themselves. Personal questionnaires contained a number of questions referring to headaches that met the criteria of IHS Classification of Headaches. The students were inquired about localization of pains, their radiation, duration, frequency, time of occurrence (day or night), year and age of first onset of pains, associated symptoms, behaviour during pains, circumstances under which pains come on, family history relating to headaches. Headache subjects were then passed on for verification procedures consisting of questioning and physical examination. The results obtained were statistically elaborated basing on the independence chi-square test and F-Fisher's exact test. We studied 2351 students (1500 females, 851 males) aged 15-19 years. Headache in the past year was found in 2059 subjects: migraine in 511 (426 females, 85 males), of which 302 had migraine attacks more than once a month, and 67 had migrainous state; tension-type headache (T-TH) in 1346 (847 females, 499 males), of which 414 had headache more than 12 days per year; chronic T-TH in 21; mixed headache in 148 (113 females, 35 males). Mixed headache frequency was determined on the basis of migraine attacks. A total of 125 students reported more than 12 attacks. Sixteen subjects had migrainous state. Idiopathic stabbing headache occurred in 54 students (19 females, 35 males) of which 12 suffered from more than 12 attacks per year.

Physical and genetic map of 5q31: use of fluorescence in situ hybridization data to identify errors in the CEPH database. Centre d'Etude de Polymorphisme Humain.

Chromosome 5, band q31, contains the genes responsible for a number of interesting genetic and malignant diseases, as well as many cloned genes. To prepare a high-resolution map of this region, eight anonymous DNA markers were mapped by combining genetic data derived from linkage analysis, with physical data obtained using two-color fluorescent in situ hybridization (FISH). Probe order was determined by FISH on metaphase cells, supplemented with interphase analysis, while genetic distance and likely order were determined by multipoint linkage analysis using genotype data from Centre d'Etude de Polymorphisme Humain (CEPH) pedigrees. Discrepancies between the genetic and physical maps suggested that there was a high rate of genotyping errors in the CEPH data for these markers, and prompted a statistical analysis to identify these errors. By assuming a known physical order (as determined by FISH) it was possible to identify markers which had the greatest degree of error. The average typing error was estimated at 1.8%, but several markers had much higher error rates; a 14% error rate was predicted for one locus, which was subsequently confirmed by retyping. The analysis led to the preparation of a revised map spanning 24.5 cM of 5q31. This study illustrates the power of FISH to determine physical order over a wide genomic distance, and demonstrates how order can be used as an adjunct to linkage analysis, particularly in the identification of genotyping errors.

Cytogenetic and molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases.

Loss of a whole chromosome 5 or a deletion of its long arm (5q) is a recurring abnormality in malignant myeloid neoplasms. To determine the location of genes on 5q that may be involved in leukemogenesis, we examined the deleted chromosome 5 homologs in a series of 135 patients with malignant myeloid diseases. By comparing the breakpoints, we identified a small segment of 5q, consisting of band 5q31, that was deleted in each patient. This segment has been termed the critical region. Distal 5q contains a number of genes encoding growth factors, hormone receptors, and proteins involved in signal transduction or transcriptional regulation. These include several genes that are good candidates for a tumor-suppressor gene, as well as the genes encoding five hematopoietic growth factors (CSF2, IL3, IL4, IL5, and IL9). By using fluorescence in situ hybridization, we have refined the localization of these genes to 5q31.1 and have determined the order of these genes and of other markers within 5q31. By hybridizing probes to metaphase cells with overlapping deletions involving 5q31, we have narrowed the critical region to a small segment of 5q31 containing the EGR1 gene. The five hematopoietic growth factor genes and seven other genes are excluded from this region. The EGR1 gene was not deleted in nine other patients with acute myeloid leukemia who did not have abnormalities of chromosome 5. By physical mapping, the minimum size of the critical region was estimated to be 2.8 megabases. This cytogenetic map of 5q31, together with the molecular characterization of the critical region, will facilitate the identification of a putative tumor-suppressor gene in this band.

Physical localization of 70 polymorphic markers to human chromosome 5 by fluorescence in situ hybridization.

We used fluorescence in situ hybridization (FISH) to prepare a cytogenetic framework map of 21 polymorphic markers that had been used previously to construct a genetic linkage anchor map of chromosome 5. In addition, we localized 49 other markers that have been genotyped on CEPH families. This study demonstrates that FISH can be used to confirm genetic linkage data, and that it can provide a means of determining the cytogenetic locations and relative order of markers whose order could not be assigned by genetic linkage analysis alone. The cytogenetic map prepared by FISH may help to identify probes of interest for regional mapping studies.

Chromosomal loss and deletion are the most common mechanisms for loss of heterozygosity from chromosomes 5 and 7 in malignant myeloid disorders.

We have examined a population of patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) for loss of heterozygosity of polymorphic markers on chromosomes 5 and 7. The rationale for this study was the observation that the majority of patients with therapy-related leukemia (t-AML or t-MDS), resulting from cytotoxic treatment for prior malignancies, have loss of chromosome 5 and/or 7 or deletions involving the long arms of one or both of these chromosomes. This cytogenetic finding suggested that tumor-suppressor genes, important in the development of AML, may be located in these chromosomal regions. We analyzed a total of 60 patients, 43 with primary MDS/AML de novo and 17 with t-MDS/t-AML. Leukemia cells were evaluated for restriction fragment length polymorphisms (RFLPs). Leukemia cell genotypes were compared with lymphoblastoid cell genotypes from the same patients. Two cases of loss of heterozygosity were identified from chromosomes lacking visible deletions: one involving chromosome 5 in a patient with AML de novo who had a visible deletion of 5q at a later stage of the disease, and one involving chromosome 7 in a patient with t-AML. We conclude that allele loss from loci on chromosomes 5 and 7 in MDS/AML, when it occurs, usually results from major deletion or simple chromosome loss, rather than from mitotic recombination or chromosome loss with duplication of the remaining homologue.

Characterization of yeast artificial chromosomes containing interleukin genes on human chromosome 5.

To understand better the organization and linkage of the interleukin genes, IL4 and IL5, we prepared long-range restriction maps of five yeast artificial chromosomes (YACs) containing IL5. We determined that IL4 and IL5 are within 100-170 kb, and that the regions surrounding these genes contain several GC-rich areas. Fluorescence in situ chromosomal analysis demonstrated that three of the five YAC clones contain non-contiguous genomic sequences originating from multiple human chromosomes.