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.

Relationship between type of unprovoked venous thromboembolism and cancer location: An individual patient data meta-analysis.

BACKGROUND: Unprovoked venous thromboembolism (VTE) may be the first manifestation of an underlying cancer. We aimed to assess the period prevalence of occult cancer detection stratified by VTE location (deep vein thrombosis [DVT], pulmonary embolism [PE] or both) and the anatomical relationship between occult cancer and VTE. METHODS: Post-hoc analysis of a systematic review and individual patient data meta-analysis of adults with unprovoked VTE with at least 12 months of follow-up. Cancer types were grouped according to thoracic, abdomino-pelvic, or other locations. RESULTS: A total of 2300 patients were eligible including 1218 with DVT only (53%), 719 with PE only (31%), and 363 with both PE and DVT (16%). The pooled 12-month period prevalence of cancer in DVT only, PE only, and DVT + PE was 5.6% (95% CI, 4.4 to 7.2), 4.3% (95% CI, 2.7 to 6.9), and 5.6% (95% CI, 1.7 to 15.5), respectively. Most occult cancers were located in the abdomen (68.4%). The proportion of patients with an abdomino-pelvic cancer was not different in patients with DVT + PE (81%; 95% CI, 54 to 96) than in those with DVT (68%; 95% CI, 57 to 78) or PE alone (65%; 95% CI, 48 to 79). CONCLUSION: The 12-month prevalence of occult cancer was similar in patients with DVT only, PE only, or both. Most cancers were located in the abdomen, and there was no relationship between VTE type and cancer location.

Ruling out pulmonary embolism across different subgroups of patients and healthcare settings: protocol for a systematic review and individual patient data meta-analysis (IPDMA).

BACKGROUND: Diagnosing pulmonary embolism in suspected patients is notoriously difficult as signs and symptoms are non-specific. Different diagnostic strategies have been developed, usually combining clinical probability assessment with D-dimer testing. However, their predictive performance differs across different healthcare settings, patient subgroups, and clinical presentation, which are currently not accounted for in the available diagnostic approaches. METHODS: This is a protocol for a large diagnostic individual patient data meta-analysis (IPDMA) of currently available diagnostic studies in the field of pulmonary embolism. We searched MEDLINE (search date January 1, 1995, till August 25, 2016) to retrieve all primary diagnostic studies that had evaluated diagnostic strategies for pulmonary embolism. Two authors independently screened titles, abstracts, and subsequently full-text articles for eligibility from 3145 individual studies. A total of 40 studies were deemed eligible for inclusion into our IPDMA set, and principal investigators from these studies were invited to participate in a meeting at the 2017 conference from the International Society on Thrombosis and Haemostasis. All authors agreed on data sharing and participation into this project. The process of data collection of available datasets as well as potential identification of additional new datasets based upon personal contacts and an updated search will be finalized early 2018. The aim is to evaluate diagnostic strategies across three research domains: (i) the optimal diagnostic approach for different healthcare settings, (ii) influence of comorbidity on the predictive performance of each diagnostic strategy, and (iii) optimize and tailor the efficiency and safety of ruling out PE across a broad spectrum of patients with a new, patient-tailored clinical decision model that combines clinical items with quantitative D-dimer testing. DISCUSSION: This pre-planned individual patient data meta-analysis aims to contribute in resolving remaining diagnostic challenges of time-efficient diagnosis of pulmonary embolism by tailoring available diagnostic strategies for different healthcare settings and comorbidity. SYSTEMATIC REVIEW REGISTRATION: Prospero trial registration: ID 89366.

The original and simplified Wells rules and age-adjusted D-dimer testing to rule out pulmonary embolism: an individual patient data meta-analysis.

Essentials Evidence for the simplified Wells rule in ruling out acute pulmonary embolism (PE) is scarce. This was a post-hoc analysis on data from 6 studies comprising 7268 patients with suspected PE. The simplified Wells rule combined with age-adjusted D-dimer testing may safely rule out PE. Given its ease of use, the simplified Wells rule is to be preferred over the original Wells rule. SUMMARY: Background The Wells score and D-dimer testing can safely rule out pulmonary embolism (PE). A simplification of the Wells score has been proposed to improve clinical applicability, but evidence on its performance is scarce. Objectives To compare the performances of the original and simplified Wells scores alone and in combination with age-adjusted D-dimer testing. Methods Individual patient data from 7268 patients with suspected PE enrolled in six management studies were used to evaluate the discriminatory performances of the original and simplified Wells scores. The efficiency and failure rate of the dichotomized original and simplified scores combined with age-adjusted D-dimer testing were compared by use of a one-stage random effects meta-analysis. Efficiency was defined as the proportion of patients in whom PE could be considered to be excluded on the basis of a 'PE unlikely' Wells score and a negative age-adjusted D-dimer test result. Failure rate was defined as the proportion of patients with symptomatic venous thromboembolism during a 3-month follow-up. Results The discriminatory performances of the original and simplified Wells scores were comparable (c-statistic 0.73 [95% confidence interval (CI) 0.72-0.75] versus 0.72 [95% CI 0.70-0.73]). When combined with age-adjusted D-dimer testing, the original and simplified Wells rules had comparable efficiency (3% [95% CI 25-42%] versus 30% [95% CI 21-40%]) and failure rates (0.9% [95% CI 0.6-1.5%] versus 0.8% [95% CI 0.5-1.3%]). Conclusion The original and simplified Wells rules combined with age-adjusted D-dimer testing have similar performances in ruling out PE. Given its ease of use in clinical practice, the simplified Wells rule is to be preferred.

Incidental pulmonary embolism in cancer patients: Interobserver agreement on the diagnosis and extent with a focus on distal clots.

BACKGROUND: The incidence of incidental pulmonary embolism (IPE) in cancer patients is increasing. There is scant information on the interobserver agreement among radiologists about the diagnosis of distal incidental clots and the actual radiologic extension of IPE. METHODS: A total of 88 contrast-enhanced computed tomography (CT) scans of cancer patients with IPE were reassessed blindly by two expert thoracic radiologists. First, 62 scans were reassessed and the interobserver agreement on most proximal extent of IPE was calculated between the two expert radiologists as well as between the initial and expert reading, using the kappa statistic. The sample was enriched with 26 additional scans for a total of 30 segmental and 29 subsegmental IPE to determine the interobserver agreement on distal clots. RESULTS: The level of agreement regarding the most proximal extent of IPE between the expert radiologists was very good (kappa 0.84; 95% CI, 0.73-0.95) and poor between the original radiologist and expert radiologists (kappa 0.39; 95% CI, 0.22-0.56). In the patients with segmental or subsegmental IPE on initial reading, the expert radiologists agreed with the segmental location in 12 out of 30 patients (40%) and with the subsegmental location in 17 out of 29 patients (59%). The interobserver agreement between the expert radiologists was good (kappa 0.68; 95% CI, 0.46-0.90) and moderate (kappa 0.48; 95% CI, 0.25-0.71), respectively. CONCLUSIONS: While the interobserver agreement between radiologists on the most proximal location of IPE in cancer patients appears to be fairly good, it decreases significantly for more distally located incidental clots.

Prucalopride decreases esophageal acid exposure and accelerates gastric emptying in healthy subjects.

BACKGROUND: The 5-HT4 receptor agonist prucalopride is a prokinetic drug which improves colonic motility. Animal data and in vitro studies suggest that prucalopride also affects gastric and esophageal motor function. We aimed to assess the effect of prucalopride on gastric emptying, esophageal motility, and gastro-esophageal reflux in man. METHODS: In this double-blind, placebo-controlled, randomized, crossover study, we included 21 healthy volunteers who received 4 mg prucalopride or placebo per day for 6 days. We performed high-resolution manometry (HRM) followed by 120-min HRM-pH-impedance monitoring after a standardized meal, ambulatory 24-h pH-impedance monitoring, and gastric emptying for solids. KEY RESULTS: Prucalopride decreased (median [IQR]) total acid exposure time (3.4 [2.5-5.6] vs 1.7 [0.8-3.5] %, p < 0.05). The total number of reflux events was unaffected by prucalopride, however, the number of reflux events extending to the proximal esophagus was reduced by prucalopride (15.5 [9.8-25.5] vs 10.5 [5.3-17.5], p < 0.05). Furthermore, prucalopride improved acid clearance time (77.5 [47.8-108.8] vs 44.0 [30.0-67.8] s, p < 0.05). Prucalopride did not affect the number of transient lower esophageal sphincter (LES) relaxations or their association with reflux events. Esophageal motility and basal pressure of the LES were not affected by prucalopride. Prucalopride increased gastric emptying (T1/2 ; 32.7 [27.9-44.6] vs 49.8 [37.7-55.0] min, p < 0.05) and decreased residue after 120 min (8.8 [4.4-14.8] vs 2.7 [1.3-5.4] %, p < 0.05). CONCLUSIONS & INFERENCES: Prucalopride reduces esophageal acid exposure and accelerates gastric emptying in healthy male volunteers. These findings suggest that the drug could be effective for treatment of patients with reflux disease and functional dyspepsia.