MUFFIN-PTS trial, Micronized Purified Flavonoid Fraction for the Treatment of Post-Thrombotic Syndrome: protocol of a randomised controlled trial.

INTRODUCTION: After deep vein thrombosis, up to 50% of patients develop post-thrombotic syndrome (PTS). PTS is a chronic condition that reduces quality of life (QOL). Cornerstones of PTS treatment include the use of elastic compression stockings but this treatment is usually incompletely effective and is burdensome. Venoactive drugs have been reported to be effective to treat chronic venous insufficiency (CVI). However, the level of evidence supporting their use in CVI in general and in PTS in particular is low. METHODS AND ANALYSIS: The MUFFIN-PTS trial is an academic, publically funded, multicentre randomised placebo-controlled trial assessing the efficacy of micronised purified flavonoid fraction (MPFF, Venixxa), a venoactive drug, to treat PTS. Eighty-six patients with PTS (Villalta score (VS) ≥5) and experiencing at least two of the following PTS manifestations among daily leg heaviness, cramps, pain or oedema will be randomised to receive 1000 mg of oral MPFF or a similar appearing placebo for 6 months, in addition to their usual PTS treatment. Total study follow-up will be 9 months, with visits at inclusion/baseline, 3, 6 and 9 months. Primary outcome is the proportion of patients with improvement in VS in each group, where improvement is defined as a decrease of at least 30% in VS or a VS <5 in the PTS-affected leg. Main secondary outcomes include QOL and patient satisfaction. ETHICS AND DISSEMINATION: Primary ethics approval was received from Centre intégré universitaire de santé et de services sociaux (CIUSSS) West-Central Montreal Research Ethics Board. Results of the study will be disseminated via peer-reviewed publications and presentations at scientific conferences. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT03833024); Pre-results.

Adherence to, and outcomes of, a galactomannan screening protocol in high-risk hematology patients.

Background: A twice-weekly galactomannan (gm) screening protocol was implemented in high-risk hematology inpatients. Study objectives were to determine adherence to the protocol, use of selected resources, and patient outcomes. Methods: This retrospective cohort study compared outcomes of interest before and after implementation of gm screening. Adults undergoing matched related allogeneic hematopoietic stem-cell transplantation or induction chemotherapy for acute leukemia were eligible. Patients could be enrolled more than once and were evaluated as episodes. Adherence to the gm protocol was assessed in post-implementation episodes. Use of broad-spectrum antifungals (bsafs), consultations (infectious diseases, respirology), and diagnostic procedures (computed tomography imaging, bronchoalveolar lavage) were compared between phases, as were the patient outcomes of all-cause mortality and clinical success (alive and not taking a bsaf). Results: Of 182 episodes consecutively screened, 70 per phase were enrolled. Clinical characteristics and duration of assessment were similar for the phases. Full or partial adherence to the protocol was observed in 61 post-implementation episodes (87%), with full adherence in 40 episodes (57%). More episodes in the pre-implementation phase than in the post-implementation phase involved receipt of bsafs, consultations, and diagnostics (27% vs. 7%, p = 0.02; 46% vs. 26%, p = 0.014; and 46% vs. 31%, p = 0.083 respectively). Although mortality was similar in the two phases, clinical success at the final assessment was observed in fewer pre-implementation than post-implementation episodes (79% vs. 98%, p < 0.001). Conclusions: Implementation of a gm screening protocol was feasible and associated with significantly fewer episodes involving receipt of bsafs and consultations, and with significantly more episodes showing clinical success.

A prospective study of Rivaroxaban for central venous catheter associated upper extremity deep vein thrombosis in cancer patients (Catheter 2).

INTRODUCTION: Patients with cancer are at increased risk of thrombosis, particularly those with central venous catheter (CVC) placement, which may predispose to the development of upper extremity deep vein thrombosis (UEDVT). Standard treatment includes low molecular weight heparin (LMWH) or LMWH bridged to warfarin. The direct oral anticoagulants (DOACs) have become standard of care for uncomplicated venous thromboembolism (VTE), but research in patients with cancer is ongoing. OBJECTIVES: To assess rivaroxaban monotherapy in patients with cancer who develop UEDVT due to CVC for preservation of line function, and safety outcomes of VTE recurrence, bleeding risk and death. MATERIALS AND METHODS: Patients ≥18years of age with active malignancy and symptomatic proximal UEDVT with or without pulmonary embolism (PE), associated with a CVC, were eligible. Treatment included rivaroxaban 15mg oral twice daily for 3weeks, followed by 20mg oral daily for 9weeks. Patients were followed clinically for 12weeks to assess for line function, recurrent VTE and bleeding. RESULTS: Seventy patients (47 women) were included, with mean age 54.1years. The most common malignancy was breast cancer (41%). Preservation of line function was 100% at 12weeks. The risk of recurrent VTE at 12weeks was 1.43%, with one episode of fatal PE. 9 patients (12.9%) experienced 11 total bleeding episodes. CONCLUSIONS: Rivaroxaban showed promise in treating CVC-UEDVT in cancer patients, resulting in preserved line function. However, bleeding rates and a fatal pulmonary embolism on treatment are concerning safety outcomes necessitating further study before rivaroxaban can be recommended.

Clinical challenges in patients with cancer-associated thrombosis: Canadian expert consensus recommendations.

Venous thromboembolism is a common complication in cancer patients, and thromboembolism is the second most common cause of death after cancer progression. A number of clinical practice guidelines provide recommendations for the management of cancer-associated thrombosis. However, the guidelines lack recommendations covering commonly encountered clinical challenges (for example, thrombocytopenia, recurrent venous thromboembolism, etc.) for which little or no evidence exists. Accordingly, recommendations were developed to provide expert guidance to medical oncologists and other health care professionals caring for patients with cancer-associated thrombosis. The current expert consensus was developed by a team of 21 clinical experts. For each identified clinical challenge, the literature in medline, embase, and Evidence Based Medicine Reviews was systematically reviewed. The quality of the evidence was assessed, summarized, and graded. Consensus statements were generated, and the experts voted anonymously using a modified Delphi process on their level of agreement with the various statements. Statements were progressively revised through separate voting iterations and were then finalized. Clinicians using these recommendations and suggestions should tailor patient management according to the risks and benefits of the treatment options, patient values and preferences, and local cost and resource allocations.

Inflammation markers and their trajectories after deep vein thrombosis in relation to risk of post-thrombotic syndrome.

BACKGROUND: Post-thrombotic syndrome (PTS) is a frequent chronic complication of deep vein thrombosis (DVT). OBJECTIVE: In the BioSOX study, we investigated whether inflammation markers predict the risk of PTS after DVT. METHODS: We measured C-reactive protein (CRP), ICAM-1, interleukin (IL)-6, and IL-10, at baseline, and 1 month and 6 months after a first proximal DVT, among 803 participants in the SOX trial. Participants were prospectively followed for 24 months for development of PTS. RESULTS: Median CRP levels at 1 month, ICAM-1 levels at baseline, 1 month and 6 months, IL-6 levels at 1 month and 6 months and IL-10 levels at 6 months were higher in patients who developed PTS than in those who did not. Multivariable regression with the median as a cutoff showed risk ratios (RRs) for PTS of 1.23 (95% confidence interval [CI] 1.05-1.45) and 1.25 (95% CI 1.05-1.48) for ICAM-1 at 1 month and 6 months, respectively, and 1.27 (95% CI 1.07-1.51) for IL-10 at 6 months. Quartile-based analysis demonstrated a dose-response association between ICAM-1 and PTS. ICAM-1 and IL-10 were also associated with PTS severity. Analysis of biomarker trajectories after DVT demonstrated an association between the highest-trajectory group of ICAM-1 and PTS. CONCLUSIONS: In this prospective study, ICAM-1 over time was most consistently associated with the risk of PTS. Further study is required to confirm these findings and assess their potential clinical relevance.

Rivaroxaban vs. low molecular weight heparin for the prevention of venous thromboembolism after hip or knee arthroplasty: a cohort study.

BACKGROUND: Rivaroxaban is increasingly used to prevent venous thromboembolism after hip or knee arthroplasty. Studies evaluating the effectiveness of rivaroxaban compared to low molecular weight heparin after orthopedic surgery in routine practice are scarce. PATIENTS AND METHODS: We conducted a retrospective cohort study in 121 hospitals in Ontario, Canada, between 2002 and 2012. We included patients aged 66 years or older (median age 73 years) who received an outpatient prescription for subcutaneous low molecular weight heparin (n = 11 471) or oral rivaroxaban (n = 12 850) on hospital discharge after a total knee or hip arthroplasty. The two coprimary outcomes assessed within 30 days of the prescription date were emergency department visit or hospitalization with venous thromboembolism (either deep vein thrombosis or pulmonary embolism; primary efficacy outcome) and a hospitalization with non-traumatic major hemorrhage (primary safety outcome). RESULTS: Rivaroxaban use increased over the study period. Compared to low molecular weight heparin, rivaroxaban was associated with a lower 30-day risk of hospitalization with venous thromboembolism (0.47% vs. 0.81%; relative risk 0.58; 95% confidence interval 0.42-0.81; P = 0.001) with no significant difference in hospitalizations for major bleeding (0.18% vs. 0.20%; relative risk 0.89; 95% confidence interval 0.50-1.59; P = 0.700). CONCLUSIONS: In routine practice, anticoagulant prophylaxis with rivaroxaban compared to low molecular weight heparin after hospital discharge from total hip or knee arthroplasty is associated with a lower risk of symptomatic venous thromboembolism with no difference in the risk of bleeding.

The effect of low molecular weight heparin on survival in cancer patients: an updated systematic review and meta-analysis of randomized trials.

BACKGROUND: Tumors may exploit the coagulation system to enhance the survival and dissemination of cancer cells. Some studies have suggested that heparin and low molecular weight heparin (LMWH) have antitumor effects. We reported a previous meta-analysis that suggested a modest improvement in overall survival with the use of LMWH in patients with cancer. Herein, we present the results of an updated systematic review and meta-analysis. OBJECTIVE: To evaluate the effect of LMWH as compared with placebo or no anticoagulant on the overall survival in patients with solid cancers. METHODS: We conducted a systematic review and meta-analysis of randomized trials evaluating the use of LMWH vs. placebo or no anticoagulant in cancer patients without venous thrombosis. A meta-analysis was conducted with a random-effects model, and data were analyzed by the use of odds ratios (ORs) and relative risks (RRs) calculated for 1-year overall mortality. RESULTS: We identified 724 potentially relevant studies, nine of which met our inclusion criteria, and reported data on 1-year overall mortality. Studies were heterogeneous regarding types of cancer and interventions, and included 5987 patients, 98.4% of whom had advanced-stage disease (III and IV). There was no discernible effect on mortality with the use of LMWH (pooled OR 0.87, 95% CI 0.70-1.08; RR 0.94, 95% CI 0.86-1.04). CONCLUSIONS: In contrast to the previous study, these results did not show a survival benefit in cancer patients receiving LMWH. The effect of LMWH on overall survival in patients with limited-stage disease still is unknown.

Patient preferences for stopping tyrosine kinase inhibitors in chronic myeloid leukemia.

BACKGROUND: We used an interview-assisted survey of patients with chronic myeloid leukemia (cml) at a single tertiary care centre to explore patient reactions to and preferences for, and the risk-acceptability of, stopping tyrosine kinase inhibitor (tki) treatment. METHODS: The study included patients with confirmed cml currently being treated with a tki. The survey was conducted by structured interview using a standard form. Patient preferences were explored in a case-based scenario using 0%-100% visual analog scales and 5-point Likert scales. Data were analyzed using proportions for dichotomous variables and medians and interquartile ranges for continuous variables. RESULTS: Of 63 patients approached, 56 completed the survey. Participant responses suggest that the idea of stopping tki use is appealing to many patients if there is a chance of long-term stable disease and a high probability of response upon restarting a tki. Participants were more likely to stop their tki as the risk of relapse decreased. Participants reported loss of disease control and failure of disease to respond to treatment as important concerns if they chose to stop their tki. CONCLUSIONS: Given the current 60% estimated rate of relapse after discontinuation of tki therapy, most patients with cml chose to continue with tki. However, at the lower relapse rates reported with second-generation tkis, participants were more undecided, demonstrating a basic understanding of risk. Contrary to our hypothesis, neither compliance nor occurrence of side effects significantly affected patient willingness to stop their tki.

Clinical performance of bleeding risk scores for predicting major and clinically relevant non-major bleeding events in patients receiving warfarin.

BACKGROUND: Oral anticoagulant therapy is associated with an increased risk of hemorrhage, which can be assessed by bleeding risk scores. We evaluated the performance of five validated scores for predicting major and clinically relevant non-major bleeding events in patients receiving warfarin. METHODS AND RESULTS: We conducted an ambispective, single-center cohort study of 321 consecutive patients enrolled in an academic anticoagulation clinic. The following scores were calculated: modified Outpatient Bleeding Risk Index, Contemporary Bleeding Risk Model, HEMORR(2)HAGES (Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-Bleeding, Hypertension, Anemia, Genetic Factors, Excessive Fall Risk and Stroke), ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation), and HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio, Elderly, Drugs/Alcohol). Main outcomes were major bleeding and a composite of major plus clinically relevant non-major bleeding. Incidence rates for all group were 3.8 (95% confidence interval [CI] 2.0-6.4) and 11.9 (95% CI 8.6-16.4) events per 100 patient-years for major bleeding and major plus clinically relevant non-major bleeding, respectively. Agreement among the five scores was low to moderate (Kendall's tau-b coefficients 0.22-0.54). For major bleeding, the c-statistics ranged from 0.606 to 0.735, whereas for major plus clinically relevant non-major bleeding, they ranged from 0.549 to 0.613. For all scores, the 95% CI for the c-statistics crossed 0.5 or was very close. Among high-risk patients, the hazard ratios for major bleeding ranged from 0.90 to 39.01, whereas for major plus clinically relevant non-major bleeding, they ranged from 1.52 to 8.71. For intermediate-risk patients, no score, except the Contemporary Bleeding Risk Model, produced statistically significant hazard ratios. CONCLUSION: The scores demonstrated poor agreement and low to moderate discriminatory ability. General clinical implementation of these scores cannot be recommended yet.

Cisplatin and short-term 5-Fluorouracil infusion for paraneoplastic microangiopathic hemolytic anemia in gastric cancer: a case report and review of the literature.

Microangiopathic hemolytic anemia is a rare paraneoplastic syndrome accompanying adenocarcinoma of the stomach. We report on a patient presenting with anemia due to a combination of severe hemolysis and tumour bleeding, where the combination of cisplatin and 5-fluorouracil in a short course infusional regimen led to a complete response of the hematologic abnormalities in the first line setting. Relapse was successfully treated with second line docetaxel; however the response was relatively short-lived. Overall survival was 16 months from diagnosis, which compares favourably to the survival of other reported cases. The chemotherapy regimens used in previously reported similar cases are reviewed. We suggest that a regimen based on bolus 5-fluorouracil, possibly with a platinum, should be investigated as a possible regimen of choice.

Conservative perioperative anticoagulation management in patients with chronic venous thromboembolic disease: a cohort study.

BACKGROUND: Guidelines for perioperative warfarin management in patients with venous thromboembolic disease (VTE) are largely based on expert opinion. OBJECTIVES: To assess the effectiveness and safety of a conservative perioperative anticoagulation strategy in patients with VTE on chronic warfarin therapy. Our center uses a conservative bridging approach for chronic VTE patients consisting of withholding warfarin for 5 days preoperatively, with prophylactic low-molecular-weight heparin (LMWH) post-procedure only if patients are admitted to hospital. PATIENTS/METHODS: We performed a single-center retrospective cohort study. During the study period (1997-2011) there were 634 procedures in 416 patients that were reviewed for postoperative outcomes at 30 and 90 days. RESULTS: Of the 634 procedures, 156 procedures (24.6%) were completed as inpatients. Pre- and post-procedure LMWH bridging was used in 15 (2.4%) and 152 (24.0%) of all procedures, respectively. The 30-day VTE incidence was 0.32% (95% confidence interval [CI] 0.087-1.14), all non-fatal DVTs. The 30-day incidence of major and total bleeding events was 1.26% (95% CI 0.64-2.47) and 3.00% (95% CI 1.93-4.63), respectively. The all-cause mortality rate was 0.32% (95% CI 0.087-1.14) at 30 days; two patients died from arterial thrombosis events. CONCLUSIONS: A randomized controlled trial is needed to provide definitive conclusions but a conservative bridging approach appears promising.

Ambulatory management of pulmonary embolism: a pragmatic evaluation.

BACKGROUND: Patients diagnosed with pulmonary embolism should be considered for treatment on an outpatient basis; however, this practise is not accepted in many centers. OBJECTIVES: Review the safety and efficacy of ambulatory management of patients with pulmonary embolism at our institution. PATIENTS/METHODS: This was a retrospective single center cohort study of consecutive patients diagnosed with idiopathic or secondary pulmonary embolism between January 2003 and January 2008 at the London Health Sciences Centre in London, Ontario, Canada. Patients were eligible for outpatient management of pulmonary embolism if they were hemodynamically stable, did not require oxygen therapy, did not require parenteral narcotics for pain management, and were not felt to be high risk for a major hemorrhage. Patients were assessed at 3 months for thrombosis recurrence and major bleeding episodes. RESULTS: Six hundred and thirty-nine patients were included in the study, of which 314 (49.1%; 95% CI 45.2, 53.1) were managed as outpatients; among these there were three (0.95%; 95% CI, 0.25, 3) thrombotic recurrences and three hemorrhagic events. There were nine deaths (2.9%; 95% CI, 1.4, 5.6), all due to underlying cancer and all occurring after the first 7 days of treatment. CONCLUSIONS: Outpatient management of uncomplicated pulmonary embolism seems safe and effective in the absence of other indications for hospital admission.

Predicting warfarin maintenance dose in patients with venous thromboembolism based on the response to a standardized warfarin initiation nomogram.

BACKGROUND: Polymorphisms in the VKORC1 and CYP2C9 genes influence warfarin requirements. It has been suggested that dosing algorithms incorporating them might outperform usual care. Standardized warfarin initiation nomograms are safe and effective and patients' responses to them could be used to predict warfarin requirements without the need for genetic testing. OBJECTIVES: To develop a model to predict warfarin dose requirements based on the response to a standard nomogram without using genetic testing. PATIENTS/METHODS: We included 363 outpatients with acute venous thromboembolism who were started on treatment using a standardized warfarin nomogram and achieved a stable maintenance warfarin dose defined as a dose prescribed twice consecutively after two consecutive INR measurements between 2.0 and 3.0. Linear regression was used to derive equations predicting the maintenance dose and models were validated using non-parametric bootstrapping and tested in an independent cohort. RESULTS: Three models were constructed for patients completing the nomogram until day 3 (warfarin dose (mg week(-1)) = Exp [2.737 + 1.896(INR(3)(-1))-0.008(Age)]; R2adj = 0.462), day 5 (warfarin dose (mg week(-1)) = Exp[2.261 + 2.412(INR(3)(-1)) -0.285(DeltaINR(5-3))]; R2adj = 0.603) and day 8 (warfarin dose (mg week(-1)) = Exp[1.574 + 1.788(INR(8)(-1)) + 0.024(cumulated warfarin dose until nomogram day 7)]; R2adj = 0.643), where Exp is the exponential function; INR3 and INR8 are the INR on days 3 or 8 of the nomogram, and DeltaINR(5-3) is the difference in the INR on days 5 and 3. All models were internally and externally validated and were accurate to within 25% of the actual dose in >60% of patients. CONCLUSION: Maintenance warfarin dose can be accurately predicted using individual response to a standard warfarin initiation nomogram without the need for costly genetic testing.

Long-term dalteparin in pregnancy not associated with a decrease in bone mineral density: substudy of a randomized controlled trial.

BACKGROUND: The risk of decreased bone mineral density (BMD) with prophylactic dose long-term low-molecular-weight heparin (LMWH) is unknown. OBJECTIVES: We sought to determine whether long-term prophylactic dalteparin in pregnancy leads to loss of BMD. PATIENTS/METHODS: Patients in a substudy of an ongoing multicenter randomized trial investigating the effect of antepartum dalteparin prophylaxis on pregnancy outcomes in thrombophilic pregnant women were randomized to either dalteparin 5000 U s.c. daily until 20 weeks and then 5,000 U s.c. q12 h until >37 weeks or to the control group. The primary outcome was absolute spine BMD at six weeks postpartum. RESULTS: Of 77 patients eligible for the BMD substudy, 62 were analyzed. 33 patients received a mean of 212 days of dalteparin in the intervention group. 29 patients received a mean of 38 days of postpartum dalteparin in the control group. There was no difference in mean BMD between the intervention (1.11 g cm(-2)) and the control groups (1.14 g cm(-2)). Similarly, there was no difference in T-scores; the difference of -0.34 (95% confidence interval -0.93 to +0.25) in favor of the control group excludes a clinically important increase in fracture risk. CONCLUSIONS: Our results suggest that the use of long-term prophylactic dalteparin in pregnancy is not associated with a significant decrease in BMD. CLINICAL TRIAL REGISTRATION: ISRCTN87441504 at http://www.controlled-trials.com.

The effect of low-molecular-weight heparin on cancer survival. A systematic review and meta-analysis of randomized trials.

BACKGROUND: Low-molecular-weight heparins (LMWH) have an antitumor effect in vitro and in experimental animal models of malignancy. Retrospective data suggest that it might improve survival in cancer patients. OBJECTIVES: To evaluate the effect of LMWH compared to placebo or no anticoagulant intervention on the survival of cancer patients. METHODS: We conducted a systematic review of randomized trials specifically evaluating the impact of LMWH on the survival of cancer patients. DATA SOURCES WERE: MEDLINE, EMBASE, HealthSTAR, Cochrane library, gray literature and cross-referencing from reference lists. Data extraction was performed by one reviewer, and accuracy was independently verified by a second reviewer. Meta-analysis was conducted using: (i) odds ratio (OR) and relative risk (RR); (ii) survival rates using censored endpoints; and (iii) hazard ratios (HR). RESULTS: The pooled HR in all patients was 0.83 (95% CI 0.70-0.99; P = 0.03), and in patients with advanced disease it was 0.86 (95% CI 0.74-0.99; P = 0.04), both in favor of the LMWH group. The results of the OR, RR and survival meta-analysis consistently favored the LMWH group. Sensitivity analyses according to tumor type were not conducted, because of a lack of information. CONCLUSIONS: LMWH improves overall survival in cancer patients, even in those with advanced disease. Additional trials are required to define the tumor types, disease stages and dosing schedules most likely to provide the greatest survival benefit.

Moderate and severe neutropenia in patients with systemic lupus erythematosus.

OBJECTIVES: Neutropenia is an uncommon albeit relevant finding in patients with systemic lupus erythematosus (SLE). It has been ascribed to several aetiologies and represents a challenging dilemma in which clinical findings, laboratory data and medication history must be carefully evaluated. The aim of this work was to review the cases of moderate and severe neutropenia in our cohort of SLE patients in order to identify predisposing factors, clinical outcomes and related prognostic implications. METHODS: Thirty-three cases of neutropenia (neutrophil count <1000/microl) in patients with SLE were included. Sixty-five age- and sex-matched patients with SLE served as controls. Information was obtained by medical chart review. Statistical analyses included descriptive statistics, Student's t-test, paired t-test, chi 2 or Fisher's exact test, and logistic regression. RESULTS: Baseline characteristics did not differ between groups. Use of concomitant medications and immunosuppressive drugs, as well as history of thrombocytopenia and central nervous system involvement, were associated with an increased risk for developing neutropenia. Along with neutropenia, cases had lower haemoglobin and platelet values and higher levels of liver enzymes. Moreover, disease activity was lower than in controls. One month after the neutropenia event, leucocyte and total granulocyte counts were still lower in patients than in controls. Mortality did not differ between patients with neutropenia and controls. CONCLUSIONS: Most episodes of severe granulocytopenia in SLE patients occur as part of drug toxicity-induced medullar hypoplasia.