Erik Yeo

Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial.

BACKGROUND Post-thrombotic syndrome (PTS) is a common and burdensome complication of deep venous thrombosis (DVT). Previous trials suggesting benefit of elastic compression stockings (ECS) to prevent PTS were small, single-centre studies without placebo control. We aimed to assess the efficacy of ECS, compared with placebo stockings, for the prevention of PTS. METHODS We did a multicentre randomised placebo-controlled trial of active versus placebo ECS used for 2 years to prevent PTS after a first proximal DVT in centres in Canada and the USA. Patients were randomly assigned to study groups with a web-based randomisation system. Patients presenting with a first symptomatic, proximal DVT were potentially eligible to participate. They were excluded if the use of compression stockings was contraindicated, they had an expected lifespan of less than 6 months, geographical inaccessibility precluded return for follow-up visits, they were unable to apply stockings, or they received thrombolytic therapy for the initial treatment of acute DVT. The primary outcome was PTS diagnosed at 6 months or later using Ginsbergs criteria (leg pain and swelling of ≥1 month duration). We used a modified intention to treat Cox regression analysis, supplemented by a prespecified per-protocol analysis of patients who reported frequent use of their allocated treatment. This study is registered with ClinicalTrials.gov, number NCT00143598, and Current Controlled Trials, number ISRCTN71334751. FINDINGS From 2004 to 2010, 410 patients were randomly assigned to receive active ECS and 396 placebo ECS. The cumulative incidence of PTS was 14·2% in active ECS versus 12·7% in placebo ECS (hazard ratio adjusted for centre 1·13, 95% CI 0·73-1·76; p=0·58). Results were similar in a prespecified per-protocol analysis of patients who reported frequent use of stockings. INTERPRETATION ECS did not prevent PTS after a first proximal DVT, hence our findings do not support routine wearing of ECS after DVT. FUNDING Canadian Institutes of Health Research.

Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism

Background Low‐molecular‐weight heparin is the standard treatment for cancer‐associated venous thromboembolism. The role of treatment with direct oral anticoagulant agents is unclear. Methods In this open‐label, noninferiority trial, we randomly assigned patients with cancer who had acute symptomatic or incidental venous thromboembolism to receive either low‐molecular‐weight heparin for at least 5 days followed by oral edoxaban at a dose of 60 mg once daily (edoxaban group) or subcutaneous dalteparin at a dose of 200 IU per kilogram of body weight once daily for 1 month followed by dalteparin at a dose of 150 IU per kilogram once daily (dalteparin group). Treatment was given for at least 6 months and up to 12 months. The primary outcome was a composite of recurrent venous thromboembolism or major bleeding during the 12 months after randomization, regardless of treatment duration. Results Of the 1050 patients who underwent randomization, 1046 were included in the modified intention‐to‐treat analysis. A primary‐outcome event occurred in 67 of the 522 patients (12.8%) in the edoxaban group as compared with 71 of the 524 patients (13.5%) in the dalteparin group (hazard ratio, 0.97; 95% confidence interval [CI], 0.70 to 1.36; P=0.006 for noninferiority; P=0.87 for superiority). Recurrent venous thromboembolism occurred in 41 patients (7.9%) in the edoxaban group and in 59 patients (11.3%) in the dalteparin group (difference in risk, ‐3.4 percentage points; 95% CI, ‐7.0 to 0.2). Major bleeding occurred in 36 patients (6.9%) in the edoxaban group and in 21 patients (4.0%) in the dalteparin group (difference in risk, 2.9 percentage points; 95% CI, 0.1 to 5.6). Conclusions Oral edoxaban was noninferior to subcutaneous dalteparin with respect to the composite outcome of recurrent venous thromboembolism or major bleeding. The rate of recurrent venous thromboembolism was lower but the rate of major bleeding was higher with edoxaban than with dalteparin. (Funded by Daiichi Sankyo; Hokusai VTE Cancer ClinicalTrials.gov number, NCT02073682.)

Diagnosing PNH with FLAER and multiparameter flow cytometry.

PNH is an acquired hematopoietic stem cell disorder leading to a partial or absolute deficiency of all glycophosphatidyl‐inositol (GPI)‐linked proteins. The classical approach to diagnosis of PNH by cytometry involves the loss of at least two GPI‐linked antigens on RBCs and neutrophils. While flow assays are more sensitive and specific than complement‐mediated lysis or the Hams test, they suffer from several drawbacks. Bacterial aerolysin binds to the GPI moiety of cell surface GPI‐linked molecules and causes lysis of normal but not GPI‐deficient PNH cells. FLAER is an Alexa488‐labeled inactive variant of aerolysin that does not cause lysis of cells. Our goals were to develop a FLAER‐based assay to diagnose and monitor patients with PNH and to improve detection of minor populations of PNH clones in other hematologic disorders.

CD109 is expressed on a subpopulation of CD34+ cells enriched in hematopoietic stem and progenitor cells

CD109 is a monomeric cell surface glycoprotein of 170 kD that is expressed on endothelial cells, activated but not resting T-lymphocytes, activated but not resting platelets, leukemic megakaryoblasts, and a subpopulation of bone marrow CD34+ cells. Observing an apparent association between CD109 expression and the megakaryocyte lineage (MK), we sought to determine whether CD109 was expressed on MK progenitors. In fetal bone marrow (FBM), a rich source of MK progenitors, CD109 is expressed on a mean of 11% of CD34- cells. Fluorescence activated cell sorting (FACS) of FBM CD34+ cells into CD109+ and CD109- fractions revealed that the CD34+CD109+ subset contained virtually all assayable MK progenitors, including the colony-forming unit-MK (CFU-MK) and the more primitive burst-forming unit-MK (BFU-MK). The CD34+CD109+ subset also contained all the assayable burst-forming units-erythroid (BFU-E), 90% of the colony-forming units-granulocyte/macrophage (CFU-GM), and all of the more primitive mixed lineage colony-forming units (CFU-mix). In contrast, phenotypic analysis of the CD34+CD109- cells in FBM, adult bone marrow (ABM) and cytokine-mobilized peripheral blood (MPB) demonstrated that this subset comprises lymphoid-committed progenitors, predominantly of the B-cell lineage. CD109 was expressed on the brightest CD34 cells identifiable not only in FBM, but also in ABM and MPB indicating that the most primitive, candidate hematopoietic stem cells (HSC) might also be contained in the CD109+ subset. In long-term marrow cultures of FBM CD34+ cells, all assayable cobblestone area forming cell (CAFC) activity was contained within the CD109+ cell subset. Further phenotypic analysis of the CD34+CD109+ fraction in ABM indicated that this subset included candidate HSCs that stain poorly with CD38, but express Thy-1 (CD90) and AC133 antigens, and efflux the mitochondrial dye Rhodamine 123 (Rho123). When selected CD34+ cells were sorted for CD109 expression and Rho123 staining, virtually all CAFC activity was found in the CD109+ fraction that stained most poorly with Rho123. CD34+ cells were also sorted into Thy-1 CD109+ and Thy-1 CD109+ fractions and virtually all the CAFC activity was found in the Thy-1+CD109+ subset. In contrast, the Thy-1-CD109+ fraction contained most of the short-term colony-forming cell (CFC) activity. CD109, therefore, is an antigen expressed on a subset of CD34+ cells that includes pluripotent HSCs as well as all classes of MK and myelo-erythroid progenitors. In combination with Thy-1, CD109 can be used to identify and separate myelo-erythroid and all classes of MK progenitors from candidate HSCs.

Recurrent stroke/TIA in cryptogenic stroke patients with patent foramen ovale.

BACKGROUND Patent foramen ovale (PFO) is present in 40% of patients with cryptogenic stroke and may be associated with paradoxical emboli to the brain. Therapeutic options include antiplatelet agents, anticoagulation, percutaneous device and surgical closure. We assessed the hypothesis that there are differences in rates of recurrent TIA or stroke between patients in the four treatment groups. METHODS Patients presenting from January 1997 with cryptogenic stroke or TIA and PFO were followed prospectively until June 2003. Treatment choice was made on an individual case basis. The primary outcome was recurrent stroke. The secondary outcome was a composite of stroke, TIA, and vascular death. RESULTS Baseline. Our cohort consisted of 121 patients; 64 (53%) were men. Median age was 43 years. Sixty-nine percent presented with stroke and 31% with TIA. One or more vascular risk factor was present in 40%. Atrial septal aneurysm (ASA) was present in 24%. Treatment consisted of antiplatelet agents (34%), anticoagulation (17%), device (39%) and surgical closure (11%). Follow-up. Recurrent events occurred in 16 patients (9 antiplatelet, 3 anticoagulation, 4 device closure); 7 were strokes, 9 were TIA. Comparing individual treatments there was a trend toward more strokes in the antiplatelet arm (p = 0.072); a significant difference was seen for the composite endpoint (p = 0.012). Comparing closure versus combined medical therapy groups, a significant difference was seen for primary (p = 0.014) and secondary (p = 0.008) outcomes, favoring closure. Age and pre-study event predicted outcome. CONCLUSION Patent foramen ovale closure was associated with fewer recurrent events. Complications of surgical and device closure were self-limited.

The role of recombinant factor VIIa in on-pump cardiac surgery : Proceedings of the Canadian Consensus Conference

PurposeRecombinant activated factor VII (rFVIIa) is currently not approved by Health Canada or the Food and Drug Administration for treating excessive blood loss in nonhemophiliac patients undergoing on-pump cardiac surgery, but is increasingly being used “off-label” for this indication. A Canadian Consensus Conference was convened to generate recommendations for rFVIIa use in on-pump cardiac surgery.Methods: The panel undertook a literature review of the use of rFVIIa in both cardiac and non-cardiac surgery. Appropriateness, timing, and dosage considerations were addressed for three cardiac surgery indications: prophylactic, routine, and rescue uses. Recommendationswere based on evidencefromtheliterature and derived by consensus following recognized grading procedures.ResultsThe panel recommended against prophylactic or routine use of rFVIIa, as there is no evidence at this time that the benefits of rFVIIa outweigh its potential risks compared with standard hemostatic therapies. On the other hand, the panel made a weak recommendation (grade 2C) for the use of rFVIIa (one to two doses of 35–70 μg·kg-1) as rescue therapy for blood loss that is refractory to standard hemostatic therapies, despite the lack of randomized controlled trial data for this indication.ConclusionsIn cardiac surgery, the risks and benefits of rFVIIa are unclear, but current evidence suggests that its benefits may outweigh its risks for rescue therapy in selected patients. Methodologically rigorous studies are needed to clarify its risk-benefit profile in cardiac surgery patients.ObjectifLe facteur VII activé recombinant (rFVIIa) n’est actuellement approuvé ni par Santé Canada ni par la Food and Drug Administration (FDA) pour le traitement du saignement excessif chez les patients non-hémophiles subissant une chirurgie cardiaque avec circulation extra-corporelle (CEC); néanmoins, il est de plus en plus utilisé de manière ‘non conforme’ pour cette indication. Une Conférence canadienne de consensus s’est réunie afin de rédiger des recommandations quant à l’utilisation du rFVIIa lors de la chirurgie cardiaque avec CEC.MéthodeLe panel a entrepris une revue de la littérature traitant de l’utilisation du rFVIIa en chirurgies cardiaque et non cardiaque. Des considérations quant à la justification, au moment de l’administration et à la posologie ont été évaluées pour trois indications en chirurgie cardiaque: les utilisations prophylactique, de routine ou de sauvetage. Les recommandations, basées sur des données probantes tirées de la littérature, ont été interprétées par un consensus suivant des procédures de gradation reconnues.RésultatsLe panel s’est prononcé contre une utilisation prophylactique ou de routine du rFVIIa, étant donné qu’il n’existe actuellement pas de preuve que les bienfaits du rFVIIa l’emportent sur les risques potentiels encourus en comparaison des thérapies hémostatiques standard. En revanche, le panel a énoncé une recommandation faible (note 2C) en faveur de l’utilisation du rFVIIa (une à deux doses de 35–70 μg·kg-1) comme thérapie de sauvetage en cas de saignement réfractaire aux thérapies hémostatiques standard et ce, malgré le manque de données d’études randomisées contrôlées concernant cette indication.ConclusionEn chirurgie cardiaque, les risques et bienfaits du rFVIIa ne sont pas clairs; toutefois, les données actuelles suggèrent que ses bienfaits pourraient contrebalancer ses risques dans les cas de thérapie de sauvetage chez certains patients. Des études méthodologiquement rigoureuses sont nécessaires afin de clarifier le profil risque/bénéfice du rFVIIa pour les patients de chirurgie cardiaque.

A triple-blinded randomized trial comparing the hemostatic effects of large-dose 10% hydroxyethyl starch 264/0.45 versus 5% albumin during major reconstructive surgery.

In Canada, hydroxyethyl starch 264/0.45 (HES 264/0.45; molar weight 264 kDa, molar substitution 0.45) has largely replaced albumin as the colloidal fluid of choice for perioperative intravascular volume expansion. The maximum recommended dose of HES 264/0.45 is 28 mL/kg; however, there are no clinical data supporting this limit. In this study we compared the hemostatic effects of HES 264/0.45 versus 5% albumin in doses up to 45 mL/kg over 24 h during major reconstructive head and neck surgery. Fifty patients were randomized to receive HES 264/0.45 or 5% human albumin from the induction of anesthesia until 24 h thereafter. Both albumin and HES 264/0.45 effectively maintained physiologic variables in the perioperative and postoperative periods. The partial thromboplastin time and international normalized ratio were significantly increased in the HES 264/0.45 group compared with the albumin group after infusion of 30 mL/kg and 45 mL/kg (P < 0.05). Factor VIII activity and von Willebrand factor level were significantly reduced in the HES 264/0.45 group compared with the albumin group after infusion of 15 mL/kg, 30 mL/kg, and 45 mL/kg (P < 0.05). Significantly more subjects in the HES 264/0.45 group received allogeneic red blood cell transfusions (P < 0.02). We conclude that HES 264/0.45 infusions >30 mL/kg over 24 h impair coagulation to a greater extent than albumin, possibly leading to more allogeneic transfusions.

Graduated compression stockings to treat acute leg pain associated with proximal DVT. A randomised controlled trial.

Acute deep venous thrombosis (DVT) causes leg pain. Elastic compression stockings (ECS) have potential to relieve DVT-related leg pain by diminishing the diameter of distended veins and increasing venous blood flow. It was our objective to determine whether ECS reduce leg pain in patients with acute DVT. We performed a secondary analysis of the SOX Trial, a multicentre randomised placebo controlled trial of active ECS versus placebo ECS to prevent the post-thrombotic syndrome.The study was performed in 24 hospital centres in Canada and the U.S. and included 803 patients with a first episode of acute proximal DVT. Patients were randomised to receive active ECS (knee length, 30-40 mm Hg graduated pressure) or placebo ECS (manufactured to look identical to active ECS, but lacking therapeutic compression). Study outcome was leg pain severity assessed on an 11-point numerical pain rating scale (0, no pain; 10, worst possible pain) at baseline, 14, 30 and 60 days after randomisation. Mean age was 55 years and 60% were male. In active ECS patients (n=409), mean (SD) pain severity at baseline and at 60 days were 5.18 (3.29) and 1.39 (2.19), respectively, and in placebo ECS patients (n=394) were 5.38 (3.29) and 1.13 (1.86), respectively. There were no significant differences in pain scores between groups at any assessment point, and no evidence for subgroup interaction by age, sex or anatomical extent of DVT. Results were similar in an analysis restricted to patients who reported wearing stockings every day. In conclusion, ECS do not reduce leg pain in patients with acute proximal DVT.

Anti-Xa Monitoring of Enoxaparin for Acute Coronary Syndromes in Patients with Renal Disease

BACKGROUND There are limited data on dosing of enoxaparin in patients with renal disease due to the routine exclusion of this population in clinical trials. To account for the potentially delayed drug elimination in these patients, we developed guidelines for adjusting enoxaparin dosing based on anti-Xa monitoring. OBJECTIVE To evaluate anti-Xa level monitoring, resulting from the standards of practice as set out by our hospitals guidelines for enoxaparin dosing in renally impaired patients. METHODS A total of 72 separate acute coronary syndrome patient admissions were retrospectively reviewed. All patients had anti-Xa levels taken and creatinine clearance values <30 mL/min during enoxaparin therapy. RESULTS The average trough anti-Xa level at the once- and twice-daily doses was 0.40 and 0.72 IU/mL, respectively. With twice-daily dosing, only 6% of the trough concentrations were in the target range of 0.2–0.3 IU/mL compared with 36% with once-daily dosing. Of the 22 patients who had a change of dosing frequency from twice to once daily, 5% of trough anti-Xa levels were ≤0.5 IU/mL with twice-daily versus 68% with once-daily dosing. CONCLUSIONS Although the relationship between anti-Xa activity, efficacy, and adverse effects has not been definitively established, anti-Xa levels can assist with dosing of enoxaparin in renally impaired patients. Our hospital guidelines are effective in adjusting dosing to reach target anti-Xa levels.

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

Post‐thrombotic syndrome (PTS) is a frequent chronic complication of deep vein thrombosis (DVT).