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Apixaban compared with parenteral heparin and/or vitamin K antagonist in patients with nonvalvular atrial fibrillation undergoing cardioversion: Rationale and design of the EMANATE trial.
Ezekowitz, MD, Pollack, CV, Sanders, P, Halperin, JL, Spahr, J, Cater, N, Petkun, W, Breazna, A, Kirchhof, P, Oldgren, J
American heart journal. 2016;:59-68
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Abstract
BACKGROUND Stroke prevention in anticoagulation-naïve patients with atrial fibrillation undergoing cardioversion has not been systematically studied. OBJECTIVE To determine outcomes in anticoagulation-naïve patients (defined as those receiving an anticoagulant for <48 hours during the index episode of atrial fibrillation) scheduled for cardioversion. METHODS This is a randomized, prospective, open-label, real-world study comparing apixaban to heparin plus warfarin. Early image-guided cardioversion is encouraged. For apixaban, the usual dose is 5 mg BID with a dose reduction to 2.5 mg BID if 2 of the following are present: age >80 years, weight <60 kg, or serum creatinine >1.5 mg/dL. If cardioversion is immediate, a single starting dose of 10 mg (or 5 mg if the dose is down-titrated) of apixaban is administered. Cardioversion may be attempted up to 90 days after randomization. Patients are followed up for 30 days after cardioversion or 90 days postrandomization if cardioversion is not performed within that timeframe. Outcomes are stroke, systemic embolization, major bleeds, clinically relevant nonmajor bleeding, and death, all adjudication-blinded. STATISTICS The warfarin-naive cohort from the ARISTOTLE study was considered the closest data set to the patients being recruited into this study. The predicted incidence of stroke, systemic embolism, and major bleeding within 30 days after randomization was approximately 0.75%. To adequately power for a noninferiority trial, approximately 48,000 participants would be needed, a number in excess of feasibility. The figure of 1,500 patients was considered clinically meaningful and achievable. CLINICAL CONTEXT This first prospective cardioversion study of a novel anticoagulant in anticoagulation-naïve patients should influence clinical practice.
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Vitamin E-Coated and Heparin-Coated Dialyzer Membranes for Heparin-Free Hemodialysis: A Multicenter, Randomized, Crossover Trial.
Islam, MS, Hassan, ZA, Chalmin, F, Vido, S, Berrada, M, Verhelst, D, Donnadieu, P, Moranne, O, Esnault, VL
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2016;(5):752-762
Abstract
BACKGROUND Hemodialysis requires effective anticoagulation to avoid blood circuit clotting. In patients at high risk for bleeding, several alternative methods have been developed. STUDY DESIGN Multicenter, prospective, randomized, crossover study evaluating the noninferiority of vitamin E-coated compared with heparin-coated dialyzers in a 4-hour heparin-free hemodialysis strategy. SETTINGS & PARTICIPANTS 32 adult long-term hemodialysis patients from 2 French hemodialysis units with well-functioning fistulas or double-lumen catheters. INTERVENTION Patients were randomly allocated to a first period using either vitamin E- or heparin-coated dialyzers. After a washout period of 2 hemodialysis sessions, each patient was switched to the alternative dialyzer for a second period. Each study period started with 2 hemodialysis sessions with reduced heparin dose (50% and 25% of usual heparin dose, respectively, for sessions 1 and 2) followed by 2 heparin-free sessions. OUTCOMES The primary end point was the percentage of successful study periods, defined as no circuit-clotting event leading to premature interruption of any of the 4 dialysis sessions. Secondary end points included total number and cumulative duration of hemodialysis sessions without clotting, number of saline solution flushes, dialysis circuit bubble trap status and dialyzer membrane status by visual inspection, and dialysis adequacy. RESULTS The percentage of success with vitamin E-coated dialyzers (25/32 study periods [78%]) was not inferior to that with heparin-coated dialyzers (26/32 study periods [81%]). Visual inspection showed equal numbers of clean dialysis circuit bubble traps (vitamin E-coated, 34/121; heparin-coated, 32/120), whereas clean fiber bundles were more frequently noted with the vitamin E-coated compared with heparin-coated dialyzers (25/121 vs 2/120; P=0.002). LIMITATIONS Results may not extrapolate to critically ill patients. Differences in dialyzer transparency may account for visual inspection scores. CONCLUSIONS The success rate of 4-hour heparin-free hemodialysis sessions is lower than that previously claimed in uncontrolled studies. Vitamin E-coated and heparin-coated dialyzers exposed patients to similar and unacceptable high failure rates. Further studies are required to improve heparin-free hemodialysis.
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Efficacy and safety of citrate-based anticoagulation compared to heparin in patients with acute kidney injury requiring continuous renal replacement therapy: a randomized controlled trial.
Stucker, F, Ponte, B, Tataw, J, Martin, PY, Wozniak, H, Pugin, J, Saudan, P
Critical care (London, England). 2015;(1):91
Abstract
INTRODUCTION A systemic anticoagulation is often required to prevent circuit and filter clotting in ICU patients undergoing continuous renal replacement therapy (CRRT). A regional citrate-based anticoagulation (RCA) does not induce a systemic anticoagulation and prolongs the filter lifespan, but metabolic side-effects have been associated with this therapy. We conducted a randomized controlled trial with patients requiring CRRT to determine whether RCA using a balanced predilution replacement fluid is more effective than heparin in terms of renal replacement delivered dose and safety profile. METHODS One hundred and three patients with AKI requiring CRRT were included. The patients were randomized to either CRRT with RCA or heparin anticoagulation. Primary endpoints were effective daily delivered RRT dose during the first 3 days of CRRT and filter lifespan. Secondary endpoints were 28-day and 90-day survival and severe metabolic complications and bleeding disorders. RESULTS Median CRRT duration was 3.0 (2-6) days. Effective delivered daily RRT doses were 29 ± 3 and 27 ± 5 mL/kg/hr in the RCA and heparin groups, respectively (p = 0.005). Filter lifespans were 49 ± 29 versus 28 ± 23 hrs in the RCA and heparin groups (p = 0.004). Survival rates at 28 and 90 days were 80-74% in the RCA and 74-73% in the heparin group. Electrolytes and acid-base disturbances were uncommon and transient in patients treated with RCA. CONCLUSIONS These results show that RCA is superior to heparin-based anticoagulation in terms of delivered RRT dose and filter life span and is a safe and feasible method. This does not translate into an improvement in short term survival. TRIAL REGISTRATION ClinicalTrials.gov NCT01269112 . Registered 3rd January 2011.
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Citrate versus heparin for apheresis catheter locks: an efficacy analysis.
Passero, BA, Zappone, P, Lee, HE, Novak, C, Maceira, EL, Naber, M
Journal of clinical apheresis. 2015;(1):22-7
Abstract
INTRODUCTION There is a paucity of medical literature regarding the efficacy of lock solutions in preventing catheter thrombosis. Traditionally, heparin has been used as the anticoagulant of choice for catheter locking, but it has many adverse effects associated with its use. Sodium citrate 4% is an attractive alternative to heparin. METHODS Our plasmapheresis unit converted to locking all central venous catheters with sodium citrate 4% in place of heparin 100 units/mL in May 2010. We conducted a 2-year period retrospective observational cohort study comparing the outcomes of using heparin versus citrate locks. Outcomes examined were catheter patency, catheter exchanges, alteplase usage, and catheter infections. RESULTS During the study period, 84 patients who underwent a total of 554 plasmapheresis treatments were identified. Flow problems among the citrate treatments were more frequent than those among the heparin group (6.5% vs. 3.2%, P = 0.11, n = 554) but this did not reach statistical significance. The frequency of more severe flow problems requiring catheter exchange or alteplase infusion was higher among the citrate group than the heparin group (3.2% vs. 1.3%, P = 0.11, n = 554). Subgroup analysis, stratified by diagnosis, demonstrated that there was a statistically significant difference in flow problems when comparing myasthenia gravis (MG) patients to non-MG patients. There was no difference in catheter infections between the groups. CONCLUSIONS Based on the findings of our study, we conclude that citrate and heparin locks have similar efficacy in maintaining catheter patency in plasmapheresis patients. Further research is needed to examine the differences observed between MG patients versus all other patients.
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Normal saline versus heparin solution to lock totally implanted venous access devices: Results from a multicenter randomized trial.
Dal Molin, A, Clerico, M, Baccini, M, Guerretta, L, Sartorello, B, Rasero, L
European journal of oncology nursing : the official journal of European Oncology Nursing Society. 2015;(6):638-43
Abstract
PURPOSE Our aim was to determine the non-inferiority of normal saline flushing compared to heparin flushing in maintaining the patency of totally implanted venous access devices (TIVADs). METHOD Four hundred and thirty patients were recruited from 14 Italian centres. Patients were randomized to heparin group or to normal saline group. The primary outcome of the study was TIVAD occlusion. RESULTS After randomisation, 203 patients were assigned to normal saline group and 212 to heparin group. Median follow up time was 204 days in normal saline group and 294 in the heparin group. We observed 24 withdrawal occlusions (5.78%): 10 in the heparin group and 14 in the normal saline group. One total occlusion was observed in the normal saline group. Taking as reference the arm treated with heparin, the absolute risk difference was 2.67 with the 90% CI including the non - inferiority margin of 4%. No significant difference between hazards of occlusion was found. CONCLUSIONS This study failed to demonstrate that normal saline flushing is not inferior to heparin flushing, even if a significant difference between the two treatments was not found. The use of heparin is controversial and other prospective trials are necessary in this field. TRIAL REGISTRATION EudraCT number: 2009-013620-22.
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Heparin Saline Versus Normal Saline for Flushing and Locking Peripheral Venous Catheters in Decompensated Liver Cirrhosis Patients: A Randomized Controlled Trial.
Wang, R, Zhang, MG, Luo, O, He, L, Li, JX, Tang, YJ, Luo, YL, Zhou, M, Tang, L, Zhang, ZX, et al
Medicine. 2015;(31):e1292
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A prospective randomized, controlled, single-blinded trial to compare the effectiveness and safety of heparin saline (HS) to those of normal saline (NS) as flushing and locking solutions for peripheral venous catheter (PVC) in decompensated liver cirrhosis (DLC) patients.Patients with DLC at our institution between April 2012 and March 2013 were enrolled after obtaining informed consent. The patients were randomly allocated into 2 groups: the NS group received preservative-free 0.9% sodium chloride as the flushing and locking solution, while the HS group received HS (50 U/mL). PVC-related events and the duration of PVC maintenance were compared between the 2 groups. Moreover, the preinfusion and postinfusion levels of prothrombin time (PT), activated partial thromboplastin time (APTT), and platelet (PLT) were also compared.A total of 32 and 36 DLC patients in the NS (125 PVCs) and HS (65 PVCs) groups, respectively, were analyzed. Baseline characteristics, including gender, age, Child-Pugh grade, PVC type and administration of anticoagulant, and irritant agents, were comparable between the 2 groups (P > 0.05). The maintenance times of the HS and NS groups were 80.27 ± 26.47 and 84.19 ± 29.32 hours, respectively (P = 0.397). Removal of PVC for abnormal reasons occurred in 30.7% and 22.4% of patients in the HS and NS groups (P = 0.208). The PVC occlusion rates were 6.2% and 5.6% in the HS and NS groups, respectively (OR = 1.11, 95% CI 0.31-3.92). The PT, APTT, and PLT levels were comparable between the 2 groups both before and after infusion (P > 0.05). Incremental analyses showed that Child-Pugh grade C might be a risk factor for the suppression of PLT in the HS group.We consider NS to be as effective as and safer than conventional HS for flushing and locking PVC in decompensated liver cirrhosis patients.
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In vitro comparison of the novel, dual-acting FIIa/FXa-inhibitor EP217609C101, unfractionated heparin, enoxaparin, and fondaparinux in preventing cardiac catheter thrombosis.
Kaeberich, A, Raaz, U, Vogt, A, Maedgefessel, L, Neuhart, E, Krezel, C, Drouget, L, Hauroeder, B, Buerke, M, Werdan, K, et al
Journal of thrombosis and thrombolysis. 2014;(2):118-30
Abstract
Efficient and safe anticoagulation is crucial in patients requiring percutaneous coronary intervention (PCI) or extracorporeal circulation during cardiac surgery. Although new anticoagulant strategies have emerged for PCI as alternatives to the established treatment with heparins, the development of new anticoagulants with an improved efficacy/safety ratio is still necessary. Our study compared the efficacy of the novel, dual-acting, neutralizable FIIa/FXa-inhibitor EP217609C101 (EP) at 2, 1.2, 0.9, and 0.6 μg/ml to unfractionated heparin (UFH), enoxaparin, and fondaparinux in preventing cardiac catheter thrombosis under in vitro conditions. Blood drawn by venepunction from healthy male volunteers (n = 10) pretreated with 500 mg aspirin orally was treated with the anticoagulant to test and continuously circulated through a cardiac catheter for 60 min or until the catheter became blocked by thrombotic debris. Anticoagulant efficacy was assessed by thrombus weight, electron microscopic features of the developing thrombi, and laboratory parameters. Whereas UFH, enoxaparin, EP 2, and EP 1.2 μg/ml secured maximum circulation times, statistically significant premature catheter occlusions were observed for EP 0.9, EP 0.6 μg/ml, and fondaparinux. The UFH group and both high-dose concentrations of EP showed significantly lower thrombus weights than the low-dose concentrations of EP and fondaparinux, (p ≤ 0.05). On electron microscopic analysis of the thrombotic debris no differences were observed in erythrocyte deposition between UFH, enoxaparin, and all EP concentrations tested. A significant reduction in fibrin deposition was achieved by UFH and EP 2 μg/ml but no significant differences in platelet deposition were found, except for a significant reduction for EP 0.6 μg/ml. Our in vitro study showed that EP217609C101 is a promising new drug that is dose-dependently superior to classical (UFH, enoxaparin) and newer (fondaparinux) drugs in preventing heart catheter thrombosis.
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Comparing normal saline versus diluted heparin to lock non-valved totally implantable venous access devices in cancer patients: a randomised, non-inferiority, open trial.
Goossens, GA, Jérôme, M, Janssens, C, Peetermans, WE, Fieuws, S, Moons, P, Verschakelen, J, Peerlinck, K, Jacquemin, M, Stas, M
Annals of oncology : official journal of the European Society for Medical Oncology. 2013;(7):1892-1899
Abstract
BACKGROUND Heparin has been used for years as a locking solution in totally implantable venous access devices. Normal saline (NS) might be a safe alternative for heparin. However, evidence of non-inferiority of NS versus heparin is lacking. PATIENTS AND METHODS We randomly allocated 802 cancer patients with a newly inserted port either to heparin lock (300 U/3 ml) or to NS lock groups in a 1:1 assignment ratio. The primary outcome was the number of functional complications, which was defined as 'easy injection, impossible aspiration' at port access. Secondary outcomes included all functional problems and catheter-related bacteraemia. We hypothesised that NS locks do not cause more functional problems and catheter-related bacteraemia than heparin locks. Non-inferiority is established if the upper limit of the confidence interval (CI) for the relative risk of NS versus heparin is <1.4. RESULTS Three hundred and eighty-two patients from the NS group and 383 from the heparin lock group were included in the analysis. The incidence rate of our primary outcome (easy injection, impossible aspiration) was 3.70% (95% CI 2.91%-4.69%) and 3.92% (95% CI 3.09%-4.96%) of accesses in the NS and heparin groups, respectively. The relative risk was 0.94% (95% CI 0.67%-1.32%). Catheter-related bloodstream infection was 0.03 per 1000 catheter days in the NS group and 0.10 per 1000 catheter days in the heparin group. CONCLUSION NS is a safe and effective locking solution in implantable ports if combined with a strict protocol for device insertion and maintenance.
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A randomized trial comparing gentamicin/citrate and heparin locks for central venous catheters in maintenance hemodialysis patients.
Moran, J, Sun, S, Khababa, I, Pedan, A, Doss, S, Schiller, B
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2012;(1):102-7
Abstract
BACKGROUND Central venous catheters (CVCs) are used for vascular access in hemodialysis patients who have no alternative access or are awaiting placement or maturation of a permanent access. The major complications of CVCs are catheter-related bloodstream infection and clotting in the catheter lumen. STUDY DESIGN Parallel-group, randomized, multicenter clinical trial, with patients blinded to study intervention. SETTING & PARTICIPANTS 16 free-standing dialysis facilities in Northern California belonging to a single provider. 303 adult maintenance hemodialysis patients who were using a tunneled cuffed CVC for vascular access. INTERVENTION The treatment group received an antibiotic lock containing gentamicin 320 μg/mL in 4% sodium citrate, whereas the control group received the standard catheter lock containing heparin 1,000 U/mL. Both groups received triple-antibiotic ointment on the catheter exit site during dressing changes at each dialysis treatment. OUTCOMES Catheter-related bloodstream infection and catheter clotting. MEASUREMENTS Catheter-related bloodstream infection was defined as the occurrence of symptoms consistent with bacteremia together with positive blood culture results in the absence of another obvious source of infection. Catheter clotting was measured as the rate of thrombolytic agent use required to maintain adequate blood flow. A single patient could contribute more than one infection or clotting episode. RESULTS The rate of catheter-related bloodstream infection was 0.91 episodes/1,000 catheter-days in the control group and 0.28 episodes/1,000 catheter-days in the treatment group (P = 0.003). The time to the first episode of bacteremia was significantly delayed (P = 0.005). The rates of tissue plasminogen activator use were similar in the treatment and control groups: 2.36 versus 3.42 events/1,000 catheter-days, respectively (P = 0.2). LIMITATIONS The requirement for dialysis facility staff to prepare the treatment intervention prevented a completely blinded study. CONCLUSION Gentamicin 320 μg/mL in 4% sodium citrate used as a routine catheter lock in CVCs in patients on maintenance hemodialysis therapy markedly decreases the incidence of catheter-related bloodstream infection and is as effective as heparin 1,000 U/mL in preventing catheter clotting.
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Intermittent flushing with heparin versus saline for maintenance of peripheral intravenous catheters in a medical department: a pragmatic cluster-randomized controlled study.
Bertolino, G, Pitassi, A, Tinelli, C, Staniscia, A, Guglielmana, B, Scudeller, L, Luigi Balduini, C
Worldviews on evidence-based nursing. 2012;(4):221-6
Abstract
BACKGROUND Three meta-analyses conducted in the 1990s concluded that the effect of intermittent flushing with heparin at low concentration (10 U/mL) was equivalent to that of 0.9% sodium chloride flushes in preventing occlusion or superficial phlebitis. No firm conclusion was reached on the safety and efficacy of heparin concentrations of 100 U/mL used as an intermittent flush. PURPOSE To determine whether flushing peripheral intravenous catheters with 3 mL of a 100 U heparin/mL solution instead of saline improves the outcome of infusion devices. METHODS Cluster-randomized, controlled, two-arm, open trial, conducted in a research and teaching hospital in Northern Italy, involving 214 medical patients without contraindications to heparin: 107 randomly allocated to heparin and 107 to saline flushes (control group). Main outcome measure was catheter occlusion and catheter-related phlebitis. RESULTS Patients with either phlebitis or occlusion were 45 (42.1%) in the heparin group and 68 (63.6%) in the saline group (OR 0.41; 95% CI 0.24-0.72; p= 0.002); patients with occlusion alone were 23 (21.5%) and 47 (43.9%), respectively (p= 0.03); patients with phlebitis alone were 28 (26.2%) and 56 (52.6%) respectively (p= <0.001). Similar results were obtained when the analysis was based on catheters. No heparin severe side effects were identified. LIMITATIONS Lack of blinding, patient selection, cluster randomization of periods of treatment. CONCLUSIONS Heparin 100 U/mL in the maintenance of peripheral venous catheters was more effective than saline solution, in that it reduced the number of catheter-related phlebitis/occlusions and the number of catheters per patient, with potential advantages to both patients and the health system. It also appeared safe. However, subjects with platelet or coagulation defects were excluded, and, therefore, caution should be used when prescribing this type of catheter maintenance to patients at risk of bleeding.