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Fondaparinux vs Enoxaparin for the Prevention of Venous Thromboembolism in Major Orthopedic SurgeryA Meta-analysis of 4 Randomized Double-blind Studies
Abstract
Orthopedic surgery remains a condition at high risk of venous thromboembolism (VTE). Fondaparinux, the first of a new class of synthetic selective factor Xa inhibitors, may further reduce this risk compared with currently available thromboprophylactic treatments.
A meta-analysis of 4 multicenter, randomized, double-blind trials in patients undergoing elective hip replacement, elective major knee surgery, and surgery for hip fracture (N = 7344) was performed to determine whether a subcutaneous 2.5-mg, once-daily regimen of fondaparinux sodium starting 6 hours after surgery was more effective and as safe as approved enoxaparin regimens in preventing VTE. The primary efficacy outcome was VTE up to day 11, defined as deep vein thrombosis detected by mandatory bilateral venography or documented symptomatic deep vein thrombosis or pulmonary embolism. The primary safety outcome was major bleeding.
Fondaparinux significantly reduced the incidence of VTE by day 11 (182 [6.8%] of 2682 patients) compared with enoxaparin (371 [13.7%] of 2703 patients), with a common odds reduction of 55.2% (95% confidence interval, 45.8% to 63.1%; P<.001); this beneficial effect was consistent across all types of surgery and all subgroups. Although major bleeding occurred more frequently in the fondaparinux-treated group (P =.008), the incidence of clinically relevant bleeding (leading to death or reoperation or occurring in a critical organ) did not differ between groups.
In patients undergoing orthopedic surgery, 2.5 mg of fondaparinux sodium once daily, starting 6 hours postoperatively, showed a major benefit over enoxaparin, achieving an overall risk reduction of VTE greater than 50% without increasing the risk of clinically relevant bleeding.
... Fondaparinux vs control in patients with ST-elevated MI (STEMI) was randomized within 24 h after the start of symptoms in a randomized, double-blind, controlled, parallel-group, multi-center, global trial. For the use of UFH, patients with confirmed STEMI were randomized to one of two strata based on the indication [16]. ...
... Primary safety outcomes: At 9 d, the risk of significant bleeding in patients receiving Fondaparinux was 1.8% (107/6036), compared to 2.1% (130/6056) in patients given placebo or UFH. At 9 d, Fondaparinux was associated with significantly fewer serious bleeds (79 for placebo/UFH vs 61 for Fondaparinux) as well as significantly fewer cardiac tamponade episodes (48 vs 28; P = 0.02) [16]. ...
... Fondaparinux dramatically reduced the risk of death, re-MI, and serious bleeding in STEMI patients treated with thrombolytic drugs (mostly streptokinase). The results were consistent in both strata, over varied time periods from symptom start to treatment, and across different types of thrombolytics [16]. ...
In acute coronary syndrome (ACS), the use of anticoagulants in conjunction with antiplatelet agents in the acute phase has resulted in reduced ischemic events and is more effective than either class of drug used alone. Though parenteral anticoagulation is essential at the time of diagnosis, a balance must be made between ischemic benefit and the increased risk of bleeding when prescribing anticoagulants. Adverse events associated with anticoagulants, such as heparin-induced thrombocytopenia, bleeding problems, and the need for close monitoring of anticoagulant activity, have contributed to finding agents that reduce these limitations. Studies like the Organization to Assess Strategies in Ischemic Syndromes 5 and 6 and their meta-analysis have proven the efficacy of Fondaparinux over the entire ACS spectrum. The convenience of administration (once daily), lack of monitoring, reduction in mortality, and better safety profile make Fondaparinux a simple and effective anti-coagulant for the management of ACS.
... However, the authors of that review advise that clinicians be aware of the higher risk of major bleeding, especially surgical site bleeding, with fondaparinux [7]. A metaanalysis of four randomized controlled trials (RCTs) showed that fondaparinux significantly reduced VTE incidence compared with enoxaparin in major orthopedic surgery [8]. The effect was consistent across all types of surgeries and all subgroups [8]. ...
... A metaanalysis of four randomized controlled trials (RCTs) showed that fondaparinux significantly reduced VTE incidence compared with enoxaparin in major orthopedic surgery [8]. The effect was consistent across all types of surgeries and all subgroups [8]. Major bleeding occurred more significantly frequently in the fondaparinux group [8]. ...
... The effect was consistent across all types of surgeries and all subgroups [8]. Major bleeding occurred more significantly frequently in the fondaparinux group [8]. However, the incidence of clinically relevant bleeding (leading to death or reoperation) did not differ between groups [8]. ...
... Similar results regarding the safety and efficacy of fondaparinux in comparison with enoxaparin were obtained in a meta-analysis of four multicenter, randomized, double-blind trials [127]. The incidence of VTE was halved from 13.7% to 6.8% with LMWH versus fondaparinux, respectively [127]. ...
... Similar results regarding the safety and efficacy of fondaparinux in comparison with enoxaparin were obtained in a meta-analysis of four multicenter, randomized, double-blind trials [127]. The incidence of VTE was halved from 13.7% to 6.8% with LMWH versus fondaparinux, respectively [127]. FDA approved fondaparinux in the initial treatment of VTE [128]. ...
Simple Summary
People with cancer are at an increased risk of developing blood clots. Both cancer and anti-cancer treatment are responsible for this risk. In some types of cancer, such risk is higher than in others. There are different types of blood thinners also known as anticoagulants. Blood thinners prevent the recurrence of deep venous thrombosis (a blood clot in the limbs) or pulmonary embolism (a blood clot in the lungs) in people with cancer. In some clinical situations and, specifically, in patients with active cancer, injectable blood thinners are safer than tablets to be taken orally and work just as well.
Abstract
Cancer-associated thrombosis (CAT) is a leading cause of death among patients with cancer. CAT can manifest itself as venous thromboembolism (VTE), in the form of deep vein thrombosis or pulmonary embolism, or arterial thromboembolism. The pathophysiology of CAT is complex and depends on cancer-, patient-, treatment- and biomarkers-related factors. Treatment of VTE in patients with cancer is complex and includes three major classes of anticoagulant agents: heparin and its derivatives, e.g., low molecular weight heparins, direct oral anticoagulants (DOACs), and vitamin K inhibitors. Given the tremendous heterogeneity of clinical situations in patients with cancer and the challenges of CAT, there is no single universal treatment option for patients suffering from or at risk of CAT. Initial studies suggested that patients seemed to prefer an anticoagulant that would not interfere with their cancer treatment, suggesting the primacy of cancer over VTE, and favoring efficacy and safety over convenience of route of administration. Recent studies show that when the efficacy and safety aspects are similar, patients prefer the oral route of administration. Despite this, injectables are a valid option for many patients with cancer.
... Moreover, among patients who underwent hip and knee arthroplasty, the incidence of DVT among those treated with fondaparinux sodium, a chemically synthesized inhibitor of the Xa factor that does not cause heparin-induced thrombocytopenia (HIT), was 50% lower than the incidence among those receiving enoxaparin, an LMWH anticoagulant (6.8% vs. 13.7%, P < 0.001) [86]. For patients at high risk of postoperative thromboembolism and bleeding, the European consensus recommends the administration of low-dose novel anticoagulants (NOACs) at 24 h after surgery [87]. ...
... IU/mL, adjusted based on the anti-Xa activity [97]. Monitoring the anti-Xa activity is crucial to prevent bleeding in patients with renal insufficiency or thrombocytopenia [86]. ...
Trauma-induced coagulopathy (TIC) is caused by post-traumatic tissue injury and manifests as hypercoagulability that leads to thromboembolism or hypocoagulability that leads to uncontrollable massive hemorrhage. Previous studies on TIC have mainly focused on hemorrhagic coagulopathy caused by the hypocoagulable phenotype of TIC, while recent studies have found that trauma-induced hypercoagulopathy can occur in as many as 22.2–85.1% of trauma patients, in whom it can increase the risk of thrombotic events and mortality by 2- to 4-fold. Therefore, the Chinese People’s Liberation Army Professional Committee of Critical Care Medicine and the Chinese Society of Thrombosis, Hemostasis and Critical Care, Chinese Medicine Education Association jointly formulated this Chinese Expert Consensus comprising 15 recommendations for the definition, pathophysiological mechanism, assessment, prevention, and treatment of trauma-induced hypercoagulopathy.
... However, increasing CO with inotropic drugs can also reduce pO2 by increasing shunt blood flow. Regional hypocarbia can lead to bronchoconstriction, as can humoral mediators such as serotonin released from platelet-rich emboli [14,15]. ...
The article presents a clinical case report and a review of the literature regarding massive pulmonary embolism and perioperative cardiac arrest during nephrectomy for malignancy, with massive thrombus in the inferior vena cava. The case report discusses a patient undergoing nephrectomy due to malignancy who experienced sudden cardiac arrest during surgery caused by massive pulmonary embolism. The authors of the article present a description of the surgical and rescue procedure performed. The literature review includes an analysis of similar cases and management strategies for massive pulmonary embolism and perioperative cardiac arrest. The authors evaluate various methods of therapeutic interventions. The work is an important source of information for medical practitioners, especially surgeons and anesthesiologists, who may encounter similar clinical situations. The presented case and literature review may be used to better understand and manage similar medical emergencies.
... The effectiveness of fondaparinux has been extensively studied in various randomized trials and meta-analyses [3,[58][59][60][61][62][63][64][65][66][67]. In a meta-analysis conducted in 2016, which included 25 trials with a total of 21,000 patients, fondaparinux demonstrated a significant reduction in the incidence of symptomatic VTE compared to a placebo (0.2% vs. 1.2%; ...
Venous thromboembolism (VTE), comprising pulmonary embolism (PE) and deep vein thrombosis (DVT), poses a significant risk during and after hospitalization, particularly for surgical patients. Among various patient groups, those undergoing major orthopedic surgeries are considered to have a higher susceptibility to PE and DVT. Major lower-extremity orthopedic procedures carry a higher risk of symptomatic VTE compared to most other surgeries, with an estimated incidence of 4%. The greatest risk period occurs within the first 7-14 days following surgery. Major bleeding is also more prevalent in these surgeries compared to others, with rates estimated between 2% and 4%. For patients undergoing major lower-extremity orthopedic surgery who have a low bleeding risk, it is recommended to use pharmacological thromboprophylaxis with or without mechanical devices. The choice of the initial agent depends on the specific surgery and patient comorbidities. First-line options include low-molecular-weight heparins (LMWHs), direct oral anticoagulants, and aspirin. Second-line options consist of unfractionated heparin (UFH), fondaparinux, and warfarin. For most patients undergoing knee or hip arthroplasty, the initial agents recommended for the early perioperative period are LMWHs (enoxaparin or dalteparin) or direct oral anticoagulants (rivaroxaban or apixaban). In the case of hip fracture surgery, LMWH is recommended as the preferred agent for the entire duration of prophylaxis. However, emerging factor XI(a) inhibitors, as revealed by a recent meta-analysis, have shown a substantial decrease in the occurrence of VTE and bleeding events among patients undergoing major orthopedic surgery. This discovery poses a challenge to the existing paradigm of anticoagulant therapy in this specific patient population and indicates that factor XI(a) inhibitors hold great promise as a potential strategy to be taken into serious consideration.
... When bleeding occurs during anticoagulation, there is no way to prevent it. When bleeding occurs during anticoagulation, the location, cause and severity of bleeding should be evaluated as quickly and accurately as possible, and specific treatment should be given, including mechanical pressing and lowering the dose of anticoagulant (95). When massive bleeding occurs (the standard is that the bleeding is serious enough to require major medical intervention, such as blood transfusion or surgery, and the prognosis is extremely poor) (92, 96), generally speaking, it is necessary to stop anticoagulation treatment immediately, quickly evaluate the degree of bleeding and life state of the patient, use specific reversal agents to reverse the anticoagulation effect, and use mechanical ventilation and blood transfusion to maintain life if necessary (97-100). ...
Left ventricular non-compaction is a complex cardiomyopathy and the third largest childhood cardiomyopathy, for which limited knowledge is available. Both pathogenesis and prognosis are still under investigation. Currently, no effective treatment strategy exists to reduce its incidence or severity, and symptomatic treatment is the only clinical treatment strategy. Treatment strategies are constantly explored in clinical practice, and some progress has been made in coping with the corresponding symptoms because the prognosis of children with left ventricular non-compaction is usually poor if there are complications. In this review, we summarized and discussed the coping methods for different left ventricular non-compaction symptoms.
... En pacientes que no reciben tromboprofilaxis después de estos procedimientos quirúrgicos, se ha encontrado que la prevalencia de trombosis venosa profunda (TVP) en los siguientes siete a 14 días es de 41% a 85%, afectando venas proximales en 10% a 30% de los casos y aunque la tromboembolia pulmonar (TEP) ocurre en menos del 30% de los pacientes, la incidencia de TEP fatal va de 0,1% a 2% (2), lo que justifica el uso de tromboprofilaxis en estos pacientes; se ha reportado que con ella disminuye al 2% el porcentaje de eventos trombóticos postoperatorios, con tasa de sangrado clínicamente significativo de 1% (4,22). Las guías de consenso de expertos recomiendan la tromboprofilaxis por 10 a 35 días después de cirugía ortopédica mayor sin que se logre determinar la duración óptima de dicha terapia (2,23,24). ...
Objetivo: evaluar la eficacia y seguridad de la tromboprofilaxis con rivaroxaban comparada con las heparinas de bajo peso molecular en cirugía mayor de cadera o rodilla. Métodos: revisión sistemática en Central Cochrane Database, MEDLINE, EMBASE, LILACS, CINAHL y artículos referenciados. Solo se consideraron ensayos clínicos controlados. La búsqueda se realizó hasta octubre 31 de 2011.Dos revisores evaluaron de forma independiente la calidad metodológica de los artículos y extrajeron los datos. Resultados: se estudiaron 15.638 pacientes (nueve estudios) programados para reemplazo total de cadera o rodilla. Comparada con la enoxaparina, la tromboprofilaxis con rivaroxaban se asoció a menor incidencia de trombosis venosa profunda, tromboembolia pulmonar y muerte por cualquier causa posterior a cirugía ortopédica mayor tanto de cadera (5.475, riesgo relativo [RR]: 0,37; intervalo de confianza del 95% [IC 95%]: 0,29-0,48]) como de rodilla (2.878, RR: 0,65; IC 95%: 0,50-0,84) sin diferencias en los eventos hemorrágicos (sangrado mayor en cirugía de cadera: 7.684, RR: 1,79; IC 95%: 0,78-4,11; y de rodilla: 5.700, RR: 1,59; IC 95%: 0,77-3,27). Conclusión: el rivaroxaban usado para tromboprofilaxis de pacientes sometidos a cirugía ortopédica mayor es más eficaz que la enoxaparina y al menos tan seguro como ella.
... Many studies have demonstrated the efficacy and safety of fondaparinux in preventing VTE across a range of medical and surgical settings, for example, major orthopedic surgeries involving lower limbs, abdominal surgeries, and for the treatment of DVT and PE. 21 Fondaparinux was as effective and as safe as unfractionated heparin (UFH) in the initial treatment of hemodynamically stable patients with PE. 22 In the initial treatment of patients with symptomatic DVT, fondaparinux was non-inferior to enoxaparin, and both were well-tolerated. [23][24][25] A significant reduction in mortality and reinfarction was observed with fondaparinux (2.5 mg once daily SC) in patients with acute ST-elevation myocardial infarction (STEMI), particularly those not undergoing primary percutaneous coronary intervention without increasing bleeding and strokes. ...
Fondaparinux sodium is a chemically synthesized selective factor Xa inhibitor approved for the prevention and treatment of venous thromboembolic events, that is, deep vein thrombosis, pulmonary embolism, and superficial vein thrombosis, in acutely ill (including those affected by COVID-19 or cancer patients) and those undergoing surgeries. Since its approval in 2002, the efficacy and safety of fondaparinux is well demonstrated by many clinical studies, establishing the value of fondaparinux in clinical practice. Some of the advantages with fondaparinux are its chemical nature of synthesis, minimal risk of contamination, 100% absolute bioavailability subcutaneously, instant onset of action, a long half-life, direct renal excretion, fewer adverse reactions when compared with direct oral anticoagulants, and being an ideal alternative in conditions where oral anticoagulants are not approved for use or in patients intolerant to low molecular weight heparins (LMWH). In the last decade, the real-world use of fondaparinux has been explored in other conditions such as acute coronary syndromes, bariatric surgery, in patients developing vaccine-induced immune thrombotic thrombocytopenia (VITT) and in pregnant women with heparin-induced thrombocytopenia (HIT), or those intolerant to LMWH. The emerging data from these studies have culminated in recent updates in the guidelines that recommend the use of fondaparinux under various conditions. This paper aims to review the recent data and the subsequent updates in the recommendations of various guidelines on the use of fondaparinux sodium.
... However, these agents have certain important limitations, such as higher cost, shorter half-life, immunogenicity, and intravenous administration of these agents are also known to cause hemorrhage. [6,7] These undesirable side effects have created interest in the field of thrombolytic agents, and motivated investigators to search for novel and effective fibrinolytic enzymes for safer use. Over the last decades, many thrombolytic agents have been identified, studied and characterized from various sources, such as earthworms, [8] snake venoms, [9] centipede venoms, [10] insects, [11] and leeches. ...
... Traditionally, physicians use some standard scoring tables [7,24,25] to calculate a risk score for each patient prior to a hip or knee replacement surgery and determine if one is at high risk of VTE and requires special preventive and post-operative care. The table works as a checklist in which each known risk factor (e.g., recent pregnancy and obesity) has been given a risk score, and depending on its existence in a patient's records, the corresponding score will be added to the total risk score for that patient. ...
Venous thromboembolism (VTE) is a well-recognized complication that is prevalent in patients undergoing major orthopedic surgery (e.g., total hip arthroplasty and total knee arthroplasty). For years, to identify patients at high risk of developing VTE, physicians have relied on traditional risk scoring systems, which are too simplistic to capture the risk level accurately. In this paper, we propose a data-driven machine learning framework to identify such high-risk patients before they undergo a major hip or knee surgery. Using electronic health records of more than 392,000 patients who undergone a major orthopedic surgery, and following a guided feature selection using the genetic algorithm, we trained a fully connected deep neural network model to predict high-risk patients for developing VTE. We identified several risk factors for VTE that were not previously recognized. The best FCDNN model trained using the selected features yielded an area under the ROC curve (AUC) of 0.873, which was remarkably higher than the best AUC obtained by including only risk factors previously known in the medical literature. Our findings suggest several interesting and important insights. The traditional risk scoring tables that are being widely used by physicians to identify high-risk patients are not considering a comprehensive set of risk factors, nor are they as powerful as cutting-edge machine learning methods in distinguishing low-from high-risk patients.
... Osoczowy okres półtrwania fondaparynuksu wynosi 17-20 godzin przy zachowanej czynności nerek, natomiast przekracza 72 godziny kiedy klirens kreatyniny wynosi poniżej 30 ml/minutę [37,38]. Jak wynika z badania klinicznego, w którym wzięło udział ponad 7 tysięcy pacjentów, fondaparynuks wykazuje podobną do HDCz skuteczność w ochronie przeciwzakrzepowej podczas operacji ortopedycznych [39]. Ponadto podobnie jak heparyny jest skuteczny w leczeniu ostrej fazy zakrzepicy żył głębokich oraz zatoru płucnego [13,14]. ...
Leki przeciwkrzepliwe stanowią podstawę leczenia i zapobiegania chorobom zakrzepowo-zatorowym. Głównym zagrożeniem związanym z terapią tymi lekami są poważne krwawienia, które wymagają odpowiedniej interwencji medycznej. Ogólna strategia postępowania w przypadku tego rodzaju krwawień polega na zaprzestaniu podawania leku przeciwkrzepliwego oraz odwróceniu skutków leczenia przeciwkrzepliwego przy użyciu dostępnych specyficznych odtrutek oraz ogólnych środków prohemostatycznych. W prezentowanej pracy przedstawiliśmy najczęściej stosowane leki przeciwkrzepliwe z uwzględnieniem ich podstawowych mechanizmów działania, farmakokinetyki i działań niepożądanych oraz ogólnych wytycznych dotyczących postępowania w przypadku poważnych krwawień po ich stosowaniu. Wskazaliśmy metody, które w przyszłości mogłyby poprawić bezpieczeństwo terapii przeciwzakrzepowej, a obecnie są w fazie badań przedklinicznych i klinicznych. Opisaliśmy przykład zaangażowania farmaceutów w poprawę skuteczności i bezpieczeństwa terapii antykoagulacyjnej.
... [1][2][3] Fondaparinux has made its way in clinical practice for deep vein thrombosis (DVT) and pulmonary embolism (PE) treatment, for prophylaxis of thromboembolic events following orthopedic surgery and is part of the therapeutic arsenal for heparin-induced thrombocytopenia (HIT) among other indications. [4][5][6][7] Thrombosis progression occurring despite anticoagulation is challenging to treat. Therapeutic options are limited when dose escalation of low molecular weight heparin (LMWH) or unfractionated heparin (UFH) fail. ...
Background:
Recurrent thrombosis treatment options are limited when anticoagulation with dose escalation of low molecular weight heparin or unfractionated heparin fail. Fondaparinux is a pure, synthetic pentasaccharide that consists of heparin's essential five-sugar chain that binds antithrombin to inactivate factor Xa. There is scarce data regarding fondaparinux's use in recurrent thrombosis.
Key clinical question:
We aim to explore fondaparinux's role in recurrent thrombosis when other standard anticoagulation treatments fail.
Clinical approach:
We report a case series of six high thrombotic risk patients successfully treated with fondaparinux after thrombosis progression while on supratherapeutic low molecular weight heparin or unfractionated heparin. Of our six patients, two were previously diagnosed with a high-risk thrombophilia: triple positive antiphospholipid syndrome, and homozygous factor V Leiden. The other four had an underlying malignancy.
Conclusion:
With fondaparinux, no thrombosis progression was observed, and no bleeding complications occurred.
... Un avance fue la síntesis de la fracción pentasacárida de la HNF, que permitió obtener una droga superior a las HBPM. Esto ha quedado demostrado en múltiples ensayos y publicaciones (13) , por lo cual, a la fecha, se le considera como la droga antitrombótica de mayor potencia. ...
El desarrollo y prescripción de drogas que alteran el equilibrio del sistema de hemostasia ha constituido un gran avance en el tratamiento y la prevención de eventos tromboembólicos, que ha logrado disminuir de manera drástica la morbimortalidad asociada a ellos. El descubrimiento de la heparina y de los cumarínicos, así como la descripción de sus actividades trombóticas, abrió un nuevo panorama terapéutico.
... LMWHs in patients with impaired renal function should be used with caution, as drug bioaccumulation may lead to bleeding [53]. Prophylactic doses of fondaparinux 2.5 mg daily are associated with minor bleeding than therapeutic LMWHs doses [54] and the same risk as UFH [55] or prophylactic LMWHs doses [56]. ...
These days, anticoagulants are in great demand. They are used as a prophylaxis for thromboembolic complications in various diseases and conditions in general therapeutic practice, cardiology, neurology, as well as obstetrics to manage high-risk pregnancies. The relevance of anticoagulants competent use has come to the fore in connection with the emergence of a new disease – COVID-19 and its serious complications such as developing thrombotic storm, in which the timely applied anticoagulant therapy is the key to the success of therapy. The risk of bleeding should be considered when using any anticoagulant. Age, impaired renal function and concomitant use of antiplatelet agents are common risk factors for bleeding. Moreover, only vitamin K antagonists and heparin have specific antidotes – vitamin K and protamine, respectively. Inhibitors of other anticoagulants are universal presented as inactivated or activated prothrombin complex concentrate and recombinant factor VIIa. Hemodialysis effectively reduces dabigatran concentration, activated charcoal is effective in the case of recent oral administration of lipophilic drugs. Research on new antidotes of currently available anticoagulants is under way, similar to testing of new types of anticoagulants that are sufficiently effective in preventing and treating thromboembolic complications with minimal risk of hemorrhagic. The main contraindication to anticoagulants use is the doctor's ignorance of the mechanisms of drug action and opportunities for suppressing its effect.
... 93 In the very few available case reports of a fondaparinuxrelated spinal haematoma, these were associated with either the use of high doses (>2.5 mg d À1 ) [94][95][96] or not respecting the then recommended 36 to 42 h time interval 97 following a lower dose of fondaparinux before withdrawing the indwelling neuraxial catheter. 98 A metaanalysis by Turpie et al. 15 demonstrated that the administration of low-dose fondaparinux starting 6 h after surgery did not result in an increase in any clinically relevant bleeding, and even less if a 8 to 9 h delay was used. ...
Background:
Bleeding is a potential complication after neuraxial and peripheral nerve blocks. The risk is increased in patients on antiplatelet and anticoagulant drugs. This joint guideline from the European Society of Anaesthesiology and Intensive Care and the European Society of Regional Anaesthesia aims to provide an evidence-based set of recommendations and suggestions on how to reduce the risk of antithrombotic drug-induced haematoma formation related to the practice of regional anaesthesia and analgesia.
Design:
A systematic literature search was performed, examining seven drug comparators and 10 types of clinical intervention with the outcome being peripheral and neuraxial haematoma. Grading of Recommendations, Assessment, Development and Evaluation (GRADE) was used for assessing the methodological quality of the included studies and for formulating recommendations. A Delphi process was used to prepare a clinical practice guideline.
Results:
Clinical studies were limited in number and quality and the certainty of evidence was assessed to be GRADE C throughout. Forty clinical practice statements were formulated. Using the Delphi-process, strong consensus (>90% agreement) was achieved in 57.5% of recommendations and consensus (75 to 90% agreement) in 42.5%.
Discussion:
Specific time intervals should be observed concerning the adminstration of antithrombotic drugs both prior to, and after, neuraxial procedures or those peripheral nerve blocks with higher bleeding risk (deep, noncompressible). These time intervals vary according to the type and dose of anticoagulant drugs, renal function and whether a traumatic puncture has occured. Drug measurements may be used to guide certain time intervals, whilst specific reversal for vitamin K antagonists and dabigatran may also influence these. Ultrasound guidance, drug combinations and bleeding risk scores do not modify the time intervals. In peripheral nerve blocks with low bleeding risk (superficial, compressible), these time intervals do not apply.
Conclusion:
In patients taking antiplatelet or anticoagulant medications, practitioners must consider the bleeding risk both before and after nerve blockade and during insertion or removal of a catheter. Healthcare teams managing such patients must be aware of the risk and be competent in detecting and managing any possible haematomas.
... The novel agent fondaparinux is a selective inhibitor of factor Xa that has been proven by several studies to be more effective in preventing thromboembolic events than enoxaparin. 71,74 However, some studies have reported increased bleeding complications with fondaparinux, which may make it a less desirable alternative to LMWH. 70 When to start VTE prophylaxis depends on the drug chosen and varies among surgeons. ...
Hip fractures are considered a significant public health issue, representing a substantial burden on our healthcare system and society. They are one of the leading causes of disability among older adults, especially women. Globally, an estimated 18% of women and 6% of men will be affected by hip fractures at some time in life. Hip fractures are a major cause of long-term disability among older adults and more significant than mortality, as only 60% of patients regain their preinjury level of mobility. This has detrimental effects on quality of life and activities of daily living, imposing a level of dependence that has personal, social, and systemic consequences.
... El fondaparinux (inhibidor indirecto del factor Xa) es más eficaz que las HBPM para la prevención de la ETEV pero, como contrapartida, con un aumento del riesgo hemorrágico [112] . En cirugía ortopédica, se puede utilizar tras PTR, PTC y FESF. ...
Resumen
Las especificidades de la anestesia en cirugía ortopédica y traumatología son: antes de la cirugía, la evaluación de los riesgos infeccioso, hemorrágico y trombótico y la información al paciente sobre el tratamiento analgésico; durante la intervención quirúrgica, la colocación del paciente, el manejo de los riesgos específicos relacionados con el uso del torniquete de isquemia del miembro, del cemento quirúrgico, el manejo de los riesgos relacionados con las osteotomías y con las fracturas (embolia grasa, riesgo hemorrágico, riesgo de infección); tras la intervención, la analgesia postoperatoria (PO) y la rehabilitación mejorada, el riesgo trombótico PO; por último, tener en cuenta las patologías especificas (espondiloartropatías y escoliosis). La cirugía del miembro inferior es cada vez más frecuente (artrosis invalidante) y afecta a pacientes con frecuencia ancianos y con puntuaciones ASA (American Society of Anesthesiologists) más altas y, por lo tanto, con más posibilidades de presentar complicaciones. En el caso de la cirugía protésica programada de cadera o de rodilla, diversos estudios (incluidos varios metaanálisis) están a favor de la anestesia raquídea (AR). En el caso de la cirugía por prótesis total de cadera (PTC), la elección de la vía de acceso debe estar guiada por la experiencia del cirujano y las particularidades anatómicas del paciente. La prótesis total de rodilla (PTR) es, junto con la PTC, la más frecuente de las prótesis en cirugía ortopédica. Tras una PTR, una analgesia PO ineficaz es un freno para la rehabilitación y la recuperación funcional. También es origen de dolor crónico PO (DCPO). Los bloqueos nerviosos periféricos han demostrado todo su interés. Las fracturas del extremo superior del fémur (FESF) son una de las urgencias ortopédicas más frecuentes y se asocian a un riesgo alto de descompensación de patologías previas, de síndrome de deslizamiento, de discapacidad y de mortalidad. Un tratamiento multidisciplinario por un equipo de referencia (anestesistas-reanimadores, cirujanos, geriatras) permite reducir la morbimortalidad. La posición semisentada denominada en «silla de playa» está indicada para la instalación en cirugía del hombro, incluida la artroscopia. Esta posición expone a complicaciones neurológicas secundarias a un bajo flujo cerebral o a un estiramiento del plexo braquial, o del XII par craneal, y a la compresión de los nervios ciáticos. El uso de un catéter perineural está indicado en todas las cirugías que presentan un umbral doloroso alto (artroplastia, cirugía del manguito de los rotadores, artrólisis). En el caso de las cirugías periféricas, mano y pie, la anestesia locorregional (ALR) ocupa un lugar importante.
... Il fondaparinux (inibitore indiretto del fattore Xa) è più efficace delle EBPM per la prevenzione della MTEV, ma, tuttavia, con un aumento del rischio di sanguinamento [112] . In chirurgia ortopedica può essere utilizzato dopo PTG, PTA e FESF. ...
Riassunto
Le specificità dell’anestesia in chirurgia ortopedica/traumatologica sono: prima dell’intervento, la valutazione dei rischi infettivi, emorragici e trombotici e l’informazione del paziente sulla gestione degli analgesici; durante l’intervento, l’installazione del paziente, la gestione dei rischi specifici associati all’uso del laccio emostatico all’arto e del cemento chirurgico e la gestione dei rischi correlati alle osteotomie e alle fratture (embolia adiposa, rischio emorragico, rischio infettivo); dopo l’intervento, l’analgesia postoperatoria (PO), la riabilitazione migliorata e il rischio di trombosi PO; infine, la considerazione di specifiche condizioni (spondiloartropatie e scoliosi). La chirurgia degli arti inferiori è sempre più frequente (artrosi invalidante) e spesso riguarda pazienti anziani con punteggi ASA più elevati e, quindi, più propensi a presentare complicanze. Nella chirurgia protesica programmata dell’anca o del ginocchio, diversi studi (comprese diverse metanalisi) sono a favore dell’anestesia spinale (AS). Nella chirurgia per protesi totale d’anca (PTA), la scelta della via d’accesso deve essere guidata dall’esperienza del chirurgo e dalle peculiarità anatomiche del paziente. La protesi di ginocchio (PTG) è, insieme alla PTA, la protesi ortopedica più frequente. Dopo PTG, un’analgesia PO inefficace è un ostacolo alla riabilitazione e al recupero funzionale. È anche una fonte di dolori cronici PO (DCPO). I blocchi nervosi periferici hanno dimostrato tutto il loro interesse. La frattura dell’estremità superiore del femore (FESF) è una delle urgenze ortopediche più frequenti ed è associata a un alto rischio di scompenso dei difetti, di sindrome da scivolamento, di disabilità e di mortalità. La gestione multidisciplinare da parte di un’equipe di riferimento (anestesisti, chirurghi, geriatri) permette di ridurre la morbimortalità. La posizione semiseduta, detta della “beach chair”, è indicata per l’installazione in chirurgia della spalla, artroscopia inclusa. Questa posizione espone a complicanze neurologiche secondarie a un basso flusso cerebrale o a uno stiramento del plesso brachiale o, anche, del XII paio di nervi cranici e alla compressione dei nervi sciatici. L’utilizzo di un catetere perinervoso (BIS) è indicato in tutti gli interventi chirurgici con elevata soglia del dolore (artroplastica, chirurgia della cuffia dei rotatori, artrolisi). Negli interventi chirurgici periferici, della mano e del piede, l’anestesia locoregionale (ALR) occupa un posto importante.
... Fondaparinux acts by selectively inhibiting factor Xa, without any direct activity against factor IIa, while enoxaparin inhibits both factor IIa (thrombin) and factor Xa. [8,9] Many clinical trials have demonstrated that fondaparinux has superior efficacy. [10][11][12][13][14] In contrast, a registry-based study, conducted in a large population of unselected patients, showed that fondaparinux was less effective than LMWH in preventing DVT. [15] This study was undertaken with the objective to compare their efficacy in actual clinical practice. ...
... It was also shown in a cohort study of more than 12,500 patients that LMWHs differ in the frequency of bleeding episodes (van Rein et al., 2017). In the most clinical trials involving the management of thrombotic disorders with LMWHs, the incidence of major bleeding was between 1.5% and 4.7% and depended mainly on the type and duration of anticoagulation used and on the indication claimed (Simonneau et al., 1997;Hull et al., 2000;Turpie et al., 2002;Petersen et al., 2004;Mismetti et al., 2005;Crowther and Warkentin, 2008). This article has not been copyedited and formatted. ...
Bleeding resulting from the application of low-molecular-weight heparins (LMWHs) may be treated with protamine sulfate but lacks efficiency; its action against anti-factor Xa activity is limited to ~60%. Moreover, protamine sulfate can cause life-threatening hypersensitivity reactions. We developed diblock heparin-binding copolymer (HBC) that can neutralize the anticoagulant activity of parenteral anticoagulants. In the present study, we explored the safety profile of HBC and its potential to reverse enoxaparin, nadroparin, dalteparin, and tinzaparin in human plasma and at in vivo conditions. HBC-LMWHs complexes were characterized using zeta potential, isothermal titration calorimetry, and dynamic light scattering. The rat cardiomyocytes and human endothelial cells were used for the assessment of in vitro toxicity. Male Wistar rats were observed for up to 4 days after HBC administration for clinical evaluation, gross necropsy, and biochemistry and histopathological analysis. Rats were treated with LMWHs alone or followed by short-time intravenous infusion of HBC, and bleeding time and anti-factor Xa activity were measured. HBC completely reversed anti-factor Xa activity prolonged in vitro by all LMWHs with an optimal weight ratio of 2.5:1. The complexes of HBC-LMWHs were below 5 µm. We observed no effects on the viability of cardiovascular cells treated with HBC at concentrations up to 0.05 mg/mL. Single doses up to 20 mg/kg of HBC were well-tolerated by rats. HBC completely reversed the effects of LMWHs on bleeding time and anti-factor Xa activity in vivo after 20 minutes, and retained ~80% and ~60% of reversal activity after 1 hour and 2 hours, respectively. Well-documented efficacy and safety of HBC both in vitro and in vivo make this polymer a promising candidate for LMWHs reversal. SIGNIFICANCE STATEMENT: Over the last decade, there has been significant progress in developing antidotes for the reversal of anticoagulants. Until now, there is no effective and safe treatment for patients with severe bleeding under low-molecular-weight heparin therapy. Based on our in vitro and in vivo studies, heparin-binding copolymer seems to be a promising candidate for neutralizing all clinically relevant low-molecular-weight heparins.
... Desde hace décadas, diferentes estrategias como el uso de medias de compresión elástica (10,11), la compresión neumática intermitente (12,13), la administración de heparina no fraccionada (14)(15)(16), warfarina (17,18), heparinas de bajo peso molécular (19,20) y más recientemente fondaparinux (21)(22), han demostrado disminuir la incidencia del TEV en los pacientes en riesgo (23); sin embargo, a pesar de ello, su uso permanece muy limitado (24,25). ...
El tromboembolismo venoso (TEV) es una enfermedad frecuente en el ámbito hospitalario, potencialmente mortal, causante de morbilidad significativa en los sobrevivientes y ampliamente prevenible. A pesar de ello, la profilaxis antitrombótica con frecuencia es subutilizada. Objetivo: establecer el grado de adherencia de los médicos de la clínica del Country (Bogotá, Colombia) a su Guía para la Prevención del Tromboembolismo Venoso en el Paciente Hospitalizado. Resultados: se analizaron 262 historias clínicas de pacientes hospitalizados entre julio 1 y 31 de 2008 y se excluyeron 22. De los 240 pacientes incluidos, 158 (65.8%) requerían profilaxis antitrombótica de acuerdo con la guía institucional. De ellos, solamente 83 (52.5%) recibió la intervención. El porcentaje de prescripción fue mayor en los pacientes de medicina interna (60%) que en los de cirugía general y especialidades (41.3%). Esta prescripción fue totalmente adecuada en cuanto a tipo de intervención, tiempo de uso y dosificación solamente en 34.5% de los pacientes. En un grupo de sujetos con riesgo tromboembólico significativo y con ausencia de la prescripción o error en la formulación de la profilaxis, las razones más importantes para ello fueron: olvido (35%), error en dosificación o tiempo de uso (27%) y subestimación del riesgo (13%). Conclusiones: la tasa de utilización de profilaxis antitrombótica en nuestra institución es similar a la reportada para el país y para el mundo, pero dista mucho de ser la deseada. Es necesario implementar medidas que modifiquen de forma eficaz la conducta médica para mejorar la prevención del TEV en los pacientes hospitalizados
... The meta analysis by Turpie et al. [15] too pointed out that although major bleeding was significantly higher in the fondaparinux-treated group, the incidence of clinically relevant bleeding (leading to death or reoperation or occurring in a critical organ) did not differ between groups. ...
... Prophylaxis for VTE after major surgeries is well studied and has proven to be effective in reducing rates of both DVT and PE. In general and orthopedic surgery the use of prophylactic subcutaneous heparin, 19,20 low-molecular-weight heparin, 21 fondaparinux, 22 and compression stockings 23,24 have resulted in a significant decrease in rates of VTE. Despite these benefits in other surgeries VTE prophylaxis remains controversial in cardiac surgery. ...
Background:
Deep venous thrombosis and pulmonary embolism are life-threatening complications following surgery, warranting prophylaxis. However, prophylaxis is not uniformly practiced among cardiac surgical patients. This study aimed to characterize the national incidence, mortality, and costs associated with thromboembolism following cardiac surgery.
Methods:
The 2005-2015 National Inpatient Sample was used to identify all adult patients undergoing coronary artery bypass grafting or valve surgery. International Classification of Disease codes were used to identify patients with deep venous thrombosis and pulmonary embolism.
Results:
Of approximately 3 million patients undergoing cardiac surgery, 1.62% developed deep venous thrombosis and 0.38% pulmonary embolism. Those with deep venous thrombosis and pulmonary embolism were more commonly female (33.2% and 36.2 vs. 31.2%, P<0.001), older (68.1 and 66.0% vs. 65.7 years, P<0.001), and had a higher Elixhauser comorbidity index (4.0 and 4.7 vs. 3.7, P<0.001). Deep venous thrombosis and pulmonary embolism were associated with increased mortality (4.95% and 14.8% vs. 2.67%, P<0.001). After adjustment for baseline differences, deep venous thrombosis was associated with an incremental increase in cost of $12,308, while pulmonary embolism was associated with $13,879 cost increase following cardiac surgery. Pulmonary embolism was an independent predictor of mortality (Adjusted Odds Ratio, 3.39; 95% Confidence Interval 2.74-4.18).
Conclusions:
The mortality and financial burden related to thromboembolism in cardiac surgery are significant. Prophylaxis may be indicated in cardiac surgery patients to improve quality of care and reduce healthcare costs. Future controlled randomized trials investigating the benefit of thromboembolism prophylaxis in cardiac surgery are warranted.
... The shortest anticoagulant heparin-like molecule, fondaparinux, a 5-mer resembling the binding site for antithrombin, is currently the only commercially available synthetic analog of heparin. 14,15 In recent years it became possible to synthesize heparins of different lengths and to substitute these heparins by additional side groups. 16,17 Such synthetic heparins will likely be the only way to overcome shortages of heparin in case of increasing demand. ...
Background:
Heparins are usually produced from animal tissues. It is now possible to synthesize heparins. This provides the perspectives to overcome shortages of heparin, to optimize biological effects, and to reduce adverse drug effects. Heparins interact with platelet factor 4 (PF4), which can induce an immune response causing thrombocytopenia. This side effect is called heparin-induced thrombocytopenia (HIT). We characterized the interaction of PF4 and HIT antibodies with oligosaccharides of 6-, 8-, 10-, and 12-mer size and a hyper-sulfated 12-mer (S12-mer).
Methods:
We utilized multiple methodologies including isothermal calorimetry, circular dichroism spectroscopy, single molecule force spectroscopy (SMFS), enzyme immunosorbent assay (EIA), and platelet aggregation test to characterize the interaction of synthetic heparin analogs with PF4 and anti-PF4/heparin antibodies.
Results:
The synthetic heparin-like compounds display stronger binding characteristics to PF4 than animal-derived heparins of corresponding lengths. Upon complexation with PF4, 6-mer and S12-mer heparins showed much lower enthalpy, induced less conformational changes in PF4, and interacted with weaker forces than 8-, 10-, and 12-mer heparins. Anti-PF4/heparin antibodies bind weaker to complexes formed between PF4 and heparins ≤8-mer than with complexes formed between PF4 and heparins ≥10-mer. Addition of one sulfate group to the 12-mer resulted in a S12-mer which showed substantial changes in its binding characteristics to PF4.
Conclusions:
We provide a template for characterizing interactions of newly developed heparin-based anticoagulant drugs with proteins, especially PF4 and the resulting potential antigenicity.
Introduction: Prothrombotic is considered a condition that leads to the development of venous or arterial thrombosis and its consequences. There are many factors that cause a violation of the hemostatic potential in patients undergoing surgery with existing risk factors for thromboembolism, a more detailed study of the blood coagulation system, including the study of the compensatory capabilities of the hemocoagulation system, should be conducted. One of these methods is a functional test with double local hypoxia of the upper limb (DLHUL) under the control of thromboelastography (TEG). Goals: The purpose of the study - to identify the degree of thrombotic risk in patients preparing for planned surgical intervention, who belong to the risk group of thrombotic complications, to compare and evaluate the state of the hemostasis system in healthy volunteers and in this cohort of patients using a functional test with double local hypoxia of the upper limb by the method of thromboelastography. Materials and methods: A randomized prospective study was conducted. Patients were divided into two groups depending on the presence of risk factors for thrombosis. Group 1 consisted of healthy volunteers (n = 40) who are not at risk of thrombosis. Group 2 includes patients with existing factors of thrombotic risk (n = 120) who are preparing for scheduled surgical interventions. These patients underwent a functional test of "double local hypoxia of the upper limb" (DLHUL) using thromboelastographic (TEG) methods of studying the hemocoagulation system. The main task of this functional test is to create a trigger component to determine the limits of hemostasis, the origin and duration of adaptive and compensatory reactions of the hemostasis system. Indicators of the hemostasis system are recorded using a thromboelastograph before and after the test. The links of hemostasis are reflected by the following indicators: aggregate state of blood (A0), contact coagulation intensity (CCI), coagulation drive intensity (ICD), maximum clot density - maximum activity (MA), fibrinolytic activity - clot retraction and lysis index (IRCL). The results. Analyzing the data of thromboelastography after performing DLHUL, among the patients of Group 1, two types of reaction of the hemostasis system were found in patients without predictors of thrombotic risk: compensated (n= 20) (characterized by a decrease in the indicators of the vascular-platelet component; subcompensated (n = 20) (characterized by an increase in the indicators of the vascular -platelet component). In subjects of Group 1, TEG indicators indicate an increase in the external mechanism of prothrombinase formation, and the reaction of the procoagulant link of the blood coagulation system in response to the influence of a trigger indicates a change in the directionality of the hemostatic potential towards hypercoagulation. In subjects of group 1 with a compensated type, there is an increase in the components of fibrinolysis and a deviation of the hemostatic potential towards hypocoagulation is observed. The state of the hemostasis system in patients of Group 2 is characterized by pronounced changes in the hemostatic potential in all links. In the vascular-platelet link, a violation of platelet aggregation was noted, with an increase in indicators in response to a stimulus. When conducting the DLHUL test in the subjects of group 2, a decompensated (n = 98) and exhausted (n = 22) type of reaction to the test with local hypoxia of the upper limb was determined. That is, with increased platelet aggregation, hypercoagulation, inhibition of the anticoagulant system and fibrinolysis before the action of the trigger factor, after performing the DLHUL test, these disorders in the hemostasis system progress towards hypercoagulation, which is indicated by the increase in platelet aggregation, the strengthening of the coagulation link of the hemostatic system, the depression of fibrinolysis increases . However, the intensity of these changes is not as high as in patients of group 1 after the DLHUL test. Conclusions: The test with double local hypoxia of the upper limb is effective as a trigger factor to determine the compensatory capabilities of the HS. Depending on the type of reaction of the platelet-vascular, coagulation components of hemostasis and fibrinolysis to the influence of the trigger, two types of reaction of the blood aggregate state regulation system are possible in people who do not have an anamnesis of factors provoking a hypercoagulable state: compensated and subcompensated. Therefore, when planning surgical intervention in this cohort of patients, the risk of thrombotic complications is low. Depending on the type of reaction of the platelet-vascular, coagulation components of hemostasis and fibrinolysis to the influence of the trigger, two types of reaction of the blood aggregate state regulation system are possible in people with an anamnesis of factors provoking a hypercoagulable state: decompensated (more often) and depleted (less often). Patients with a history of factors provoking a hypercoagulable state have a high risk of perioperative thrombotic complications and a possible risk of thrombo-hemorrhagic complications, including the syndrome of disseminated intravascular coagulation. Changes in all links of the hemostasis system in response to the DLHUL test indicate the need to use anticoagulant therapy in patients with an anamnesis of factors provoking a hypercoagulable state as one of the components of preoperative preparation.
Thromboembolism is a major cause of preventable morbidity and mortality. Hospital acquired thrombosis (HAT) accounts for 50–60% of all thromboembolic events. As well as effects on patient safety, there are considerable cost implications to both prophylaxis and treatment. While guidance exists on thromboprophylaxis for patients in obstetrics and those undergoing general surgery, there is paucity of guidance relating to gynaecological practice. Increasing prevalence of risk factors and multimorbidity is paralleled by higher risk of thromboembolic events. Gynaecological surgery presents some unique risk factors for thrombosis. To understand the basic pathophysiology of thrombosis in relation to risk factors particularly relevant to gynaecology and pelvic surgery To know the current evidence in key areas relevant to gynaecological practice: early pregnancy; day case surgery; minimally invasive gynaecological surgery; open and complex benign gynaecology and gynaecological oncology To be aware of proposed guidance on risk assessment and prophylaxis in thrombosis as relevant to the gynaecologist based on current evidence Problems with thromboprophylaxis in high‐risk patients include noncompliance and refusing animal products/injections. Clinicians may be reluctant to institute thromboprophylaxis, most times because of the possible risks of bleeding.
Numerous systemic infections may have hypercoagulation as one of the complications, which may range from asymptomatic presentation of elevation of biochemical markers of coagulation such as that of fibrin and thrombin generation, to a much severe, symptomatic, life-threatening, disseminated intravascular coagulation (DIC), which results in the formation of thrombi in the microvasculature of various organs. This phenomenon contributes to increase in morbidity and mortality in various infectious diseases. The current review discusses various mechanisms of hypercoagulation during infections such as tissue factor activation, endothelial cell activation, inhibition of physiological anticoagulant pathways, and fibrinolysis inhibition. The review also discusses pathophysiological changes in the coagulation system and its management in the recent pandemic of COVID-19. The article also discusses role of various parenteral and oral anticoagulants in the management of infectious diseases. The review provides clinical data on various anticoagulants used during hospitalization and extended prophylaxis for the management of venous thromboembolism in various infections.
Methodology Because this is a review of published literature and no humans or animals were involved, ethical committee approval was not required and patient consent was not required.
This review critically evaluates the benefit/risk ratio of some strategies for venous thromboembolism (VTE) prophylaxis. The physiopathology of VTE, the risk for thrombosis, and the risk for bleeding are addressed. Then the different methods for mechanical and pharmacologic prevention are described. A growing body of evidence shows that graduated elastic stockings are not effective in medical patients, as opposed to intermittent pneumatic compression. Conventional treatments with Vitamin K antagonists, unfractionated and low-molecular-weight heparins, and fondaparinux are detailed. The properties and the management of the direct oral anticoagulants are also explained. The comeback of aspirin is also addressed.
Update
This article was updated on June 17, 2022, because of a previous error. In the note on page 231, the name “Armin Arish” now reads “Armin Arshi.”
An erratum has been published: J Bone Joint Surg Am. 2022 Aug 3;104(15):e70.
Update
This article was updated on June 17, 2022 because of a previous error. On page 33, in the section entitled “17 - Does administration of tranexamic acid (TXA) to patients undergoing orthopaedic procedures increase the risk of subsequent VTE?”, and in the note on page 161, the name “Armin Arish” now reads “Armin Arshi.”
An erratum has been published: J Bone Joint Surg Am. 2022 Aug 3;104(15):e69.
Objective
Obesity is a risk factor for developing venous thromboembolism (VTE). Optimal dosage of enoxaparin has not been established in the obese population. We aimed to study clinical outcomes and complications with enoxaparin in obese patients.
Methods
A retrospective, single centre observational study of obese patients treated with enoxaparin for VTE (n = 47) using a body mass index (BMI)-stratified dosing, thromboprophylaxis (n = 46), and non-obese controls (n = 20) was performed. Anti-Xa was used to measure enoxaparin efficacy.
Results
Patients with a median BMI of 36.3 kg/m² (range 30–52.7) with a median weight of 136 kg (range 68–240) received therapeutic enoxaparin at median 120 mg BID (range 60–200). A median targeted anti-Xa level of 0.79 (95% CI 0.72–1.03) IU/mL was achieved in 58% of patients. Dose reduction, or increase was needed in 25%, and 16% patients respectively. Mild or major haemorrhage, or VTE occurred in 10%, 2% and 2% patients respectively.
Patients with a median weight of 160 kg (range 130–245) received thromboprophylaxis with 40 mg BID enoxaparin. Targeted median anti-Xa of 0.22 IU/mL (95% CI 0.19–0.24) was achieved in 59% patients. Mild haemorrhage was seen in 2%, while none developed major haemorrhage or VTE.
Control patients who received enoxaparin 40 mg daily did not develop VTE; 5% had minor bleeding events.
Conclusions
BMI-stratified therapeutic enoxaparin dosing regimen is safe and effective therapy in obese patients. Fixed dosing without monitoring may not be appropriate. Thromboprophylaxis with 40 mg BID in obese patients was efficacious in preventing VTE without excess bleeding compared to control patients.
Resumen
A pesar de una política sistematizada de prevención primaria y secundaria de la enfermedad tromboembólica venosa, basada en la eficacia de los tratamientos anticoagulantes, la incidencia anual de la embolia pulmonar se estima entre 75-269 casos por cada 100.000 habitantes, y esta tasa se eleva a más de 700 por cada 100.000 habitantes después de los 70 años. La interrupción de la vena cava inferior es una importante técnica de prevención que debe ofrecerse a los pacientes con contraindicaciones o fracaso del tratamiento anticoagulante, pero conlleva un riesgo significativo de trombosis venosa profunda secundaria. Por eso, los grandes avances en la tecnología de los filtros de cava (FC) permanentes, pero también opcionales o convertibles, y en sus técnicas de implantación bajo eco-Doppler o ecografía endovascular, a veces efectuadas en reanimación, han generado una amplia literatura anglosajona, aunque con pocos estudios aleatorizados. Este artículo describe las técnicas de colocación de FC permanentes y opcionales, sus respectivas indicaciones, en particular las relativas (cáncer, politraumatismo, cirugía bariátrica, mujeres embarazadas) y sus resultados.
Background/aim:
Endoscopic sphincterotomy is considered high risk for post-procedure bleeding. Sphincterotomy in patients on therapeutic anticoagulation is avoided given increased bleeding risk. There is minimal data on the risk of post-sphincterotomy bleeding (PSB) among those on prophylactic anticoagulation for venous thromboembolism (VTE) prophylaxis.
Methods:
We performed a retrospective case control study of all inpatient endoscopic retrograde cholangiopancreatographies (ERCPs) with a sphincterotomy at our institution between July 2016 to February 2020. Cases were divided into two groups based on administration of peri‑procedural pharmacologic VTE prophylaxis. The outcomes were the rates of PSB and VTE within 30-days of the ERCP.
Results:
A total of 369 inpatient ERCPs with a sphincterotomy were identified. 151 cases received peri‑procedural pharmacologic VTE prophylaxis and 218 did not. The mean Padua score and American Society of Anesthesiologists physical status classification were significantly greater in the prophylaxis group. PSB was statistically similar between both groups (3.3% vs. 5.5%, p=.32). VTE was statistically similar (0.7% vs. 0.5%, p=.79). Multivariate analysis did not reveal an association between PSB and peri‑procedural pharmacologic VTE prophylaxis.
Conclusion:
Peri-procedural pharmacologic VTE prophylaxis is not associated with increased rates of PSB. These findings suggest that pharmacologic VTE prophylaxis can be safely continued in those undergoing an endoscopic sphincterotomy.
Heparin-induced thrombocytopenia (HIT) is caused by IgG antibodies that recognize platelet factor 4 (PF4) bound to heparin or certain other polyanions. Although many heparin-exposed patients form nonpathogenic anti-PF4/heparin antibodies, pathologic antibodies capable of triggering HIT activate platelets via their FcγIIa receptors. HIT is strongly associated with thrombosis, both venous and arterial. Approximately 5% of patients develop limb ischemic necrosis due to arterial thrombosis or even venous limb gangrene. HIT usually causes moderate thrombocytopenia: the median platelet count nadir is 60×109/L, and only 5% of patients have a platelet count <15×109/L. Bleeding is uncommon; indeed, adrenal hemorrhage complicating HIT is caused by adrenal vein thrombosis (with secondary hemorrhage). HIT has characteristic timing: the platelet count usually begins to fall 5 to 10 days after an immunizing heparin exposure (typical-onset HIT); however, an abrupt platelet count fall can occur (rapid-onset HIT) when heparin is restarted in a patient who already has circulating HIT antibodies. “Autoimmune HIT” is explained by antibodies that activate platelets in both heparin-dependent and heparin-independent fashion; associated syndromes include delayed-onset HIT (thrombocytopenia that begins or worsens after stopping heparin) and spontaneous HIT syndrome (clinical/serological picture of HIT without proximate heparin exposure). HIT presents numerous treatment paradoxes, including high risk of microthrombosis/limb gangrene with warfarin treatment (hence, vitamin K antagonism is contraindicated during acute thrombocytopenia) and frequent failure of PTT-adjusted anticoagulant therapy of severe HIT complicated by disseminated intravascular coagulation (“PTT confounding”). The author advocates treating HIT with non–PTT-adjusted therapies such as fondaparinux and even direct oral anticoagulants (e.g., rivaroxaban).
Purpose
One of the most common adverse events after orthopaedic surgery, with a potential for subsequent serious morbidity and mortality is venous thromboembolism (VTE). Bibliometric analysis has been performed regarding many topics and across orthopaedics. As DVT prophylaxis is a major component of both orthopaedic surgery considerations and research, a bibliometric analysis in this area would prove beneficial in not only in understanding the research done in the field thus far, but would also direct future research efforts.
Methods
The Web of Science (WoS) database from the Institute of Scientific Information (ISI) was used to compile articles for bibliometric analysis using Boolean search: ((Orthopaedic∗ OR Orthopaedic∗) AND (thromboprophylaxis OR Thromboembolism OR Deep vein thrombosis OR thrombus OR embolism OR anticoagulation OR Embolus OR prophylaxis)).
Results
The Top 100 cited articles included in the final list generated a total of 21,099 citations. The highest cited article was Prevention of venous thromboembolism by Geerts et al. published in Chest, which had a total of 2802 on WoS, and a calculated citation density of 215.54 of citations/years since publication. Comparing the overall citation against the year of publication there was a slight positive trend favoring more recent publications (R-value: 0.142; adjusted R-squared: 0.01; p = 0.16). Analysis of an articles Level of Evidence (LOE), 17 were grade with a level of I.
Conclusions
Orthopaedic thromboprophylaxis is an ever-changing field that is at the forefront of orthopaedic literature. The significant trend favoring high quality research within orthopaedic thromboprophylaxis demonstrates the importance of this topic and there was a need for a guide to best understand the evolution of DVT prophylaxis.
Fizyolojik yaşlanmanın biyolojik kayıplar ve atipik hastalık süreçleri adına yarattığı kimi riskler mevcuttur. Bu risklerin yönetilebilmesi adına cerrahi müdahaleler gerekebilmektedir. Geriatrik cerrahide hedefler kişinin sağlıklı ömür uzunluğunu, hayatta kalma süresini ve yaşam kalitesini olabildiğince uzatmaktır. Geriatrik cerrahi öncesinde, sırasında ve sonrasında diğer yaş gruplarında alınan önlemlere ek olarak planlanması gereken tedbirler ve düzenlemelerin güncel yaklaşımlar ve bilimsel kılavuzlar ışığında incelenmesi gerekmektedir.
Anesthesia and surgery have a significant effect on hematological parameters, including hemoglobin, hematocrit, coagulation factors, natural anticoagulants, fibrinolytic system etc. that may vary from person to person, mostly due to their unique genetic profile. Anesthesia drugs differ in their metabolism and efficacy, based on the person’s profile, which indicates the importance of pharmacogenetic/pharmacogenomic. Pharmacogenomic, the cornerstone of personalized medicine, can make clearer the physician’s comprehension of the individual’s response to treatment based on his or her genome profile. With detailed hematological parameters and new genome sequencing technologies such as next-generation sequencing (NGS) or high-throughput sequencing, appropriate anesthetic technique and anesthetic agents for the patient can be chosen for safe, less eventful anesthesia and surgery. Since thrombotic and hemorrhagic disorders are potentially serious perioperative complications, with the development of diagnostic tools and our knowledge, preoperative genetic analysis can be useful in predicting the risks, and optimizing the patient’s management. Genetic research and cutting-edge technologies are progressing at a rapid pace, leading to safer, and more particular, personalized anesthesia.
Heparin is a naturally occurring glycosaminoglycan from livestock, principally porcine intestine, and is clinically used as an anticoagulant drug. A limitation to heparin production is that it depends on a single animal species and potential problems have been associated with animal-derived heparin. The contamination crisis in 2008 led to a search for new animal sources and the investigation of non-animal sources of heparin. Over the past 5 years, new animal sources, chemical, and chemoenzymatic methods have been introduced to prepare heparin-based drugs. In this review, we describe advances in the preparation and synthesis of heparin and related products.
Riassunto
Nonostante una politica sistematizzata di prevenzione primaria e secondaria della malattia venosa tromboembolica, basata sull’efficacia dei trattamenti anticoagulanti, l’incidenza annuale dell’embolia polmonare è stimata tra 75 e 269 casi all’anno per 100 000 abitanti, e questo tasso sale a oltre 700 per 100 000 abitanti dopo i 70 anni. L’interruzione della vena cava inferiore è un’importante tecnica di prevenzione, che deve essere offerta ai pazienti con controindicazione o fallimento della terapia anticoagulante, ma comporta un rischio significativo di trombosi venosa profonda secondaria. Di conseguenza, progressi significativi realizzati nella tecnologia dei filtri cavali (FC) permanenti, ma anche opzionali o convertibili, e nelle loro tecniche di impianto sotto eco-Doppler o ecografia endovascolare, a volte realizzata in rianimazione, hanno generato un ampio corpus di letteratura anglosassone, con, tuttavia, pochi studi randomizzati. Questo articolo descrive le tecniche per l’installazione dei FC permanenti e opzionali, le loro rispettive indicazioni, in particolare le indicazioni relative (pazienti oncologici, politraumatizzati, chirurgia bariatrica, donne in gravidanza) e i loro risultati.
Background
Direct oral anticoagulants (DOACs) have promised superior efficacy to low molecular weight heparins (LMWHs) in the prevention of venous thromboembolism (VTE) in total hip and knee arthroplasty (THR and TKR). However, there are concerns about raised associated bleeding and wound problems with these agents. This study aims to evaluate and compare the efficacy and safety of the three DOAC drugs; rivaroxaban, dabigatran and apixaban.
Methods
The primary outcome measures were rate of symptomatic VTE and major bleeding. Secondary outcome measures were wound healing problems and requirement for return to theatre. A total of 2431 patients received one of the DOAC drugs as thromboprophylaxis following THA (35 days) or TKA (14 days) between 2011 and 2015. Binary variables were compared between the three groups by using the chi-square test or Fisher’s exact test. Relative risks of selected primary and secondary end points were also calculated for the pre-specified pairwise comparison.
Results
The overall symptomatic VTE rate was 2%. Rivaroxaban had a statistically significant superior efficacy for overall VTE prevention (0.8% vs 2.6%) compared with dabigatran (p<0.01) and apixaban (p<0.01), and deep vein thrombosis prevention (0.3% vs 2.2%) over dabigatran (p<0.01). The overall rate of major bleeding was 1.2% with no significant difference observed between the three studied drugs.
Conclusion
All three drugs had symptomatic VTE rates comparable with LMWH from the published literature. Rivaroxaban appears to have superior efficacy in VTE prevention over apixaban and dabigatran. No statistical difference was observed for major bleeding with any of the three agents.
The perioperative management of patients on long term OAT is an open issue. The problem is the prevention of both the thromboembolic (TE) and the hemorrhagic complications. The therapeutic options are: 1) discontinuation of OAT with an INR target <2.0 at the scheduled time and its resumption after surgery, 2) substitution of OAT with low molecular weight heparin (LMWH) in the perioperative period. We report on 477 consecutive patients who underwent elective surgery in 7 FCSA centers (November 2001 to August 2003). Major and minor surgery and other minor procedures were carried out in 68, 206 and 203 patients respectively; median age 72 years (25–97); 279 males, 198 females. The aim of the study was to evaluate the complications occurring during and within 2 months after surgery with the different modalities of prophylaxis. Indications for OAT./bold]Low and intermediate TE risk patients:secondary prophylaxis of venous thrombosis (VT) 75; non valvular atrial fibrillation (AF) 225; aortic mechanical or biological valves 58, dilatative myocardiopathy 8, valvulopathy 10; myocardial infarction 3; coronary artery by-pass graft 4; stroke 4.High TE risk patients: mitral mechanical valve, mechanical valves + AF or previous TE 53, AF + ≥2 other risk factors (arterial hypertension, dilatative myocardiopathy, previous TE, biological heart valve) 6; intracardiac thrombosis 1.
Results: LMWH therapy: Nadroparin (Seleparina®) and enoxaparin (Clexane®) in 394 and 28 patients respectively. Comments . One patients with high thromboembolic risk died because of sudden cardiac arrest 13 days after a procedure. TE events (0.6%) occurred in 2 patients with mechanical aortic valve and valvulopathy respectively and treated with s.i.d dose. Incidence of major bleeding is higher in patients treated with LMWH b.i.d but it is in accordance with the data reported in the literature.
Table I
Therapy no OAT LMWH (s.i.d.) LMWH (b.i.d.) s.i.d.=single in die; b.i.d.= bis in die Dose (U/kg) 60.6 (±12.8) 65.9 (±17.4) Patients-number 55 329 93 Complications TE n (%) 0 2 (0.6) 0 arterial 0 2 (0.6) 0 venous 0 0 0 Bleeding n (%) 0 9 (2.7) 7 (7.5) major 0 4 (1.2) 3 (3.2) minor 0 5 (1.5) 4 (4.3)
The synthetic antithrombin-binding heparin pentasaccharide and a full-length heparin of approximately 26 saccharides containing this specific sequence have been compared with respect to their interactions with antithrombin and their ability to promote inhibition and substrate reactions of antithrombin with thrombin and factor Xa. The aim of these studies was to elucidate the pentasaccharide contribution to heparin's accelerating effect on antithrombin-proteinase reactions. Pentasaccharide and full-length heparins bound antithrombin with comparable high affinities (KD values of 36 +/- 11 and 10 +/- 3 nM, respectively, at I 0.15) and induced highly similar protein fluorescence, ultraviolet and circular dichroism changes in the inhibitor. Stopped-flow fluorescence kinetic studies of the heparin binding interactions at I 0.15 were consistent with a two-step binding process for both heparins, involving an initial weak encounter complex interaction formed with similar affinities (KD 20-30 microM), followed by an inhibitor conformational change with indistinguishable forward rate constants of 520-700 s-1 but dissimilar reverse rate constants of approximately 1 s-1 for the pentasaccharide and approximately 0.2 s-1 for the full-length heparin. Second order rate constants for antithrombin reactions with thrombin and factor Xa were maximally enhanced by the pentasaccharide only 1.7-fold for thrombin, but a substantial 270-fold for factor Xa, in an ionic strength-independent manner at saturating oligosaccharide. In contrast, the full-length heparin produced large ionic strength-dependent enhancements in second order rate constants for both antithrombin reactions of 4,300-fold for thrombin and 580-fold for factor Xa at I 0.15. These enhancements were resolvable into a nonionic component ascribable to the pentasaccharide and an ionic component responsible for the additional rate increase of the larger heparin. Stoichiometric titrations of thrombin and factor Xa inactivation by antithrombin, as well as sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the products of these reactions, indicated that pentasaccharide and full-length heparins similarly promoted the formation of proteolytically modified inhibitor during the inactivation of factor Xa by antithrombin, whereas only the full-length heparin was effective in promoting this substrate reaction of antithrombin during the reaction with thrombin.(ABSTRACT TRUNCATED AT 400 WORDS)
Despite thromboprophylaxis, major knee surgery carries a high risk of venous thromboembolism. Fondaparinux, the first of a new class of synthetic antithrombotic agents, may reduce this risk.
In a double-blind study, we randomly assigned 1049 consecutive patients undergoing elective major knee surgery to receive subcutaneous doses of either 2.5 mg of fondaparinux once daily or 30 mg of enoxaparin twice daily, with both treatments initiated postoperatively. The primary efficacy outcome was venous thromboembolism up to postoperative day 11, defined as deep-vein thrombosis detected by mandatory bilateral venography, documented symptomatic deep-vein thrombosis, or documented symptomatic pulmonary embolism. The primary safety outcome was major bleeding.
The primary efficacy outcome was assessed in 724 patients. The fondaparinux group had a significantly lower incidence of venous thromboembolism by day 11 (12.5 percent [45 of 361 patients]) than the enoxaparin group (27.8 percent [101 of 363 patients]; reduction in risk, 55.2 percent; 95 percent confidence interval, 36.2 to 70.2; P<0.001). Major bleeding (including overt bleeding with a bleeding index of 2 or more) occurred more frequently in the fondaparinux group (P=0.006), but there were no significant differences between the two groups in the incidence of bleeding leading to death or reoperation or occurring in a critical organ.
In patients undergoing elective major knee surgery, postoperative treatment with 2.5 mg of fondaparinux once daily was significantly more effective in preventing deep-vein thrombosis than 30 mg of enoxaparin twice daily.
Heparin, a sulfated glycosaminoglycan, is well known for its anticoagulant effect mediated by the serine protease inhibitor antithrombin III (AT III). Heparin has been used clinically for more than half a century for the prophylaxis and treatment of venous thrombosis and thromboembolism. Up until the 1980s it was assumed that the biological activity of heparin was mainly caused by its polyanionic character. However, this paradigm was contradicted when it was discovered that part of the heparin polysaccharides contains a well-defined pentasaccharide domain that specifically binds and activates AT III. The specificity of the interaction between the characteristic pentasaccharide and AT III has become more obvious after the synthesis and biological testing of various heparin analogues. This article reviews the synthesis of the heparin pentasaccharide, some closely related counterparts, and some highly modified analogues. With the aid of molecular modeling and through “tailored” molecular modifications of the pentasaccharide, much knowledge has been gained concerning structure-activity relationships. On this basis not only have more potent and simplified derivatives been developed, but also the recognition between heparin and AT III can now be understood in greater detail at the molecular level.
To review noninvasive methods for diagnosis of first and recurrent deep venous thrombosis and provide evidence-based recommendations for the diagnosis of deep venous thrombosis in symptomatic, asymptomatic, and pregnant patients.
Accuracy (comparison with contrast venography) and management (safety of withholding anticoagulants when results were normal) studies that evaluated tests for diagnosis of deep venous thrombosis were identified from a MEDLINE search, personal files, and bibliographies of reviews and original studies.
Prospective cohort studies (accuracy and management studies) and randomized comparisons (management studies) that satisfied predefined methodologic criteria were included.
Sensitivity, specificity, and positive and negative predictive values were determined for accuracy studies. Rates of venous thromboembolism during long-term follow-up of patients with normal results were determined for management studies.
Data from individual studies were combined under a random-effects model. The accuracy of noninvasive tests was compared, with emphasis on within-study comparisons. Recommendations for diagnosis of deep venous thrombosis were developed by a multidisciplinary group and graded according to the strength of the supporting evidence. Venous ultrasonography is the most accurate noninvasive test for the diagnosis of a first symptomatic proximal deep venous thrombosis. However, neither ultrasonography nor impedance plethysmography is accurate in asymptomatic postoperative patients. Venous ultrasonography is less accurate for symptomatic isolated distal (calf) deep venous thrombosis than for proximal deep venous thrombosis, and the clinical utility of venous ultrasonography of the distal veins is uncertain. Withholding anticoagulant therapy in symptomatic patients with suspected deep venous thrombosis who have normal results on serial venous ultrasonography or impedance plethysmography is safe. Diagnosis of recurrent deep venous thrombosis requires evidence of new thrombus formation, such as a new noncompressible venous segment detected by venous ultrasonography, conversion of a normal result on impedance plethysmography to abnormal, or presence of an intraluminal filling defect on venography. Suspected deep venous thrombosis in pregnant patients can usually be managed with serial venous ultrasonography or impedance plethysmography. In symptomatic patients with a suspected first episode of deep venous thrombosis, clinical assessment and D-dimer testing are complementary to testing with venous ultrasonography and impedance plethysmography.
Patients with suspected deep venous thrombosis can usually be managed with noninvasive testing. However, if the results of this testing are nondiagnostic or are discordant with the clinical assessment, venography should be considered.
Low-molecular-weight heparins (LMWHs) have theoretical advantages over standard heparin as postoperative thromboprophylactic agents. We conducted a meta-analysis of studies reported between 1984 and April, 1991, in which LMWHs were compared with standard heparin for postoperative prophylaxis. We included only randomised studies (reported in English, French, or German) in which investigators compared currently recommended doses of the agents and used adequate screening techniques for deep vein thrombosis. For all surgical studies the relative risk (LMWH versus standard heparin) for deep vein thrombosis was 0.74 (95% Cl 0.65-0.86), for pulmonary embolism 0.43 (95% Cl 0.26-0.72), and for major bleeding 0.98 (95% Cl 0.69-1.40). Comparable relative risks were observed for the general and orthopaedic surgery studies separately. When the analysis for the general surgery studies was limited to those of strong methodology, assessed by eight criteria defined in advance, the benefit/risk ratio was less favourable--relative risk for deep vein thrombosis 0.91 (95% Cl 0.68-1.23), for major bleeding 1.32 (95% Cl 0.69-2.56). There is at present no convincing evidence that in general surgery patients LMWHs, compared with standard heparin, generate a clinically important improvement in the benefit to risk ratio. However, LMWHs may be preferable for orthopaedic surgery patients, in view of the larger absolute risk reduction for venous thrombosis.
Several clinical studies have evaluated the efficacy and safety of LMWH in the prevention of postoperative thromboembolic complications. We subjected 42 studies to a statistical meta-analysis in order to evaluate the efficacy of different prophylactic regimens compared with LMWH prophylaxis. In general surgery LMWH was more effective than LDH three times daily and placebo, but comparable with LDH twice daily. In elective hip surgery, thromboprophylaxis with LMWH was more effective than placebo, LDH, and dextran 70, but comparable with LDH in combination with dihydroergotamine. In patients undergoing surgery for hip fractures LMWH was more effective than placebo, but the studies comparing LMWH with LDH were too small to show any clinically relevant difference, although there was a trend toward a better efficacy of LMWH. This study demonstrated that LMWH is clinically effective and safe to use in the prevention of thromboembolic complications after general and orthopedic surgery.
In a prospective, randomized, double-blind study, the efficacy and safety of a low-molecular-weight heparin were compared with those of unfractionated sodium heparin (standard heparin) in 136 patients who had elective total hip replacement. The patients received subcutaneous injection of either 5000 international units of low-molecular-weight heparin once daily or 5000 international units of standard heparin three times a day. Treatment with low-molecular-weight heparin began twelve hours before the operation, and treatment with standard heparin began two hours preoperatively; both regimens were continued for ten days. Twelve days postoperatively, bilateral ascending phlebography was performed in 122 patients, sixty-three in the treatment group that received low-molecular-weight heparin and fifty-nine in the treatment group that received standard heparin. Pulmonary scintigraphy was performed in 127 patients. Deep-vein thrombosis was diagnosed in forty-four patients: nineteen (30 per cent) of the sixty-three who received low-molecular-weight heparin and twenty-five (42 per cent) of the fifty-nine who received standard heparin. All but four patients, two from each treatment group, were asymptomatic. The difference in the total rate of thrombosis in the two groups was not significant (p = 0.189). However, thrombosis occurred in the thigh in only six (10 per cent) of the patients who received low-molecular-weight heparin but in eighteen (31 per cent) of those who received standard heparin, a significant difference (p = 0.011). Pulmonary embolism was detected in twenty-seven patients: eight (12.3 per cent) of those who received low-molecular-weight heparin and nineteen (30.6 per cent) of those who received standard heparin. Only three patients had clinical signs of embolism. Pulmonary embolism was significantly more frequent in the group that received standard heparin (p = 0.016). Total loss of blood and the total amount of blood that was transfused were significantly reduced in the patients who received low-molecular-weight heparin compared with those who received standard heparin. Prophylaxis was not discontinued because of hemorrhage in any patient. The efficacy of low-molecular-weight heparin was superior to that of standard heparin in the prevention of femoral thrombosis and pulmonary embolism, although the over-all incidence of deep-vein thrombosis was not statistically different.(ABSTRACT TRUNCATED AT 400 WORDS)
Sanofi, Elf Aquitaine's pharmaceutical subsidiary is a world leader in antithrombotic drugs. This article traces the development of Heparin-based antithrombotic drugs and describes the company's progress in producing synthetic substitutes.
A chemically synthesized heparin pentasaccharide (Institut Choay, Paris, France) has been shown to exhibit an antithrombotic action in a rabbit stasis induced thrombosis model, in an IV dose range of 25 to 200 micrograms/kg (0.5 to 3.5 micrograms/ml plasma circulating concentrations). Ex vivo plasma analysis from treated animals revealed expected anti-factor Xa activity but no direct inhibitory effect against thrombin. Global anticoagulant activities were not found by PT and APTT methods. Platelet activation remained unaffected at the antithrombotic dosages of pentasaccharide. To more specifically elucidate the anti-factor Xa mediated antithrombotic mechanism of action of this pentasaccharide, it was studied in several thrombin generation assays. Pentasaccharide added to human and rabbit plasmas in vitro from 0 to 5.0 micrograms/ml produced a concentration dependent effect up to a 35 to 50% inhibition of generated thrombin. In ex vivo studies similar concentration dependent inhibition of thrombin generation was observed. Analysis of plasma obtained from animals in which a complete antithrombotic effect was observed in vivo demonstrated an approximate 45 to 55% inhibition of thrombin generation. These results indicate that a relationship exists between the pentasaccharide induced inhibition of experimental venous stasis thrombosis and the inhibition of thrombin generation.
In technique for lower extremity phlebography the patient is in a semi-upright position, supporting his weight on the contralateral foot. The dye injection is made into a dorsal pedal vein and no tourniquet is used. Fluoroscopy is used to maximize efficiency of the filming. More than 300 phlebograms have been made with this method. The four cardinal signs of phlebothrombosis are constant filling defects, abrupt termination of the dye column, nonfilling of the entire deep venous system or portions thereof, and diversion of flow. Pitfalls in interpretation occur when artifacts are created by bearing weight on the leg under study, by tourniquets, by an improper injection site, or by incomplete mixing of the contrast material as it flows through the veins.
Sixty-eight patients clinically suspected of having (33), or at high risk for (35), deep venous thrombosis were studied with contrast venography, radiofibrinogen leg scanning, and impedance plethysmography as well as ventilation and perfusion lung scans. Thrombosis limited to the veins in the calf of the leg (unilateral or bilateral) was shown by venography in 12 patients. None of these patients had clinical symptoms or scan results indicating embolism. Fifteen patients had thrombosis involving proximal (thigh) as well as distal (calf) veins by venography. Eight had scan evidence of embolism, although only one was symptomatic. The combination of radiofibrinogen and impedance tests allows accurate detection of both the presence and location of deep venous thrombosis. The availability of sensitive and specific, noninvasive methods for detecting and localizing venous thrombosis, as well as the apparently low embolic risk of calf-only thrombosis may condition future approaches to prophylaxis and treatment of patients with or at high risk for deep venous thrombosis.
While several methods of prophylaxis have been shown to reduce the risk of venous thromboembolism following total hip replacement, the safest and most effective agent is unclear. To clarify this issue, we performed a meta-analysis of the randomized trials of methods used to prevent venous thromboembolism following total hip replacement.
English-language human studies articles from 1966 through 1993 were obtained from a MEDLINE database search with indexing terms including thromboembolism, hip replacement or hip prosthesis, and randomized controlled trials. Additional references were obtained from study bibliographies.
The following criteria were used to select studies for inclusion: study design--randomized clinical trial; study population--patients undergoing elective total hip replacement; interventions--aspirin, warfarin, dextran, heparin, low-molecular-weight heparin, compression stockings; and outcomes--venous thromboembolism, major hemorrhage.
Methodological and descriptive data from each study were abstracted by one author who was blinded to quantitative outcomes data.
Ninety-one treatment groups and 25 control groups were identified from 56 trials. Four treatment groups were excluded because of rarely used combinations. Trial populations were clinically homogeneous. When compared with the control arm, all treatments except aspirin reduced the risk of all deep venous thromboses (risk differences range, 0.18 to 0.31; all P values < .05). All treatments except aspirin reduced the risk of proximal venous thrombosis (risk differences range, 0.09 to 0.18; all P values < .05). Only low-molecular-weight heparin and stockings reduced the risk of pulmonary embolism, both with risk differences equal to 0.02. The crude risks of clinically important bleeding as defined by the individual trials were 0% for stockings, 0.3% for controls, and 1.8% for low-molecular-weight heparin.
The results suggest that low-molecular-weight heparin and compression stockings have the greatest relative efficacy in preventing venous thromboembolism following total hip replacement. Low-molecular-weight heparin may be more effective, though at a small risk of clinically important bleeding.
To evaluate the thromboprophylactic use of low molecular weight heparins (LMWHs), publications from 27 orthopaedic trials and 35 studies of patients undergoing general or gynaecological surgery were scrutinized and subjected to a partial meta-analysis. In orthopaedic surgery, LMWHs were superior to placebo or dextran and at least as efficient as unfractionated heparin in the prevention of deep vein thrombosis (DVT). Compared with unfractionated heparin, one of the LMWH preparations significantly reduced the total incidence of DVT. The rate of non-fatal pulmonary embolism was 0.49 per cent in patients receiving LMWH and 1.22 per cent in controls. Seven orthopaedic patients (0.15 per cent) died from pulmonary embolism, none of whom received LMWH. In general surgery, the LMWHs were at least as efficient as unfractionated heparin, with a trend towards a lower risk of pulmonary embolism with the former. Compared with unfractionated heparin, LMWHs did not reduce the postoperative mortality rate, nor did they cause haemorrhage. LMWHs provide safe and efficient prophylaxis by administration once daily.
The frequency of thromboembolism after major orthopaedic surgery continues to be high despite prophylaxis. New agents such as CGP 39393, a recombinant form of hirudin, may be more effective than existing therapies.
In this double-blind, multicentre, European study the efficacy of three doses of CGP 39393, in comparison with unfractionated heparin, were examined in 1119 patients undergoing elective hip surgery. Patients were randomly allocated to receive by subcutaneous injection either 10, 15, or 20 mg of CGP 39393 twice daily or 5000 IU of heparin three times daily. All treatments were started just before surgery and continued for 8-11 days, until bilateral venography was performed.
The occurrence of thromboembolism was significantly reduced in patients treated with CGP 39393 compared to heparin. The frequency of deep-vein thrombosis was 34.2% in the heparin group as compared to 23.9% (p=0.0113), 18.4% (p=0.0003), and 17.7% (p=0.0001) in the 10 mg, 15 mg, and 20 mg CGP 39393 groups, respectively. At all dose levels, CGP 39393 was more effective than heparin in preventing proximal deep-vein thrombosis. The frequency of proximal thrombosis was 19.6% in the heparin group as compared to 8.5% (p<0.001), 3.1% (p<0.001), and 2.4% (p<0.001) in the 10 mg, 15 mg, and 20 mg CGP 39393 groups, respectively. All treatments were well tolerated.
This study indicates that specific inhibition of thrombin by prophylactic CGP 39393 significantly reduces thromboembolic complications in patients undergoing total hip replacement.
To compare the effectiveness and safety of fixed-dose enoxaparin and adjusted dose warfarin in preventing venous thromboembolism after knee arthroplasty.
A randomized, double-blind controlled trial.
8 university hospitals.
670 consecutive patients who had knee arthroplasty.
Patients were randomly assigned to receive enoxaparin (30 mg subcutaneously every 12 hours) or adjusted-dose warfarin (international normalized ratio, 2.0 to 3.0). Both regimens were started after surgery.
The primary end point was the incidence of deep venous thrombosis in patients with adequate bilateral venograms; the secondary end point was hemorrhage.
Among the 417 patients with adequate venograms, 109 of 211 warfarin recipients (51.7%) had deep venous thrombosis compared with 76 of 206 enoxaparin recipients (36.9%) (P = 0.003). The absolute risk difference was 14.8% in favor of enoxaparin (95% Cl, 5.3% to 24.1%) Twenty-two warfarin recipients (10.4%) and 24 enoxaparin recipients (11.7%) had proximal venous thrombosis (P>0.2). The absolute risk difference was 1.2% in favor of warfarin (Cl, -7.2% to 4.8%). The incidence of major bleeding was 1.8% (6 of 334 patients) in the warfarin group and 2.1% (7 of 336 patients) in the enoxaparin group (P>0.2). The absolute risk difference was 0.3% in favor of warfarin (Cl, -2.4% to 1.8%).
A postoperative, fixed-dose enoxaparin regimen is more effective than adjusted-dose warfarin in preventing deep venous thrombosis after knee arthroplasty. No differences were seen in the incidence of proximal venous thrombosis or clinically overt hemorrhage.
Previous meta-analyses comparing low molecular weight heparin (LMWH) and unfractionated heparin for thrombosis prophylaxis after surgical interventions need updating.
This is a publication-based meta-analysis of 36 double-blind studies including 16583 patients. Main outcome measures are incidence of deep vein thrombosis (efficacy) and wound haematoma (safety).
In general surgery there is no increased efficacy in favour of LMWH (odds ratio (OR) 0.88, 95 per cent confidence interval (c.i.) 0.60-1.30) but there exists a higher incidence of bleeding complications (OR 1.47, 95 per cent c.i. 1.07-2.01). Low-dose LMWH is equally efficacious (OR 1.03, 95 per cent c.i. 0.85-1.26) but safer than unfractionated heparin (OR 0.68, 95 per cent c.i. 0.56-0.82). In orthopaedic surgery there is a trend towards an increased efficacy for LMWH (OR 0.83, 95 per cent c.i. 0.68-1.02) with equivalent safety (OR 0.96, 95 per cent c.i. 0.68-1.36).
A superiority of LMWH is suggested but heterogeneity might make generalizability to future patients questionable. A meta-analysis on individual patient data should be the next step before randomizing additional patients in future trials.
Unlabelled:
The efficacy and safety of low molecular weight heparin (LMWH), unfractionated heparin (UFH) and warfarin for prophylaxis of thrombo-embolism in orthopaedic surgery were compared using meta-analysis techniques. Twenty-two studies were included, 2 of which compared LMWH to warfarin. The mean probabilities to develop deep-vein thrombosis (DVT), pulmonary embolism and major and minor bleeding using UFH were: 0.21 (95% confidence interval, CI: 0.18-0.24); 0.01 (95% CI: 0.01-0.02); 0.05 (95% CI: 0.03-0.07), and 0.19 (95% CI: 0.17-0.22), respectively. The relative risk (RR) of DVT for LMWH vs. UFH was 0.76 (95% CI: 0.60-0.91), p < 0.05 and for LMWH vs. warfarin 0.78 (95% CI: 0.69-0.87), p < 0.05. The RR of minor bleeding for LMWH vs. UFH was 0.76 (95% CI: 0.64-0.92), p < 0.05. The RR of minor bleeding for LMWH vs. warfarin was 3.28 (95% CI: 2.21-4.70), p < 0.05.
Conclusion:
in orthopaedic surgery, LMWH is significantly superior to both UFH and warfarin in the prevention of DVT and results in significantly less minor bleeding complications when compared to UFH, but significantly more minor bleeding when compared to warfarin.
Patients who undergo total hip replacement have a high risk of thromboembolic complications. Recombinant hirudin (desirudin), a specific inhibitor of thrombin, represents a new development in antithrombotic therapy. We compared the efficacy and safety of desirudin with those of a low-molecular-weight heparin (enoxaparin) for the prevention of thromboembolic complications in patients undergoing primary total hip replacement.
Both treatments, which were assigned in a randomized, double-blind manner, were started preoperatively: enoxaparin on the evening before surgery, and desirudin within 30 minutes before the start of surgery. The dose of desirudin was 15 mg subcutaneously twice daily, and the dose of enoxaparin was 40 mg subcutaneously once daily. The duration of treatment was 8 to 12 days. Deep-vein thrombosis was verified by bilateral venography performed at the end of the treatment period or earlier, if there were clinical signs of deep-vein thrombosis.
At 31 centers in 10 European countries, 2079 eligible patients were randomly assigned to receive desirudin or enoxaparin. A total of 1587 patients were included in the primary analysis of efficacy. In the desirudin group, as compared with the enoxaparin group, there was a significantly lower rate of proximal deep-vein thrombosis (4.5 vs. 7.5 percent, P=0.01; relative reduction in risk, 40.3 percent) and a lower overall rate of deep-vein thrombosis (18.4 vs. 25.5 percent, P=0.001; relative reduction in risk, 28.0 percent). The safety profiles were similar in the two treatment groups.
When administered 30 minutes before total hip replacement surgery, desirudin is more effective than enoxaparin in preventing deep-vein thrombosis.
To assess the efficacy and safety of low molecular weight heparin (LMWH) as deep venous thrombosis (DVT) prophylaxis following total knee arthroplasty.
Medline 1986 to June 1997, Embase, and manufacturers were used to identify randomized controlled trials.
Trials included were randomized studies of LMWH with routine radiological screening for DVT. Placebo or active controls were included. Two reviewers independently screened trials for inclusion, and assessed their quality. Pooled relative risk estimates of DVT and proximal DVT rates were calculated using a DerSimonian and Laird random effects model. Sensitivity of the results to the type of control used and the quality of the trial was assessed.
The relative risk of DVT for a patient given LMWH is 0.73 (95% CI 0.66 to 0.80) when compared with patients treated with adjusted dose heparin or warfarin controls. The relative risk for proximal DVT is 0.58 (95% CI 0.38 to 0.90). The relative risk of pulmonary emboli in the LMWH group was 0.55 (95% C.I. 0.20 to 1.57). No excess of bleeding was recorded in the LMWH group.
Low molecular weight heparin is more efficacious than either adjusted dose heparin or adjusted dose warfarin, when used to prevent DVT and proximal DVT following total knee arthroplasty.
Numerous considerations and controversies attend the question of which endpoints to use in venous thromboembolism prophylaxis trials. In this paper, a rationale is presented for a new approach that simplifies certain aspects of endpoint detection in deep vein thrombosis and pulmonary embolism trials, and complicates others. The goal of this approach is to use reliably ascertainable endpoints that are clinically relevant and most probably predictive of clinical efficacy, in order to optimally inform the drug development process.
Although several agents have been shown to reduce the risk of thromboembolic disease, there is no clear preference for thromboembolic prophylaxis in elective total hip arthroplasty. The purpose of this study was to define the efficacy and safety of the agents that are currently used for prophylaxis against deep venous thrombosis -- namely, low-molecular-weight heparin, warfarin, aspirin, low-dose heparin, and pneumatic compression.
A Medline search identified all randomized, controlled trials, published from January 1966 to May 1998, that compared the use of one of the prophylactic agents with the use of any other agent or a placebo in patients undergoing elective total hip arthroplasty. For a study to be included in our analysis, bilateral venography had to have been performed to confirm the presence or absence of deep venous thrombosis. Fifty-two studies, in which 10,929 patients had been enrolled, met the inclusion criteria and were included in the analysis. The rates of distal, proximal, and total (distal and proximal) deep venous thrombosis; symptomatic and fatal pulmonary embolism; minor and major wound-bleeding complications; major non-wound bleeding complications; and total mortality were determined for each agent in each study. The absolute risk of each outcome was determined by dividing the number of events by the number of patients at risk. A general linear model with random effects was used to calculate the 95 percent confidence interval of risk. A crosstabs of study by outcome was performed to test homogeneity (ability to combine studies). The risk of each outcome was compared among agents and between each agent and the placebo.
With prophylaxis, the risk of total (proximal and distal) deep venous thrombosis ranged from 17.7 percent (low-molecular-weight heparin) to 31.1 percent (low-dose heparin); the risk with prophylaxis with any agent was significantly lower than the risk with the placebo (48.5 percent) (p < 0.0001). The risk of proximal deep venous thrombosis was lowest with warfarin (6.3 percent) and low-molecular-weight heparin (7.7 percent), and again the risk with any prophylactic agent was significantly lower than the risk with the placebo (25.8 percent) (p < 0.0001). Compared with the risk with the placebo (1.51 percent), only warfarin (0.16 percent), pneumatic compression (0.26 percent), and low-molecular-weight heparin (0.36 percent) were associated with a significantly lower risk of symptomatic pulmonary embolism. There were no significant differences among agents with regard to the risk of fatal pulmonary embolism or of mortality with any cause. The risk of minor wound-bleeding was significantly higher with low-molecular-weight heparin (8.9 percent) and low-dose heparin (7.6 percent) than it was with the placebo (2.2 percent) (p < 0.05). Compared with the risk with the placebo (0.28 percent), only low-dose heparin was associated with a significantly higher risk of major wound-bleeding (2.56 percent) and total major bleeding (3.46 percent) (p < 0.0001).
The best prophylactic agent in terms of both efficacy and safety was warfarin, followed by pneumatic compression, and the least effective and safe was low-dose heparin. Warfarin provided the lowest risk of both proximal deep venous thrombosis and symptomatic pulmonary embolism. However, there were no identifiable significant differences in the rates of fatal pulmonary embolism or death among the agents. Significant risks of minor and major bleeding complications were observed with greater frequency with certain prophylactic agents, particularly low-molecular-weight heparin (minor bleeding) and low-dose heparin (both major and minor bleeding).
Venous thromboembolism is a frequent complication of total hip replacement. The pentasaccharide Org31540/SR90107A, a highly selective, indirect inhibitor of activated factor X, is the first of a new class of synthetic antithrombotic agents. To determine the optimal dose for phase 3 studies, we conducted a dose-ranging study in which Org31540/SR90107A was compared with a low-molecular-weight heparin, enoxaparin, in patients undergoing total hip replacement.
In a double-blind study, patients were randomly assigned to postoperative administration of one of five daily doses of Org31540/SR90107A, given once daily, or to 30 mg of enoxaparin, given every 12 hours. Treatment was continued for 10 days or until bilateral venography was performed after a minimum of 5 days.
Of 933 patients treated, 593 were eligible for the efficacy analysis. With Org31540/SR90107A a dose effect was observed (P=0.002), with rates of venous thromboembolism of 11.8 percent, 6.7 percent, 1.7 percent, 4.4 percent, and 0 percent for the groups assigned to 0.75 mg, 1.5 mg, 3.0 mg, 6.0 mg, and 8.0 mg of the drug, respectively, as compared with a rate of 9.4 percent in the enoxaparin group. The reduction in the risk of venous thromboembolism was 82 percent for the 3.0-mg Org31540/SR90107A group (P=0.01) and 29 percent for the 1.5-mg group (P=0.51). Enrollment in the 6.0-mg and 8.0-mg Org31540/SR90107A groups was discontinued because of bleeding complications. Major bleeding occurred 3.5 percent less frequently in the 0.75-mg group (P=0.01) and 3.0 percent less frequently in the 1.5-mg group (P=0.05) than in the enoxaparin group (in which the rate was similar to that in the 3.0-mg group).
A synthetic pentasaccharide, Org31540/SR90107A, has the potential to improve significantly the risk-benefit ratio for the prevention of venous thromboembolism, as compared with low-molecular-weight heparin.
for the European Pentasaccha-ride Hip Elective Surgery Study (EPHESUS) Steering Committee Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous throm-boembolisminelectivehip-replacementsurgery:arandomiseddouble-blindcom-parison
- Mr Lassen
- Ka Bauer
- Eriksson
- Turpie
Lassen MR, Bauer KA, Eriksson BI, Turpie AG, for the European Pentasaccha-ride Hip Elective Surgery Study (EPHESUS) Steering Committee. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous throm-boembolisminelectivehip-replacementsurgery:arandomiseddouble-blindcom-parison. Lancet. 2002;359:1715-1720
Postoperative fondaparinux versus postoperative enoxa-parinforpreventionofvenousthromboembolismafterelectivehip-replacement surgery: a randomised double-blind trial
- Turpieag
- Bauerka
- Erikssonbi
- Lassenmr
TurpieAG,BauerKA,ErikssonBI,LassenMR,forthePENTATHLON2000Study Steering Committee. Postoperative fondaparinux versus postoperative enoxa-parinforpreventionofvenousthromboembolismafterelectivehip-replacement surgery: a randomised double-blind trial. Lancet. 2002;359:1721-1726
Efficacy and safety of low molecular weight heparin (ardeparin sodium) com-paredtowarfarinforthepreventionofvenousthromboembolismaftertotalknee replacementsurgery:adouble-blind,dose-rangingstudy
- Heitja
- Berkowitzsd
- Bonar
HeitJA,BerkowitzSD,BonaR,etal,fortheArdeparinArthroplastyStudyGroup. Efficacy and safety of low molecular weight heparin (ardeparin sodium) com-paredtowarfarinforthepreventionofvenousthromboembolismaftertotalknee replacementsurgery:adouble-blind,dose-rangingstudy.ThrombHaemost.1997; 77:32-38
The effect of the synthetic pentasaccharide SR90107/ Org31540onthrombingenerationexvivoisuniquelyduetoATIII-mediatedneu-tralization of factor Xa
- Jc Lormeau
- Herault
Lormeau JC, Herault JP. The effect of the synthetic pentasaccharide SR90107/ Org31540onthrombingenerationexvivoisuniquelyduetoATIII-mediatedneu-tralization of factor Xa. Thromb Haemost. 1995;74:1474-1477
for the North American Fragmin Trial Inves-tigators.Low-molecular-weightheparinprophylaxisusingdalteparinincloseprox-imitytosurgeryvswarfarininhiparthroplasty:adouble-blind,randomizedcom-parison
- Rd Hull
- Gf Pineo
- C Francis
Hull RD, Pineo GF, Francis C, et al, for the North American Fragmin Trial Inves-tigators.Low-molecular-weightheparinprophylaxisusingdalteparinincloseprox-imitytosurgeryvswarfarininhiparthroplasty:adouble-blind,randomizedcom-parison. Arch Intern Med. 2000;160:2199-2207
for the Pentasaccharide Investigators. A syn-theticpentasaccharideforthepreventionofdeep-veinthrombosisaftertotalhip replacement
- Ag Turpie
- As Gallus
- Hoek
Turpie AG, Gallus AS, Hoek JA, for the Pentasaccharide Investigators. A syn-theticpentasaccharideforthepreventionofdeep-veinthrombosisaftertotalhip replacement. N Engl J Med. 2001;344:619-625
Lowmolecu-lar weight heparin in prevention of postoperative thrombosis
- Leizorovicza
- Haughmc
- R Chapuisf
- Samamamm
LeizoroviczA,HaughMC,ChapuisF-R,SamamaMM,BoisselJ-P.Lowmolecu-lar weight heparin in prevention of postoperative thrombosis. BMJ. 1992;305: 913-920
fortheSteeringCommitteeofthe Pentasaccharide in Hip-Fracture Surgery Study. Fondaparinux compared with enoxaparinforthepreventionofvenousthromboembolismafterhip-fracturesur-gery
- Erikssonbi
- Bauerka
- Lassenmr
ErikssonBI,BauerKA,LassenMR,TurpieAG,fortheSteeringCommitteeofthe Pentasaccharide in Hip-Fracture Surgery Study. Fondaparinux compared with enoxaparinforthepreventionofvenousthromboembolismafterhip-fracturesur-gery. N Engl J Med. 2001;345:1298-1304
Whatarethemostreliabledetectionmethodsfordeepveinthrom-bosisandpulmonaryembolismtobeusedasendpointsintrialsofvenousthrom-boprophylaxis
- Davidsonbl
DavidsonBL.Whatarethemostreliabledetectionmethodsfordeepveinthrom-bosisandpulmonaryembolismtobeusedasendpointsintrialsofvenousthrom-boprophylaxis. Haemostasis. 1998;28(suppl 3):113-119