fondaparinux and apixaban

Topics: Administration, Oral; Factor Xa Inhibitors; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Patient Compliance; Pyrazoles; Pyridones; Venous Thromboembolism; Warfarin

Venous thromboembolism (VTE) is a common and potentially fatal complication of arthroplasty.. We reviewed randomized trials to determine which anticoagulant has the best safety and efficacy in hip and knee arthroplasty patients. We searched PubMed, MEDLINE, and EMBASE through January 2016.. Compared to enoxaparin (most commonly dosed 40 mg once daily), the relative risk (RR) of VTE was lowest for edoxaban 30 mg once daily (0.49; 95% confidence interval [CI], 0.32-0.75), fondaparinux 2.5 mg once daily (0.53; 95% CI, 0.45-0.63), and rivaroxaban 10 mg once daily (0.55; 95% CI, 0.46-0.66), and highest for dabigatran 150 mg once daily (1.19; 95% CI; 0.98-1.44). The RR of major/clinically relevant bleeding was lowest for apixaban 2.5 mg twice daily (0.84; 95% CI; 0.70-0.99) and highest for rivaroxaban (1.27; 95% CI, 1.01-1.59) and fondaparinux (1.64; 95% CI, 0.24-11.35). Fondaparinux was the only agent that was more effective than enoxaparin 30 mg twice daily (VTE RR = 0.58; 95% CI, 0.43-0.76).. With the possible exception of apixaban, newer anticoagulants that lower the risk of postoperative VTE increase bleeding.

Topics: Anticoagulants; Arthroplasty, Replacement, Knee; Dabigatran; Enoxaparin; Fondaparinux; Hemorrhage; Humans; Morpholines; Polysaccharides; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism

Several new anticoagulants have entered the clinical arena or are under clinical development. These drugs include indirect (fondaparinux) and direct oral factor Xa inhibitors (rivaroxaban, apixaban, edoxaban, betrixaban), and the direct thrombin inhibitor dabigatran. Especially the oral direct FXa and FIIa inhibitors overcome many of the shortcomings of heparins and vitamin K antagonists (VKAs). They are administered orally at a fixed dose; regular monitoring is not necessary; interaction with other drugs or nutrition occur less than with VKAs and they are at least as effective as VKAs for most indications tested. They are associated with about 50 % less intracranial bleeding than VKAs. Nevertheless, they are still associated with bleeding complications. Bleeding can occur spontaneously or as a result of trauma or urgent surgery. In such situations rapid reversal of the anticoagulant effect is highly desirable. For unfractionated heparin protamine, and for VKAs prothrombin complex concentrates are available as specific antidotes. Under clinical development are: for the direct and indirect FXa inhibitors a modified recombinant FXa (andexanet alpha), which lacks enzymatic activity; and for dabigatran a Fab fragment of a monoclonal antibody (idarucizumab). In addition a small molecule (aripazine) has entered phase I clinical trials, which seems to inhibit nearly all anticoagulants but VKAs and argatroban. This review summarises the current options and strategies in development to antagonise anticoagulants with a focus on the status of the development of antidotes for the oral direct FXa and FIIa inhibitors.

Topics: Administration, Oral; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticoagulants; Antithrombins; Benzamides; Clinical Trials as Topic; Dabigatran; Factor Xa; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Hemostatics; Heparin; Humans; Infusions, Parenteral; Intracranial Hemorrhages; Polysaccharides; Protamines; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiazoles; Thrombosis; Vitamin K

Regarding anticoagulant therapies there has been a remarkable shift in recent years. The objective of this brief overview is to provide relevant information and guidelines on the advantages and disadvantages of novel anticoagulants addressing specifically the surgical disciplines. Hitherto, conventional anticoagulant therapy in patients with a high thrombosis risk was largely limited to heparins and vitamin-K antagonists (VKA). Their modes of action, the difficulties in managing VKAs (e.g., bridging therapy) and the risk of HIT (heparin-induced thrombocytopenia) associated with heparins are briefly discussed. Novel anticoagulants supposedly eliminate these obstacles. Fondaparinux (Arixtra®) is a fully synthetic pentasaccharide which acts like a heparin but has an increased half life. Fondaparinux has a diminished risk of HIT. However, no specific antidote is currently available for Fondaparinux. The novel oral anticoagulants (NOAC) dabigatran etexilat (Pradaxa®), rivaroxaban (Xarelto®) and apixaban (Eliquis®), also known as "direct" anticoagulants, act independently from antithrombin by inhibiting thrombin, as in the case of dabigatran, or by inhibiting factor Xa, as in the case of rivaroxaban and apixaban. It is assumed that they are suitable for long-term use and do not require laboratory monitoring. Nevertheless, clinical experience is very limited and caution rather than quick conclusions is necessary. Two major drawbacks are on the one hand the risk of drug accumulation in kidney and/or liver disease and, on the other hand, the lack of specific antidotes. In addition, interactions with other medication may have unexpected effects on serum drug levels. Therefore, the analysis of drug levels in the plasma may become necessary in subgroups of patients.. Studies establishing clear recommendations for the desirable and measurable reference range are needed. Similarly, evidence-based recommendations regarding perioperative prevention of thrombosis are required ("bridging": yes or no?). Irrespective of these issues, the authors predict a further expansion of the use of NOACs.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; Blood Coagulation Tests; Dabigatran; Drug Interactions; Factor Xa Inhibitors; Fondaparinux; Heparin; Humans; International Normalized Ratio; Liver Failure; Metabolic Clearance Rate; Morpholines; Perioperative Care; Polysaccharides; Pyrazoles; Pyridines; Pyridones; Renal Insufficiency; Rivaroxaban; Thiophenes; Thrombocytopenia; Thrombosis; Vitamin K

Antiplatelet and anticoagulant drugs are the mainstay of treatment of acute coronary syndrome (ACS). The last 30 years have seen the development of various agents, a deeper understanding of the pathobiology of this disease, and an evolution in its treatment. We review the role of contemporary agents in ACS and highlight key clinical trials of these agents.

Topics: Acute Coronary Syndrome; Adenosine; Anticoagulants; Aspirin; Benzimidazoles; beta-Alanine; Clopidogrel; Dabigatran; Enoxaparin; Fondaparinux; Heparin; Hirudins; Humans; Morpholines; Peptide Fragments; Piperazines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Polysaccharides; Prasugrel Hydrochloride; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban; Thiophenes; Ticagrelor; Ticlopidine; Warfarin

The management of thromboprophylaxis in patients with pelvic and acetabular fractures remains a highly controversial topic within the trauma community. Despite anticoagulation, venous thromboembolism (VTE) remains the most common cause of surgical morbidity and mortality in this high-risk patient group. Although various thromboprophylactic regimes are employed, evidence relating to the most effective method remains unclear. Controversies surrounding screening, the use of prophylactic inferior vena cava filters (IVCF) and chemothromboprophylaxis in polytraumatised patients, particularly those with pelvic and acetabular fractures, form the basis of considerable debate. With the absence of a well-designed clinical trial and the presence of ongoing controversies within the literature, this review will explore current treatment options available to trauma surgeons and highlight differing scientific opinions, providing an update on the role of screening and current available preventative measures. We cover existing as well as recent advances in chemical thromboprophylactic agents and discuss external mechanical compression devices, the usefulness of serial duplex ultrasonography and the role of extended chemothromboprophylaxis on discharge. The evidence behind prophylactic IVCF is also considered, along with reported complication profiles. We conclude with a proposed protocol for use in major trauma centres, which can form the basis of local policy for the prevention of VTE in trauma patients with pelvic and acetabular fractures.

Topics: Acetabulum; Anticoagulants; Aspirin; Benzimidazoles; beta-Alanine; Coumarins; Dabigatran; Fondaparinux; Fractures, Bone; Heparin; Humans; Mass Screening; Morpholines; Multiple Trauma; Pelvis; Polysaccharides; Pulmonary Embolism; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Thiophenes; Vena Cava Filters; Venous Thromboembolism

Topics: Anticoagulants; Aspirin; Benzimidazoles; Clopidogrel; Dabigatran; Emergencies; Enoxaparin; Fondaparinux; Heparin; Humans; Morpholines; Platelet Aggregation Inhibitors; Platelet Transfusion; Polysaccharides; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Surgical Procedures, Operative; Thiophenes; Ticlopidine; Warfarin

As acute coronary syndrome (ACS) becomes more common nationwide and current anticoagulation regimens used in patients with ACS continue to possess their shortcomings, the need for new anticoagulants is on the rise. Although heparin and warfarin are used effectively in patients with ACS, they both have significant side effects and delivery issues. New factor Xa inhibitors offer an oral alternative that functions early in the coagulation cascade. The role of these new drugs in ACS is explored here. Electronic search strategies were used to collect reviews, randomized controlled trials, and other studies. Databases used included Medline and Cochrane Library and hand selection. Sources selected were limited to those that discussed factor Xa inhibitors in the context of ACS. Selected studies were then assessed for quality and relevance and those deemed relevant included for analysis. Some of the factor Xa inhibitors such as rivaroxaban offer anticoagulation as effective as, if not more effective, heparin and warfarin with lower risks of bleeding and other adverse effects such as heparin-induced thrombocytopenia. Many of these new agents also come in oral form, making them easy for patients to manage and use daily.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Cyclic N-Oxides; Factor Xa Inhibitors; Fondaparinux; Heparin; Humans; Morpholines; Naphthalenes; Polysaccharides; Propionates; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Treatment Outcome; Warfarin

Topics: Acute Coronary Syndrome; Anticoagulants; Antithrombins; Cyclic N-Oxides; Fondaparinux; Hirudins; Humans; Morpholines; Peptide Fragments; Polysaccharides; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiophenes

The prevalence of obesity has increased substantially over recent years. Clinicians are increasingly being challenged with making uncertain anticoagulant dosing decisions, as the optimal dosing strategy for most anticoagulants in the obese patient population remains unknown. Research published to date suggests that the clearance of anticoagulants increases with weight. As obesity is associated with an increased risk of venous thromboembolism and arterial disease, there is an urgent need to establish appropriate anticoagulation regimens for this patient group. Research studies applying the method of pharmacokinetic-pharmacodynamic modelling and simulation could establish an appropriate evidence base and provide direction and reassurance to prescribing clinicians.

Topics: Acute Coronary Syndrome; Anticoagulants; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Double-Blind Method; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Heparin; Humans; Morpholines; Multicenter Studies as Topic; Obesity; Polysaccharides; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiophenes; Thrombin; Thrombophilia; Venous Thrombosis; Warfarin

Heparin, low molecular weight heparin (LMWH) and warfarin are well-established anticoagulants still in widespread use despite their well known drawbacks. Heparin requires continuous monitoring, has serious side-effects such as haemorrhage, thrombosis and osteoporosis, and lacks an oral route of administration. LMWH is a safer, more convenient anticoagulant to use but it cannot be given orally, does not have an antidote and may be difficult to administer in patients with renal failure. Warfarin has a narrow therapeutic window, interacts with other drugs and foods and requires monitoring like heparin. The limitations of all three of these established anticoagulants have prompted the search for better more convenient agents. The major examples of these newer anticoagulants are the direct and indirect factor Xa inhibitors and the direct thrombin inhibitors. These new agents tend to have more predictable pharmacokinetic properties, superior efficacy and safety and some can be administered orally. In this review, we summarise the advantages and disadvantages of three established anticoagulants (heparin, LMWH and warfarin) and the most promising new anticoagulants (fondaparinux, idraparinux, rivaroxaban, apixaban, dabigatran and ximelagatran) by discussing their pharmacodynamics and pharmacokinetics. We also discuss recent patents in the field of anticoagulation, which aim to improve the safety and effectiveness of antithrombotic agents currently in use or offer alternative ways for anticoagulation.

Topics: Animals; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; Dabigatran; Factor Xa; Factor Xa Inhibitors; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Morpholines; Oligosaccharides; Polysaccharides; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Thrombin; Warfarin

Acutely ill medical patients are at moderate to high risk of venous thromboembolism (VTE): approximately 10-30% of general medical patients may develop deep-vein thrombosis or pulmonary embolism, and the latter is a leading contributor to deaths in hospital. Medical conditions associated with a high risk of VTE include cardiac disease, cancer, respiratory disease, inflammatory bowel disease, rheumatological and infectious diseases. Pre-disposing risk factors in medical patients include a history of VTE, history of malignancy, complicating infections, increasing age, thrombophilia, prolonged immobility and obesity. Hence active cancer and a history of cancer are both strongly related to VTE in medical (non-surgical) patients. Heparins, both unfractionated (UFH) and low molecular weight (LMWH) and fondaparinux have been shown to be effective agents in prevention of VTE in this setting. However, it has not yet been possible to demonstrate a significant effect on mortality rates in this population. In medical patients, unfractionated heparin has a higher rate of bleeding complications than low molecular weight heparin. Thromboprophylaxis has been shown to be effective in medical patients with cancer and may have an effect on cancer outcomes. Thromboprophylaxis in patients receiving chemotherapy remains controversial and requires further investigation. There is no evidence for the use of aspirin, warfarin or mechanical methods. We recommend either low molecular weight heparin or fondaparinux as safe and effective agents in the thromboprophylaxis of medical patients.

Topics: Anticoagulants; Aspirin; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Morpholines; Neoplasms; Polysaccharides; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism; Warfarin

Heparin and low molecular weight heparins have limitations in their efficacy and safety for the prevention and treatment of venous thromboembolism (VTE). New synthetic antithrombotic drugs, designed with the intention of improving the therapeutic window for prophylaxis and treatment, are in various stages of development. Synthetic pentasaccharides include fondaparinux and its long-acting analogue idraparinux. Dabigatran is a direct thrombin inhibitor that has undergone clinical trials for VTE prophylaxis and treatment. Direct factor Xa inhibitors include rivaroxiban, which has shown promising results for VTE prophylaxis and is being studied for VTE treatment, as well as apixaban and betrixaban, which are at earlier stages of clinical validation. These newer agents may represent viable options for prophylaxis and therapy as further clinical studies are performed.

Topics: Anticoagulants; Benzamides; Benzimidazoles; beta-Alanine; Dabigatran; Fondaparinux; Humans; Morpholines; Oligosaccharides; Polysaccharides; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiophenes; Venous Thromboembolism

The treatment of choice for acute venous thromboembolism is anticoagulant therapy with fast-acting drugs (unfractionated or low-molecular-weight heparin or fondaparinux) aimed at preventing thrombus extension, followed by extended prophylaxis with vitamin K antagonists aimed at preventing recurrence. Experience accumulated over the years has demonstrated that strict laboratory monitoring is required for unfractionated heparin and vitamin K antagonists, making use of these drugs problematic for patients and physicians and prompting researchers to develop new anticoagulants equally effective but without the requirement for laboratory monitoring. The results of clinical trials to date, albeit limited, suggest that these new drugs will probably keep their promise. However, the definitive answer will come subsequent to these clinical trials, when clinicians will start to use these drugs to treat patients in the real world. It is likely that some sort of laboratory monitoring will be required at least for selected categories of patients. Accordingly, clinical laboratories should still be prepared to monitor patients, although the numbers may hopefully decrease sharply in the next decade or so.

Topics: Anticoagulants; Blood Coagulation; Clinical Trials as Topic; Fondaparinux; Heparin; Heparin, Low-Molecular-Weight; Humans; Incidence; International Normalized Ratio; Monitoring, Physiologic; Morpholines; Polysaccharides; Prothrombin Time; Pulmonary Embolism; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism; Venous Thrombosis; Vitamin K

Topics: Angina, Unstable; Anticoagulants; Azetidines; Benzimidazoles; Benzylamines; Brain Ischemia; Clinical Trials as Topic; Coumarins; Dabigatran; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Forecasting; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Hirudins; Humans; Morpholines; Myocardial Infarction; Peptide Fragments; Polysaccharides; Prothrombin; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiophenes; Thrombin; Thrombophilia; Thrombosis; Warfarin

Despite their usefulness in perioperative and acute care settings, factor-Xa inhibitor-specific assays are scarcely available, contrary to heparin anti-Xa assay. We assessed whether the heparin anti-Xa assay can (1) be used as a screening test to rule out apixaban, rivaroxaban, fondaparinux, and danaparoid levels that contraindicate invasive procedures according to current guidelines (>30 ng·mL-1, >30 ng·mL-1, >0.1 µg·mL-1, and >0.1 IU·mL-1, respectively), (2) quantify the anticoagulant level if found significant, that is, if it exceeded the abovementioned threshold.. In the derivation cohort then in the validation cohort, via receiver operating characteristics (ROC) curve analysis, we evaluated the ability of heparin anti-Xa assay to detect levels of factor-Xa inhibitors above or below the abovementioned safety thresholds recommended for an invasive procedure (screening test). Among samples with relevant levels of factor-Xa inhibitor, we determined the conversion factor linking the measured level and heparin anti-Xa activity in a derivation cohort. In a validation cohort, the estimated level of each factor-Xa inhibitor was thus inferred from heparin anti-Xa activity. The agreement between measured and estimated levels of factor-Xa inhibitors was assessed.. Among 989 (355 patients) and 756 blood samples (420 patients) in the derivation and validation cohort, there was a strong linear relationship between heparin anti-Xa activities and factor-Xa inhibitors measured level (r = 0.99 [95% confidence interval {CI}, 0.99-0.99]). In the derivation cohort, heparin anti-Xa activity ≤0.2, ≤0.3, <0.1, <0.1 IU·mL-1 reliably ruled out a relevant level of apixaban, rivaroxaban, fondaparinux, and danaparoid, respectively (area under the ROC curve ≥0.99). In the validation cohort, these cutoffs yielded excellent classification accuracy (≥96%). If this screening test indicated relevant level of factor-Xa inhibitor, estimated and measured levels closely agreed (Lin's correlation coefficient close to its maximal value: 95% CI, 0.99-0.99). More than 96% of the estimated levels fell into the predefined range of acceptability (ie, 80%-120% of the measured level).. A unique simple test already widely used to assay heparin was also useful for quantifying these 4 other anticoagulants. Both clinical and economic impacts of these findings should be assessed in a specific study.

Topics: Blood Coagulation; Blood Coagulation Tests; Chondroitin Sulfates; Dermatan Sulfate; Drug Monitoring; Factor Xa Inhibitors; Fondaparinux; France; Heparitin Sulfate; Humans; Predictive Value of Tests; Pyrazoles; Pyridones; Reproducibility of Results; Retrospective Studies; Rivaroxaban

The safety and efficacy of nonvitamin K antagonist oral anticoagulants (NOACs) for the treatment of venous thromboembolism (VTE) have been established in randomized controlled trials, but limited data are available on their use in clinical practice across geographical regions.. In the international RE-COVERY DVT/PE observational study (enrollment January 2016 to May 2017), we sought to characterize the patient population and describe the prescribed anticoagulant. Patient characteristics and anticoagulants administered after objective diagnosis of VTE were recorded at the baseline visit and again at hospital discharge or at 14 days after the diagnosis, whichever was later.. A total of 6095 patients were included, 50.2% were male, and the mean age was 61.5 years. The most common comorbidities were hypertension (35%), diabetes mellitus (11%), cancer (11%), prior VTE(11%), and trauma/surgery (7%). Overall, 77% of patients received oral anticoagulants, with 54% on NOACs and 23% on vitamin K antagonists (VKAs); 20% received parenteral anticoagulation only. NOACs comprised about 60% of anticoagulant treatment in Europe and Asia but substantially less in Latin America (29%) and the Middle East (21%). For NOAC therapies, the distribution (as a percentage of the total cohort) was rivaroxaban 25.6%, dabigatran 15.5%, apixaban 11.3%, and edoxaban 1.7%. Treatment with NOACs was less frequent in patients who had cancer, chronic renal disease, heart failure, or stroke.. These findings enhance our understanding of baseline characteristics and the initial management of patients with VTE in routine practice.

Topics: Administration, Oral; Adult; Age Distribution; Aged; Anticoagulants; Asia; Comorbidity; Cross-Sectional Studies; Dabigatran; Diabetes Mellitus; Europe; Factor Xa Inhibitors; Female; Fondaparinux; Heparin; Humans; Hypertension; Latin America; Male; Middle Aged; Middle East; Neoplasms; Postoperative Complications; Practice Patterns, Physicians'; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Venous Thromboembolism; Venous Thrombosis; Wounds and Injuries

The present article addresses clinical challenges associated with the choice of the anticoagulant agent, the definition of the duration of anticoagulant treatment and the assessment of the risk-to-benefit ratio of prolonged anticoagulation for patients with pulmonary embolism (PE).Anticoagulation is performed with unfractionated heparin (UFH) in hemodynamically unstable patients and with low molecular weight heparins (LWMH) or fondaparinux in normotensive patients. In patients with high or intermediate clinical probability of pulmonary embolism, anticoagulation should be initiated without delay while awaiting the results of diagnostic tests. LMWH and fondaparinux are preferred over UFH in the initial anticoagulation of PE since they are associated with a lower risk of bleeding.All patients with PE require therapeutic anticoagulation for at least three months. The current 2019 guidelines of the European Society of Cardiology (ESC) recommend that all eligible patients should be treated with a non-vitamin K antagonist oral anticoagulant (NOAC) in preference to a vitamin K antagonist (VKA). In patients with active cancer, Apixaban, Edoxaban and Rivaroxaban are effective alternatives to treatment with LMWH.The decision on the duration of anticoagulation should consider both, the individual risk of PE recurrence and the individual risk of bleeding. The risk for recurrent PE after discontinuation of treatment is related to the features of the index PE event. While patients with a strong transient risk factor have a low risk of recurrence and anticoagulation can be discontinued after three months, patients with strong persistent risk factor (such as active cancer) have a high risk of recurrence and thus should receive anticoagulant treatment of indefinite duration. Given the favourable safety profile of NOACs (especially if a reduced dosage of Apixaban or Rivaroxaban is initiated after at least six months of therapeutic anticoagulation), extended oral anticoagulation of indefinite duration should be considered for all patients with intermediate risk of recurrence.

Topics: Acute Disease; Dalteparin; Dose-Response Relationship, Drug; Drug Administration Schedule; Fibrinolytic Agents; Fondaparinux; Guideline Adherence; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Long-Term Care; Neoplasms; Pulmonary Embolism; Pyrazoles; Pyridines; Pyridones; Recurrence; Risk Assessment; Risk Factors; Rivaroxaban; Thiazoles

Clinically apparent venous thromboembolism (VTE) occurs in approximately 7% of patients with membranous nephropathy. Hypoalbuminemia at diagnosis is an independent risk factor for VTE, and risk increases significantly as albumin falls. Optimal prophylactic and treatment anticoagulation regimens in the nephrotic syndrome remain unproven but novel oral anti-coagulants have become attractive therapeutic options. We describe a patient diagnosed with anti-phospholipase A2 receptor antibody positive membranous nephropathy and recurrent VTE while on therapeutic dosing of apixaban. A direct factor Xa inhibitor, apixaban has been shown to be non-inferior to warfarin for the treatment of VTE in the general population. However, because it is highly protein-bound, apixaban may have altered pharmacokinetics and pharmacodynamics in patients with nephrotic syndrome and hypoalbuminemia. This case report highlights the need for further studies of direct oral anticoagulants to fully assess their effectiveness in this high-risk population.

Topics: Factor Xa Inhibitors; Fondaparinux; Glomerulonephritis, Membranous; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Recurrence; Serum Albumin; Venous Thromboembolism

A 45-year-old woman who required lifelong anticoagulation for recurrent thrombosis had her therapeutic choices limited by heparin-induced thrombocytopenia and abnormal pharmacokinetics (greatly reduced absorption) resulting from short gut syndrome from extensive gut resection after mesenteric thrombosis. As an alternative to inconvenient and expensive injections of fondaparinux, personalized dosing of a direct oral anticoagulant was sought using clinical pharmacology techniques. Enteral absorption was ascertained with small test doses of apixaban, and the ability of supraconventional doses to deliver effective concentrations was verified.

Topics: Administration, Oral; Chronic Disease; Female; Fibrinolytic Agents; Follow-Up Studies; Fondaparinux; Humans; Injections, Subcutaneous; Middle Aged; Patient Safety; Polysaccharides; Precision Medicine; Pyrazoles; Pyridones; Risk Assessment; Severity of Illness Index; Short Bowel Syndrome; Treatment Outcome; Venous Thromboembolism

There are numerous studies discussing thromboprophylaxis after total joint arthroplasty (TJA), with varying conclusions. Patient inclusion criteria may be different for each study, which may lead to selection bias and misrepresentation of data. This study aimed to investigate if industry funding impacted patient demographics and overall reported outcomes of studies analyzing venous thromboembolism (VTE) prevention after TJA.. Electronic searches were completed using Ovid, PubMed, and Embase databases. Studies were included if (1) they are published in the English language between 2000 and 2016; (2) they included patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA); and (3) they evaluated prevention and control of postoperative VTE with at least one of the following thromboprophylactic agents: aspirin, enoxaparin, dalteparin, dabigatran, apixaban, rivaroxaban, dabigatran, ximelagatran, fondaparinux, or coumadin. Data were extracted and analyzed via mixed-effect logistic regression.. Fifty-seven studies were included; 29 were industry funded, and 28, nonfunded. There were no significant differences between patient's age, body mass index, or revision exclusions between funded and nonfunded studies. Funded studies reported less pulmonary embolisms, fewer events of major bleeding, and significantly less 90-day mortality compared with nonfunded studies.. Industry-funded studies reported less pulmonary embolisms, major bleeding, and mortality compared with nonfunded studies. Detailed demographic data were missing from the literature, and we were unable to demonstrate the cause of different reported outcomes between industry-funded and nonfunded studies. Further investigations should be aimed toward understanding how funded studies report less adverse outcomes in analyzing VTE after TJA.

Topics: Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Aspirin; Conflict of Interest; Dabigatran; Enoxaparin; Female; Fondaparinux; Health Care Sector; Hemorrhage; Humans; Male; Pulmonary Embolism; Pyrazoles; Pyridones; Rivaroxaban; Venous Thromboembolism; Warfarin

Essentials Simple and fast assaying of different anticoagulants (ACs) is useful in emergent situations. We used highly diluted prothrombin time (dPT) or highly diluted Fiix-PT (dFiix-PT) to assay ACs. Both tests could quantify target specific anticoagulants and warfarin anticoagulation. Improved results were consistently observed with the dFiix-PT compared with the dPT.. Background Assaying anticoagulants is useful in emergency situations or before surgery. Different specific assays are currently needed depending on the anticoagulant. Objectives We hypothesized that levels of warfarin, dabigatran, rivaroxaban, apixaban, and heparins could be measured with use of the diluted prothrombin time (dPT) and diluted Fiix-PT (dFiix-PT), using highly diluted thromboplastin (TP). The latter test is affected only by reduced levels of active factors II and X but corrects test plasma for other deficiencies Methods Increasing TP dilutions were used to identify suitable dilutions to measure dabigatran, rivaroxaban, apixaban, unfractionated heparin (UFH), and enoxaparin. Calibrators containing known amounts of direct oral anticoagulants (DOACs) were used to make standard curves. Citrated plasma samples were obtained from patients taking warfarin or DOACs with known drug concentrations as determined by specific assays. Results The dFiix-PT at a TP dilution of 1:1156 could be used to measure all of the drugs tested at therapeutic concentrations except for fondaparinux. The dPT achieved the same but required two TP dilutions (1:750 and 1:300). The warfarin effect could be assessed by using dFiix-PT at 1:1156 with a PT ratio identical to the international normalized ratio. Six different TPs yielded similar results, but two were less sensitive. Dabigatran, rivaroxaban, and apixaban could be accurately measured in patient samples using both dilute PT assays, but a better correlation was consistently observed between the dFiix-PT and specific assays than with the dPT. Conclusion The dFiix-PT using a single dilution of TP may be suitable to assess the anticoagulant effects of warfarin, dabigatran, rivaroxaban, apixaban, heparin, and enoxaparin.

Topics: Anticoagulants; Blood Coagulation Tests; Blood Donors; Calibration; Dabigatran; Enoxaparin; Factor X; Female; Fondaparinux; Heparin; Humans; International Normalized Ratio; Male; Polysaccharides; Prothrombin; Prothrombin Time; Pyrazoles; Pyridones; Reproducibility of Results; Rivaroxaban; Thromboplastin; Warfarin

Cancer cells may alter the efficiency of the antithrombotic agents. To explore this possibility, the present study compared the capacity of the LMWH enoxaparin and the specific inhibitors of Xa (apixaban and fondaparinux) to inhibit thrombin generation triggered by pancreas adenocarcinoma cells (BXPC3) and human breast carcinoma cells (MCF7).. Samples of platelet poor (PPP) or platelet rich plasma (PRP) spiked with apixaban, fondaparinux or enoxaparin were added in micro wells carrying cancer cells and assessed for thrombin generation. In the control experiment thrombin generation was triggered with tissue factor reagent.. The three antithrombotics inhibited thrombin generation in a concentration dependent manner. The BXPC3 and MCF7 cells reversed in a different intensity the effect of the studied agents. According to the histological type of the cancer the antithrombotic efficiency of apixaban was preserved or partially reversed. Fondaparinux, was more vulnerable to the presence of cancer cells as compared to apixaban. The effect of BXCP3 or MCF7 cells on the antithrombotic potency of enoxaparin was of similar magnitude as that on apixaban.. The type of cancer cells is determinant for the antithrombotic efficiency of the specific factor Xa inhibitors. In contrast it does not significantly influence the potency of enoxaparin. The present study shows that the impact of the type of cancer cells on the antithrombotic activity of the specific Xa inhibitors should not be neglected. This has to be taken into consideration for the design of dose-finding studies of the direct orally active FXa inhibitors in patients with different histological types of cancer.

Topics: Anticoagulants; Blood Platelets; Breast Neoplasms; Cell Line, Tumor; Enoxaparin; Factor Xa; Female; Fibrinolytic Agents; Fondaparinux; Heparin, Low-Molecular-Weight; Humans; Inhibitory Concentration 50; MCF-7 Cells; Pancreatic Neoplasms; Polysaccharides; Pyrazoles; Pyridones; Thrombin; Thrombosis

In recent years, several selectively acting anticoagulants, including the direct thrombin inhibitors (DTI; argatroban, dabigatran) and the factor Xa inhibitors (rivaroxaban, apixaban, fondaparinux), have been developed. With their clinical application increasing, it is of interest to evaluate their interference with classical haemostaseological point-of-care tests. Additionally, the effect of the investigated anticoagulants on platelet function tests will come increasingly more into focus for monitoring not only hereditary platelet dysfunction, but also antiplatelet therapy.. Blood samples from healthy volunteers were spiked with therapeutic and supratherapeutic concentrations of the drugs listed above and investigated with regard to their effects on the following POCTs: activated clotting time (ACT), thromboelastometry with ROTEM, PFA and Multiplate. Light-transmission aggregometry (LTA) was used for a platelet function assay.. At supratherapeutic concentrations, ACT and ROTEM analysis were always influenced after administration of the drugs listed above (except fondaparinux in EXTEM-CT). Therapeutic concentrations showed differential effects on these assays. LTA measurements revealed a distinct decrease in α-thrombin-induced platelet aggregation for both DTIs (therapeutic and supratherapeutic concentrations), while argatroban reduced platelet function in supratherapeutic concentrations. None of the drugs seemed to have any influence on PFA or Multiplate.. Selective thrombin and factor Xa inhibitors exhibit distinct effects on POCTs and platelet function tests. This must be considered in assessing assay results when taking medical decisions.

Topics: Anticoagulants; Arginine; Artifacts; Benzimidazoles; beta-Alanine; Blood Coagulation; Dabigatran; Fondaparinux; Humans; Morpholines; Pipecolic Acids; Platelet Function Tests; Point-of-Care Systems; Polysaccharides; Pyrazoles; Pyridones; Rivaroxaban; Sulfonamides; Thiophenes; Thrombelastography; Whole Blood Coagulation Time

Inhibitors of coagulation factor Xa (fXa) have emerged as a new class of antithrombotics but lack effective antidotes for patients experiencing serious bleeding. We designed and expressed a modified form of fXa as an antidote for fXa inhibitors. This recombinant protein (r-Antidote, PRT064445) is catalytically inactive and lacks the membrane-binding γ-carboxyglutamic acid domain of native fXa but retains the ability of native fXa to bind direct fXa inhibitors as well as low molecular weight heparin-activated antithrombin III (ATIII). r-Antidote dose-dependently reversed the inhibition of fXa by direct fXa inhibitors and corrected the prolongation of ex vivo clotting times by such inhibitors. In rabbits treated with the direct fXa inhibitor rivaroxaban, r-Antidote restored hemostasis in a liver laceration model. The effect of r-Antidote was mediated by reducing plasma anti-fXa activity and the non-protein bound fraction of the fXa inhibitor in plasma. In rats, r-Antidote administration dose-dependently and completely corrected increases in blood loss resulting from ATIII-dependent anticoagulation by enoxaparin or fondaparinux. r-Antidote has the potential to be used as a universal antidote for a broad range of fXa inhibitors.

Topics: Animals; Anticoagulants; Antidotes; Benzamides; Dose-Response Relationship, Drug; Enoxaparin; Factor Xa; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Hemostasis; Male; Mice; Mice, Inbred C57BL; Morpholines; Polysaccharides; Pyrazoles; Pyridines; Pyridones; Rabbits; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Rivaroxaban; Thiophenes

Due to high health care costs of venous thromboembolism (VTE), economic analyses are needed to determine the efficiency of different drug treatments. Consequently, a study was conducted to estimate the budgetary impact for the National Health System (NHS) with apixaban for prevention of venous thromboembolism (VTE) in total hip (THR) or knee (TKR) replacement.. Cost considered: the drugs for the prevention of VTE (apixaban, dabigatran, enoxaparin, fondaparinux, other heparins, rivaroxaban and warfarin) and the complications of VTE in the short term and in 5 years (deep vein thrombosis, pulmonary embolism, bleedings and the post-thrombotic syndrome). The effectiveness of prophylaxis was estimated using a meta-analysis. The VTE rates and death with apixaban are lower in THR and TKR than enoxaparin (-3.5% and -10.0%, respectively) with less bleeding events (-0.7% and -1.6%, respectively). Population data and unit costs were obtained from Spanish sources.. 5 years. All costs were discounted by 3.5% annually. Five years after commercialization, the use of apixaban was estimated to account for 23% of the prophylaxis of VTE and the use of enoxaparin decrease from the 60% to 33%.. Apixaban´s introduction for the prophylaxis of VTE would have a significant impact for the NHS, resulting in a saving of 547,422 Euro over a period of 5 years. In the case of outpatient administration of heparin did not have a cost, the savings for the NHS five years amount to 270,068 Euro.. According to this study, the introduction of apixaban may reduce the rate of VTE and bleeding compared with enoxaparin, decreasing the expenditure of NHS in VTE prophylaxis.

Topics: Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Benzimidazoles; beta-Alanine; Budgets; Cost Control; Dabigatran; Enoxaparin; Female; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Humans; Morpholines; Polysaccharides; Pulmonary Embolism; Pyrazoles; Pyridones; Rivaroxaban; Spain; State Medicine; Thiophenes; Venous Thromboembolism

Orally available direct thrombin inhibitors (DTI) and direct activated factor X inhibitors (DFXaI) may replace vitamin K antagonists in patients needing long-term anticoagulant treatment. We investigated the influence on the fibrin network of anticoagulants with different modes of action: AR-H067637 (DTI), the active metabolite of AZD0837, apixaban (DFXaI), fondaparinux (indirect FXaI) and warfarin. Counteraction of the anticoagulant effect by FEIBA(®) (Factor Eight Inhibitor Bypass Activity) was also investigated. Tissue factor, phospholipids and calcium were used to initiate coagulation in human platelet poor plasma. The permeability constant (Ks), reflecting the amount of buffer passing through the coagulum, was calculated and the fibrin network was visualized by 3D confocal microscopy. Warfarin (International Normalized Ratio 2-3) increased Ks in plasma by 28-50% compared with control. 'Therapeutic' plasma concentrations of AR-H067637 (0·3-0·6 μmol/l), apixaban (0·2-0·4 μmol/l) and fondaparinux (0·1-0·3 μmol/l) increased Ks by 72-91%, 58-76% and 36-53% respectively. Addition of FEIBA(®) totally reversed the warfarin effect but only partially reversed effects of the other anticoagulants at concentrations that increased Ks by 50% or more. Fibrin network observed with 3D confocal microscopy agreed well with the permeability results. In conclusion, all examined anticoagulants rendered the fibrin network more porous. FEIBA(®) reversed the increased permeability in warfarin plasma but had only partial effects on the other anticoagulants.

Topics: Amidines; Anticoagulants; Azetidines; Blood Coagulation Factors; Dose-Response Relationship, Drug; Fibrin; Fondaparinux; Humans; International Normalized Ratio; Microscopy, Confocal; Permeability; Polysaccharides; Porosity; Pyrazoles; Pyridones; Warfarin

The range of anticoagulants has been very active recently with the development of new compounds including injectable anti-Xa such as fondaparinux, and new oral drugs which can be divided into anti-IIa with dabigatran, and anti-Xa, such as rivaroxaban and apixaban still in the development stage. Others are coming forward. They are more convenient to use and do not require routine coagulation monitoring. However, several points need to be clarified and the place for each drug remains to be determined. In case of massive bleeding, management is unclear and none of these newer agents has a specific antidote that completely reverses its anticoagulant effect.

Topics: Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Fondaparinux; Humans; Morpholines; Polysaccharides; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes