New Generation Of Oral Anticoagulants Research Articles

In vitro Bioaccessibility, Bioavailability, and Plasma Protein Interaction of New Oral Anticoagulants in the Presence of Macronutrients.

Over the last years, a new generation of oral anticoagulants (NOACs), including apixaban, rivaroxaban and dabigatran, has been developed for the control of thrombosis and related disorders. The presence of food within the gastrointestinal (GI) tract can potentially affect the oral bioavailability of drugs. In the present paper, we evaluated the stability of these drugs in in vitro GI digestion, with and without the main macronutrients such as proteins, lipids, carbohydrates, and fibers, and their ability to enter into the systemic circulation. In addition, we examined the percentage of the drug binding to plasma proteins, such as human serum albumin, high density- and low density lipoproteins. The NOACs bioaccessibility was evaluated by an in vitro procedure simulating the gastrointestinal enzymatic system, while their bioavailability was studied by cell culture of Caco-2 cells and in vitro study of transepithelial transport. The in vitro transepithelial permeated NOACs were added to plasma protein solutions simulating the average fasting plasma protein concentrations. The NOACs detection was carried out by HPLC-DAD/ESI-MS analysis. GI digestion significantly reduces intestinal bioaccessibility and bioavailability of NOACs, especially as regards apixaban and dabigatran. Interestingly, the co-digestion of fibers led to a strong decrease of NOAC intestinal bioaccessibility and bioavailability, while the effects of the other macronutrients, as well as a low fiber standard meal, had no significant influence in this sense. Dabigatran, rivaroxaban and apixaban may be administered independently of a standard meal, provided that it does not include a high amount of dietary fibers.

Medication Safety

Medication Safety

Long-term Arrhythmia Monitoring in Cryptogenic Stroke: Who, How, and for How Long?

Cryptogenic stroke and transient ischemic attack (TIA) account for approximately one-third of stroke patients [1]. Paroxys-mal atrial fibrillation (PAF) has been suggested as a major etiology of these cryptogenic strokes [2, 3]. PAF can be difficult to diagnose because it is intermittent, often brief, and asymptomatic. PAF might be more prevalent than persistent atrial fibrillation in stroke and TIA patients, especially in younger populations [4, 5]. In patients with atrial fibrillation, anticoagulation provides significant risk reduction [6]. A new generation of oral anticoagulants has been approved for non-valvular atrial fibrillation, providing a variety of therapeutic options for patients with atrial fibrillation and risk of stroke [7].Prior practice included an admission electrocardiogram (ECG) and continuous telemetry monitoring while in hospital [8]. However, this approach can lead to under-detection of brief asymptomatic events, which can occur at variable intervals, often outside of the hospital setting. Technological advancements have led to devices that can monitor cardiac rhythms outside of the hospital for longer durations resulting in higher yield of detection of atrial fibrillation events. Moreover, recent studies show that the normal monitoring time for arrhythmias may be shorter than ideal in order to detect atrial fibrillation, and increasing this interval could significantly improve detection of atrial fibrillation in these patients [9, 10].The aim of this study is to review the literature in order to define what subgroup of patients, with what methodologies, and for how long monitoring for atrial fibrillation should occur in patients presenting with cryptogenic stroke.

Reversal Agents for the New Generation of Oral Anticoagulants: Implications for the Perioperative Physician.

Reversal Agents for the New Generation of Oral Anticoagulants: Implications for the Perioperative Physician.

Enoxaparin Dose Reduction for Thrombocytopenia in Patients with Cancer: A Quality Assessment Study

▪Background: The development of chemotherapy-induced thrombocytopenia (CIT) in the setting of therapeutic anticoagulation for venous thromboembolic (VTE) disease is a common problem in cancer patients. The current approach to low molecular weight heparin (LMWH) dosing in the setting of CIT (Lee, AYY. J. Clin. Onc. 2009) is empirical and based on limited published experience. This approach was never validated prospectively. Since 2011, Memorial Sloan Kettering Cancer Center (MSKCC) implemented a similar guideline: administer full dose LMWH for a platelet count >50,000/mcL, half dose for a platelet count 25,000/mcL to 50,000/mcL and hold LMWH temporarily for a platelet count <25,000/mcL.Materials and Methods: In a Quality Assessment project, we evaluated cancer patients at MSKCC who were on a therapeutic dose of enoxaparin for a VTE during the years 2011 through 2013, who experienced at least one period of thrombocytopenia (platelet count ≤50,000/mcL) for at least 7 days. We assessed for adherence to the LMWH dose modification guidelines reflected by dose reduction and/or temporary hold for existing or anticipated thrombocytopenia. In addition, major bleeding, clinically relevant non-major bleeding, recurrent VTE events, and death were recorded during the episodes of thrombocytopenia.Results: We identified 101 patients with 144 episodes of thrombocytopenia, with an average duration of 21.3 days per episode. The LMWH dose was modified in 137 of the 144 episodes (95%), reflecting adherence to our institutional guidelines. The LMWH doses were reduced in 20 episodes, held in 90 episodes, and managed with combination of reduction/hold in 27 episodes. In general, the more severe thrombocytopenic episodes were managed with holding LMWH as opposed to dose reduction. The unweighted mean platelet count during episodes managed with holding LMWH was 27,000/mcL with a standard deviation (STD) of 16,000, while the mean platelet count during episodes of dose reduction was 36,000/mcL with a STD of 15,000.There were no recurrent VTE events or major bleeding episodes when the LMWH was reduced or held. In our cohort, there was only one major bleeding episode, a trauma-associated retroperitoneal hemorrhage, which occurred on the third day of a thrombocytopenic episode, prior to enoxaparin dose modification. That patient's platelet count was 28,000/mcL at the time of the event. There were 14 clinically relevant non-major bleeding episodes, of which 7 cases consisted of ecchymosis, epistaxis or gingival bleeding. Lastly, 10 patients died during the episode of thrombocytopenia.Discussion: This Quality Assessment project supports the safety and efficacy of our guidelines for therapeutic LMWH dose modification in the setting of CIT. In contrast to past case series, these patients were managed under direction of an institutional dosing guideline. We observed a 95% level of compliance with the guidelines. These data support the conclusion that the current LMWH dose reduction approach provides safety and efficacy, balancing the risks of recurrent thrombosis and bleeding during periods of CIT in cancer patients. It remains to be determined if a similar strategy would be appropriate for the new generation of oral anticoagulants. DisclosuresNo relevant conflicts of interest to declare.

Direct oral anticoagulants – new challenge for laboratory medicine

A new generation of oral anticoagulants, direct thrombin or activated factor X inhibitors gradually replaces the existing antithrombotic agents, administered parenterally (heparin) or orally (vitamin K antagonists). Currently, the most widely used class of direct oral anticoagulants (DOACs) are the direct thrombin inhibitor dabigatran and rivaroxaban, apixaban and edoxaban – Xa inhibitors. Although previous reports suggested that DOACs therapy does not require laboratory screening, recently the new indications for monitoring and the types of laboratory tests used in the evaluation of the effectiveness of treatment have been updated. To quantify the activity of direct thrombin inhibitors a dilute thrombin clotting time (dTT) or ecarin clotting time (ECT) is recommended. The effect of rivaroxaban and apixaban can be determined by anti-Xa activity assay when calibrated with a rivaroxaban and apixaban standard. Observed changes in routine coagulation tests such as activated partial thromboplastin time (APTT), and prothrombin time (PT), with varying degrees of severity, can only be an indicator of an additional screening, which is the emergency clinical interventions.

Antidotes for novel oral anticoagulants: current status and future potential.

The direct thrombin inhibitor dabigatran and the anti-Xa agents rivaroxaban, edoxaban, and apixaban are a new generation of oral anticoagulants. Their advantage over the vitamin K antagonists is the lack of the need for monitoring and dose adjustment. Their main disadvantage is currently the absence of a specific reversal agent. Dabigatran's, unlike the anti-Xa agents, absorption can be reduced by activated charcoal if administered shortly after ingestion and it can be removed from the blood with hemodialysis. Prothrombin complex concentrate, activated prothrombin complex concentrate, and recombinant factor VIIa all show some activity in reversing the anticoagulant effect of these drugs but this is based on ex vivo, animal, and volunteer studies. It is unclear, which, if any, of these drugs is the most suitable for emergency reversal. Three novel molecules (idarucizumab, andexanet, and PER977) may provide the most effective and safest way of reversal. These agents are currently in premarketing studies.

Perioperative atrial fibrillation: a systematic review of evolving therapeutic options in pharmacologic and procedural management.

Given the high incidence of atrial fibrillation (AF) in the surgical population and the associated morbidity, physicians managing these complicated patients in the perioperative period need to be aware of the new and emerging trends in its therapy. The cornerstones of AF management have always been rate/rhythm control as well as anticoagulation. Restoration of sinus rhythm remains the fundamental philosophy as it maintains the atrial contribution to cardiac output and improves ventricular function. The recent years have seen a dramatic increase in the number of randomized AF trials that have made significant advances to our understanding of both pharmacologic and procedural management, from the introduction of the new generation of oral anticoagulants (NOAC's) to catheter approaches for AF ablation. This paper will summarize the newest data that will affect the perioperative management of these patients.

Haemorrhagic stroke due to rivaroxaban and use of prothrombin complex concentrate as a reversal agent

Background Oral anticoagulation for stroke prevention in atrial fibrillation significantly reduces the risk of thromboembolism; however, intracranial haemorrhage is a serious complication. The novel oral anticoagulants such as rivaroxaban have been shown to be as efficacious as conventional therapy but with a lower risk of bleeding, specifically intracranial bleeding events. Clinical details A 68-year-old male presented to the emergency department with sudden onset confusion, severe frontal headache, photophobia and word finding difficulty. His blood pressure was 224/169 mmHg on admission and he had an irregularly irregular pulse rate of 99 bpm. A computed tomography of the head confirmed a posterior parietal intracranial haemorrhage, which was attributed to recent (3 weeks prior) commencement of rivaroxaban 15 mg daily for stroke prevention in the context of normal renal function. Outcome Intravenous (IV) hydralazine, oral amlodipine and topical glyceryl trinitrate were given to control blood pressure. Prothrombin complex concentrate was used to reverse the effects of rivaroxaban and prevent further bleeding. The patient made an excellent recovery and was discharged with short-term outpatient rehabilitation services. Aspirin was recommenced for stroke prevention 2 weeks after the initial presentation. Conclusion While the new generation of oral anticoagulants offers many benefits in comparison to warfarin (such as fewer drug interactions, more standardised dosing and the lack of need for International Normalised Ratio (INR) monitoring), there still remains a risk of potentially fatal bleeding. Careful patient selection and regular follow-up are required to reduce these risks. Patients should be counselled on the bleeding risks associated with the use of novel anticoagulants.

Comparison of the Phase III Clinical Trial Designs of Novel Oral Anticoagulants Versus Warfarin for the Treatment of Nonvalvular Atrial Fibrillation: Implications for Clinical Practice

Although vitamin K antagonists (VKAs) have been the backbone of thromboprophylaxis in nonvalvular atrial fibrillation, their limitations have encouraged the development of a new generation of oral anticoagulants. This review compares the different designs and procedures used to conduct four phase III trials that tested dabigatran, rivaroxaban, apixaban, and edoxaban versus VKAs. Although pharmacologic characteristics and results of the main trials are briefly discussed, this review mainly focuses on study designs, enrollment criteria, populations studied, quality metrics, and transition strategies between oral anticoagulants. While each of the trials was of high quality, performed independently, and led by independent academic groups, substantial differences exist in terms of drug pharmacology and trial characteristics. Caution is advised when comparing results across trials as practicing clinicians strive to personalize anticoagulation treatments for their individual patients. We believe that the differences in the pharmacokinetic and pharmacodynamic profiles of the available novel oral anticoagulants (NOACs), coupled with substantial heterogeneity in the trial populations and designs and procedures used to conduct the trials, support an important role for each of the NOACs dependent upon the specific clinical scenario faced by the practicing clinician.

New Oral Anticoagulants Increase Risk for Gastrointestinal Bleeding: A Systematic Review and Meta-analysis

A new generation of oral anticoagulants (nOAC), which includes thrombin and factor Xa inhibitors, has been shown to be effective, but little is known about whether these drugs increase patients' risk for gastrointestinal bleeding (GIB). Patients who require OAC therapy frequently have significant comorbidities and may also take aspirin and/or thienopyridines. We performed a systematic review and meta-analysis of the risk of GIB and clinically relevant bleeding in patients taking nOAC. We queried MEDLINE, EMbase, and the Cochrane library (through July 2012) without language restrictions. We analyzed data from 43 randomized controlled trials (151,578 patients) that compared nOAC (regardless of indication) with standard care for risk of bleeding (19 trials on GIB). Odds ratios (ORs) were estimated using a random-effects model. Heterogeneity was assessed with the Cochran Q test and the Higgins I(2) test. The overall OR for GIB among patients taking nOAC was 1.45 (95% confidence interval [CI], 1.07-1.97), but there was substantial heterogeneity among studies (I2,61%). Subgroup analyses showed that the OR for atrial fibrillation was 1.21 (95% CI, 0.91-1.61), for thromboprophylaxis after orthopedic surgery the OR was 0.78 (95% CI, 0.31-1.96), for treatment of venous thrombosis the OR was 1.59 (95% CI, 1.03-2.44), and for acute coronary syndrome the OR was 5.21 (95% CI, 2.58-10.53). Among the drugs studied, the OR for apixaban was 1.23 (95% CI, 0.56-2.73), the OR for dabigatran was 1.58 (95% CI, 1.29-1.93), the OR for edoxaban was 0.31 (95% CI, 0.01-7.69), and the OR for rivaroxaban was 1.48 (95% CI, 1.21-1.82). The overall OR for clinically relevant bleeding in patients taking nOAC was 1.16 (95% CI, 1.00-1.34), with similar trends among subgroups. Studies on treatment of venous thrombosis or acute coronary syndrome have shown that patients treated with nOAC have an increased risk of GIB, compared with those who receive standard care. Better reporting of GIB events in future trials could allow stratification of patients for therapy with gastroprotective agents.

A new era of stroke prevention in atrial fibrillation: comparing a new generation of oral anticoagulants with warfarin

Traditionally, warfarin has been used to prevent stroke in patients with atrial fibrillation (AF), but data from large, multinational, prospective, randomized studies suggest that novel oral anticoagulants (NOACs) may be suitable alternatives. These include the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban. These data showed that dabigatran 150 mg twice daily was more effective at preventing stroke than warfarin, with similar rates of major bleeding, while rivaroxaban 20 mg once daily was noninferior to warfarin, with no difference in major bleeding rates. In addition, apixaban 5 mg twice daily was shown to be superior to warfarin for preventing stroke, with lower bleeding rates. Currently, edoxaban is still in clinical trials. NOACs offer more predictable anticoagulant effects than warfarin and do not require regular monitoring; however, different NOACs are associated with varied drug interactions and limitations related to use in certain patient populations. Overall, the clinical data suggest that these novel agents will offer new options for stroke prevention in patients with AF.

Novedades en la prevención secundaria del ictus cardioembólico

Non-valvular atrial fibrillation (NVAF) is the main cause of cardioembolic stroke. Classically, prevention consists of oral antivitamin-K anticoagulants (AVK), which, despite their demonstrated efficacy, continue to be underused due to their numerous drawbacks. Recently, a new generation of oral anticoagulants has been shown to have a better safety profile and greater efficacy than AVK. The studies that have compared rivoraxaban, dabigatran and apixaban with warfarin have also included a substantial proportion of patients who had previously had a stroke. The results of the substudies performed in this population with a high risk of hemorrhagic and embolic events have been consistent with those in the overall populations in these studies. The new anticoagulants are a feasible alternative to AVK in the secondary prevention of ictus in patients with NVAF. When anticoagulant therapy is contraindicated, percutaneous closure of the left atrial appendage could be an alternative.

Challenging pulmonary embolism - A new generation of oral anticoagulants.

Acute pulmonary embolism (PE) is a relatively common cardiovascular emergency, with an estimated annual incidence of 70 cases per 100,000 individuals (1). Occlusion of the pulmonary arterial bed may lead to acute life-threatening but potentially reversible right ventricular failure, highlighting the need for an early and accurate diagnosis. Initial therapy aims primarily at restoration of flow through occluded pulmonary arteries and the prevention of early recurrences.

Preventing Venous Thromboembolic Events After Total Hip Arthroplasty: New Developments in Clinical Practice

Total hip arthroplasty is a frequently performed orthopedic surgical procedure, and the number of these surgeries is expected to increase significantly over the coming years. Patients undergoing joint arthroplasty are at a particularly high risk for developing venous thromboembolic events (eg, deep vein thrombosis and pulmonary embolism). Prevention of postoperative complications is an important responsibility not only for orthopedic surgeons, but also for other clinicians involved in patients' care. Effective thromboprophylaxis is crucial to reduce the risk of developing venous thromboembolism following total hip arthroplasty and is an important goal of therapy. In response to some of the practical limitations of traditional anticoagulants, a new generation of oral anticoagulants has been developed. These agents include the selective factor Xa inhibitors, rivaroxaban and apixaban, and the direct thrombin inhibitor dabigatran etexilate. The objective of this review article is to update hospitalists on the trial data and clinical considerations surrounding the new anticoagulants. Hospitalists play a key role in caring for surgical patients either in a consultative role or in conjunction with surgical teams. Thus, a practical knowledge of recent developments in thromboprophylaxis is essential for providing high-quality, evidence-based care.

Mouse Models, Risk Factors, and Treatments of Venous Thrombosis

Deep vein thrombosis and pulmonary embolism are collectively called venous thromboembolism (VTE) and are a major cause of morbidity and mortality in the United States and Europe. March is deep vein thrombosis awareness month in the United States, and each year Arteriosclerosis, Thrombosis, and Vascular Biology marks this event with a series of reviews on VTE. This year we have 3 excellent articles on (1) mouse models of venous thrombosis, (2) risk factors for VTE in humans, and (3) the new generation of oral anticoagulants that are available to treat VTE. See accompanying articles on pages 556, 563, and 569 The first review, by Diaz et al1 describes how the use of mouse models has increased our understanding of the mechanisms of initiation, propagation, and resolution of venous clots. The obvious advantage of mice is that we can determine the effect of the loss or mutation of any given gene on thrombosis. Indeed, work with P-selectin knockout mice suggested a role for P-selectin in venous thrombosis that was subsequently confirmed in nonhuman primates. It will be interesting to see whether P-selectin inhibitors will be successfully developed as anticoagulant drugs. Mice have several disadvantages, however, including their small size, their resistance to thrombosis, and the surgical challenges of working with small vessels. Diaz et al1 evaluate 4 inferior vena cava (IVC) thrombosis models. The ferric chloride model induces oxidative damage to the vessel wall that produces an occlusive thrombosis. The advantage of this model is that it is …

Anticoagulant management in the cardiovascular setting

Vitamin K antagonists have been used as oral anticoagulants (OACs) for over five decades, yet their use in real-world practice is problematic primarily because of their narrow therapeutic window, exacerbated by extensive food and drug interactions, necessitating regular coagulation monitoring and dose adjustment. Around half of patients receiving warfarin are within the therapeutic range, exposing them to the dangers of under-anticoagulation (i.e. thrombosis formation) or over-anticoagulation (i.e. bleeding). A new generation of OACs with improved pharmacology promises to revolutionize antithrombotic management. Rivaroxaban, apixaban (both oral direct Factor Xa inhibitors) and dabigatran (a direct thrombin inhibitor) all exhibit predictable anticoagulant responses and few drug-drug interactions and do not require routine coagulation monitoring.