Lack Of Reversal Agents Research Articles

New and Future Developments in Neurotoxins.

There are 7 known serotypes of botulinum neurotoxins (A through G). Currently, commercially available toxins are those in serotypes A and B. This paper will discuss new toxins on the horizon, developments in prolonging and shortening the duration of outcomes, and novel therapeutic indications on the horizon. To provide insight into new toxins and new therapeutic modalities surrounding toxins on the horizon. The authors have reviewed the relevant literature and shared their insights and opinions as to future developments in toxin research and potential clinical applications. Botulinum neurotoxin type E's faster onset and shorter duration of effect represent true clinical differentiators. Future development of botulinum neurotoxin type E for aesthetic and therapeutic uses will be in areas where fast onset and short duration of effect are desirable. Current challenges with neuromodulators include the need for frequent treatments and lack of reversal agents. Agents to address both challenges and novel indications, including inhibition of melanogenesis, are being developed.

Prescribers' perceptions of benefits and limitations of direct acting oral anticoagulants in non-valvular atrial fibrillation.

Background:There is an acknowledged lack of robust and rigorous research focusing on the perspectives of those prescribing direct acting oral anticoagulants (DOACs) for non-valvular atrial fibrillation (AF).Objective:The objective was to describe prescribers’ experiences of using DOACs in the management of non-valvular AF, including perceptions of benefits and limitations.Methods:A cross-sectional survey of prescribers in a remote and rural area of Scotland. Among other items, the questionnaire invited free-text description of positive and negative experiences of DOACs, and benefits and limitations. Responses were independently analysed by two researchers using a summative content analysis approach. This involved counting and comparison, via keywords and content, followed by interpretation and coding of the underlying context into themes.Results:One hundred and fifty-four responses were received, 120 (77.9%) from physicians, 18 (11.7%) from nurse prescribers and 10 (6.4%) from pharmacist prescribers (6 unidentified professions). Not having to monitor INR was the most cited benefit, particularly for prescribers and patients in remote and rural settings, followed by potentially improved patient adherence. These benefits were reflected in respondents’ descriptions of positive experiences and patient feedback. The main limitations were the lack of reversal agents, cost and inability to monitor anticoagulation status. Many described their experiences of adverse effects of DOACs including fatal and non-fatal bleeding, and upper gastrointestinal disturbances.Conclusions:While prescribers have positive experiences and perceive benefits of DOACs, issues such as adverse effects and inability to monitor anticoagulation status merit further monitoring and investigation. These issues are particularly relevant given the trajectory of increased prescribing of DOACs.

Idarucizumab to revert the anticoagulant effect of dabigatran in traumatic acute subdural haematoma: a case report of first use in Latin America.

Background Direct oral anticoagulants (DOAC) are an attractive alternative over vitamin K antagonists. They have several advantages in primary and secondary prevention of thromboembolisms due to atrial fibrillation, as well as in prevention and treatment of thromboembolic venous disease. They have fast onset action, do not need laboratory controls in patients with normal renal function, and they have practically no interference with the patient’s diet or medications. The strongest objection to their use was the lack of reversal agents that could be used in case of life-threatening haemorrhage or the need for emergency surgery. Dabigatran was the first DOAC to have its own specific reversal agent: idarucizumab, a monoclonal antibody.Case summary We report here the case of a patient undergoing treatment with dabigatran that suffered an expansive subdural haematoma secondary to a cranial injury. The condition was life-threatening and required emergency surgery. Anticoagulation was successfully reversed with idarucizumab.Discussion Emergency surgery in patients in treatment with DOAC is associated with an increased risk of bleeding. With the use of a specific antidote to block the action of the anticoagulant, as in the case of idarucizumab with dabigatran, the risk of complications during and after emergency surgery is reduced. This is the first case report with which the successful use of idarucizumab in Latin America is documented.

New Anticoagulants for the Prevention and Treatment of Venous Thromboembolism

Anticoagulant drugs, like vitamin K antagonists and heparin, have been the mainstay for the treatment and prevention of venous thromboembolic disease for many years. Although effective if appropriately used, traditional anticoagulants have several limitations such as unpredictable pharmacologic and pharmacokinetic responses and various adverse effects including serious bleeding complications. New oral anticoagulants have recently emerged as an alternative because of their rapid onset/offset of action, predictable linear dose-response relationships and fewer drug interactions. However, they are still associated with problems such as bleeding, lack of reversal agents and standard laboratory monitoring. In an attempt to overcome these drawbacks, key steps of the hemostatic pathway are investigated as targets for anticoagulation. Here we reviewed the traditional and new anticoagulants with respect to their targets in the coagulation cascade, along with their therapeutic advantages and disadvantages. In addition, investigational anticoagulant drugs currently in the development stages were introduced.

Abstract TP168: Risk of Stroke and Hemorrhage in Patients Treated With Warfarin Versus Dabigatran Requiring Surgery

Introduction: Patients with atrial fibrillation (AF) cease anticoagulants prior to surgery to minimize bleeding risk. Patients requiring emergency surgery may be particularly vulnerable to bleeding if anticoagulants remain in the blood. This may be especially problematic with dabigatran (DAB) use given its lack of reversal agent. Objective: This study compares stroke or bleeding risk in patients with AF taking DAB or warfarin (WARF) that undergo elective, urgent, or emergent inpatient surgery. Methods: Medicare inpatient claims were used to identify patients with AF who underwent elective (n=20,535) and urgent or emergent (n=24,665) surgery from 11/2010 -12/2012, and had received DAB or WARF within 90 days prior to admission. Outcomes included stroke and major bleeding within 30 days of surgery, and blood units used during the admission. Other patient characteristics included demographics, operation type, and comorbid conditions. Risk adjusted differences in outcomes between patients taking DAB or WARF were estimated within admission category using multivariable regression. Results: DAB was used by 5,495 (12%) of patients prior to admission. Overall, 1.0% of patients had stroke within 30 days of surgery, 1.2% had a major bleeding event, and patients received an average 0.12 units of blood. Stroke and bleeding rates did not differ for patients taking WARF or DAB, overall or within admission category. Among elective admissions, blood units used also did not differ between WARF or DAB patients. Among urgent and emergent admissions, patients taking DAB used significantly fewer blood units than patients taking WARF (0.09 vs 0.18, respectively; p<.001). Results were consistent after controlling for other patient factors in multivariable models. Conclusions: Stroke and bleeding risk in patients taking either DAB or WARF were comparable, while patients taking DAB required significantly fewer blood units than patients taking WARF when undergoing emergency surgery. The lack of a reversal agent for DAB does not appear to increase the risk of complications even for emergency surgery.

The Dabigatran debate.

In the June 2013 issue of this Journal, we described compelling evidence for the use of three novel anticoagulants, including Dabigatran, on the basis of recent large multi-centre trials.1 We acknowledged the approval of NOACs over warfarin in the ESC update and ACCP guidelines, and foresaw the greater usage of these newer, promising, therapies for stroke prevention in non-valvular atrial fibrillation. In our review article, we also advised a degree of caution with NOACs, as ‘experience with these drugs is relatively limited and that there are no currently available agents to reverse their effect in case of major complications, such as bleeding’. At the time, the concern centred around lack of reversal agents, which was discussed in a letter to the Editor, reflecting repercussions felt in the wider medical community.2,3 We had examined and accepted the data from the RE-LY trial to show how NOACs were becoming more acceptable. In light of the emerging concerns regarding the RE-LY trial and Dabigatran, highlighted by a recent BMJ investigation, we review the debate to date, and ask whether or not we, alongside commissioning bodies, now need to retract support for the drug.

Challenges Associated With Widespread Use of Newer Oral Anticoagulants in the United States

Rivaroxaban was recently approved by the US Food and Drug Administration (FDA) for use in the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and to reduce the risk of recurrence of DVT and PE following initial treatment. This drug has already been approved for use in the prevention of DVT and PE occurring after hip or knee surgery and in stroke prevention in patients with nonvalvular atrial fibrillation. The FDA had approved dabigatran to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. These drugs selectively block factor Xa (rivaroxaban and apixaban) and factor IIa (dabigatran) in the coagulation pathway to cause their anticoagulant effect. Warfarin has been the drug of choice for the last 60 years in such indications but requires frequent monitoring and has significant food and drug interactions that require frequent dosing adjustments. The newer oral anticoagulants do not require routine laboratory monitoring and also provide easy-to-use profile due to fixed dosing regimens. However, due to relatively shorter experience and the high cost of these newer agents, their acceptance has been slow. Recent studies have used indices including the number of strokes prevented, life years gained, and quality-adjusted life years (QALY) gained to compare costs. These studies suggest that these drugs might be cost comparable to warfarin. Whether these outcomes can be applied universally or specifically to the patients in the United States may not be a simple task. Many patients in the United States rely on state run Medicaid programs, while there are others with no insurance at all. Warfarin has been added to the ‘‘4-$ list’’ for many US-based pharmacies and thus costs 4$ for a months supply. This makes it an obvious cheap option in comparison to some of the newer oral anticoagulants that may cost as much or more for daily out-of-pocket expense for the uninsured. The insured patients have their own challenges. Sometimes these drugs are not a part of the formulary of the insurance provider, and at other times, patients have to meet with large deductibles. Frequently, when cheaper options are available, doctors have to get preauthorization and justify the use of the more expensive medication to insurance providers prior to prescribing the drug. A study of patients in the United States, performed by Shah and Gage, suggested dabigatran to be cost-effective (based on QALY) for stroke prevention in patients with atrial fibrillation in comparison to warfarin. However, the study group used the average price of warfarin to be 15$ per month and the price of dabigatran to be 9$ per day. As may be expected, the variation in drug prices will significantly affect outcomes of data analysis. Another challenge is the absence of data for the newer oral anticoagulants in special situations such as pregnancy and in children. Special attention is also needed for patients who have renal dysfunction. Dosing adjustments are indicated for newer agents based on creatinine clearance both in chronic therapy and bridging with warfarin or parenteral anticoagulants. Lack of reversal agents is also of concern. Bleeding associated with newer agents may be life threatening and usually requires blood products for reversal. Patient’s compliance is another important factor in maintaining adequate anticoagulation with these newer agents, since they have shorter half-lives and require up to twice daily dosing. The developments in the world of thrombosis have provided more choices to the clinician for oral anticoagulation. As we gain more experience with these drugs, we will continue to learn more about their drug–drug interactions. We may find out about each drug’s distinctive niche patient population (and specific indication) that obtains the most benefit from them and the ones that should not have these newer agents at all. Graded approaches for complications such as bleeding are being suggested, and these may need to be addressed more definitively for the clinician based on broader experience. The studies that are listed here compare newer agents with warfarin based on QALY indices in patients with stroke. Real-life quality indicators in patient population with DVT and PE may also be needed to determine comparative effectiveness and cost efficacy. Addressing these factors may help in shifting the paradigm toward more frequent use of these new oral anticoagulants.

S1399: A Phase IB Study of the Safety and Efficacy of Multiple Doses of CNS 7056 in Volunteers Undergoing Colonoscopy, Including Reversal With Flumazenil

Fast onset/rapid clearance endoscopic sedation (FORCES) is increasingly popular. Propofol is typically administered by anesthesiologists due to a narrow therapeutic index and a lack of reversal agents. A novel benzodiazepine, CNS 7056, is metabolized by tissue esterases (not cytochrome P450) with a faster onset, a shorter duration, and more rapid recovery profile than other available drugs. We performed the first study of CNS 7056 as sedation for colonoscopy.