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June Issue - Is there a need for specific reversal agents to manage bleeding in patients taking the novel oral anticoagulants?

Jeffrey I Weitz, MD

Jeffrey I Weitz, MD

Jeffrey I Weitz, MD

Professor Jeffrey Weitz is Professor of Medicine and Biochemistry and Biomedical Sciences at McMaster University, Hamilton, ON, Canada, and holds the Canada Research Chair in Thrombosis and the Heart and Stroke Foundation J. Fraser Mustard Chair in Cardiovascular Research. His scientific interests focus on new techniques for identifying and treating the underlying causes of thrombosis, including characterizing the structure and function of various clotting enzymes and their inhibitors. Professor Weitz and his colleagues have also been instrumental in testing new drug regimens that can be administered on an outpatient basis, thereby improving patients’ quality of life and reducing healthcare costs. Click here for a full biography.

Welcome to the June 2015 edition of the Thrombosis Adviser newsletter.

Dear Ladies and Gentlemen,

The main risk associated with anticoagulant therapy is bleeding, regardless of whether a patient is taking a vitamin K antagonist (VKA) or a novel oral anticoagulant (NOAC). It is important to consider that most of the bleeding events that occur with anticoagulants are minor, and include such things as easy bruising, nosebleeds or gum bleeding. Nonetheless, these nuisance bleeding events can be troublesome for patients and are important to address because they can lead to drug discontinuation. Local measures are sufficient to control most of these bleeding events, although it may occasionally be necessary to withhold one or two doses of the anticoagulant.

Major bleeding is more serious. The first step is to assess the severity of the event. Patients with haemodynamic compromise may require supportive measures such as fluid replacement and transfusion of plasma and red blood cells. With concerning bleeding events, such as intracranial haemorrhage (ICH), pericardial bleeding and intraocular or other bleeding into a critical organ or confined space, rapid-acting reversal agents are desirable to reverse the effects of the anticoagulant. VKAs have half-lives ranging from 9 hours (acenocoumarol) to around 5 days (phenprocoumon); it should be noted that, although vitamin K is considered as an antidote for VKAs, it takes at least 6–8 hours to reduce the international normalized ratio (INR) to a near-normal range, even when given intravenously, and administration may need to be repeated, depending on the INR. Therefore, if rapid reversal of the anticoagulant effect of a VKA is needed in a patient with serious bleeding, four-factor prothrombin complex concentrate (PCC) is recommended. PCC is preferred over plasma in such cases because it not only reduces the INR more rapidly with smaller volumes than plasma, but also more reliably enables effective haemostasis in patients requiring surgery. However, rapid INR correction alone may not be sufficient to alter prognosis after VKA-associated ICH.

The NOACs include rivaroxaban, apixaban and edoxaban, which are direct factor Xa inhibitors, and dabigatran, which is a direct thrombin inhibitor. Increasing use of these agents for prevention and treatment of venous thromboembolism and for stroke prevention in patients with non-valvular atrial fibrillation (AF) has heightened interest in reversal agents. Indeed, the lack of specific reversal agents for the NOACs has prompted concerns by some patients and physicians that the outcome of serious bleeding with the NOACs may be worse than that with VKAs. It is important to point out, however, that the results of the randomized phase III clinical studies do not support this perception; not only were there fewer of the most serious bleeding events such as intracranial bleeding and fatal bleeding with NOAC compared with VKA therapy, but the outcome of patients with major bleeding events in most other critical sites was no worse with the NOACs than with VKAs and was, in some cases, better. Gastrointestinal bleeding was the only exception, with rates higher with some of the NOACs than with VKAs, but these events were rarely life-threatening.

The results of observational studies support these concepts. In the Dresden NOAC Registry, which included 1776 patients treated with rivaroxaban in routine practice in Saxony, Germany, only 6.1% of the 1082 reported bleeding events with rivaroxaban were classified as major bleeding (most commonly gastrointestinal bleeding). Over 60% of these were managed conservatively; 6.3% of the major bleeding events were fatal at 90 days. In a US pharmacovigilance study involving over 27,000 patients with AF receiving rivaroxaban, major bleeding occurred at a rate of 2.86%/year, with a case–fatality rate of 2.90%. In a 2-year retrospective analysis of US patients with AF receiving rivaroxaban or dabigatran for stroke prevention, the rates of major bleeding, ICH and fatal bleeding were 0.5%, 0.2% and <0.1%, respectively.

When major bleeding does occur, data from clinical trials and real-world studies indicate that outcomes are often better with NOACs than with VKAs, and that conservative control measures using established bleeding management protocols are usually sufficient. The short half-lives of the NOACs mean that temporarily withholding therapy is often sufficient to control minor bleeding. Of course, the most desirable situation is to prevent bleeding in the first place, and the risk can be minimized by carefully considering the benefit–risk profile of each patient and prescribing the appropriate anticoagulant at the right dose for the right duration, with due consideration of warnings and contraindications listed in the product label. This is especially relevant in patients at a higher risk of bleeding, such as the elderly or those with renal impairment.

PCC has been shown to reverse the anticoagulant effect of rivaroxaban and apixaban in studies of healthy volunteers. However, it is not widely used in clinical practice; in the Dresden NOAC Registry, PCC was used in 9.1% of major bleeding events. Given that there are no data available from dedicated clinical trials to confirm the efficacy and safety of these agents for the management of patients taking NOACs who present with serious bleeding, use of non-specific reversal agents such as PCC, activated PCC or recombinant activated factor VII should be reserved for life-threatening bleeding events, or as a last resort for the treatment of bleeding events for which other measures have failed. If they are to be used, the European Heart Rhythm Association (EHRA) guidelines recommend weight-based doses (25 U/kg) of three- or four-factor PCC repeated once or twice, if needed, and also discuss evidence that supports the use of activated PCC (50 IE/kg) or a coagulation factor VIIa recombinant (90 µg/kg).

On the basis of available data, the current lack of specific reversal agents is not a valid reason to withhold NOACs. NOACs are at least as effective as VKAs, more convenient to administer and are associated with an overall 50% reduction in the risk of intracranial bleeding and a 10% reduction in the risk of all-cause mortality. Nonetheless, specific reversal agents are in development (Table). Results from phase I, II and III studies on these specific reversal agents have been promising; andexanet alfa (Portola Pharmaceuticals) and idarucizumab (Boehringer Ingelheim) have been granted breakthrough therapy designation by the US Food and Drug Administration (FDA). However, the bleeding profiles of the NOACs indicate that specific reversal agents are unlikely to be widely used in clinical practice.

Compound Reversal agent for: Mechanism of action Status
PRT064445/ andexanet alfa (Portola Pharmaceuticals) Rivaroxaban, apixaban and edoxaban Recombinant factor Xa analogue that competes with factor Xa for inhibitor binding All phase III studies in healthy volunteers to be completed by mid-2015 (rivaroxaban and apixaban). Studies in patients with serious bleeding recently started
BI 655075/ idarucizumab (Boehringer Ingelheim) Dabigatran Antibody fragment that binds dabigatran with high affinity Phase III study in patients with serious bleeding or requiring urgent surgery or intervention well underway
PER977/aripazine (Perosphere, Inc.) All NOACs Synthetic small molecule that forms hydrogen bonds with NOACs Phase II study in healthy volunteers showed reversal of anticoagulant effect of edoxaban

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To be of practical benefit, specific reversal agents must be widely and rapidly available in hospitals across the country. Because of their short half-lives, the timing of the last dose of NOAC needs to be ascertained, and creatinine clearance should be determined because impaired renal function may slow drug clearance. Measurement of the anticoagulant effect of the NOACs or plasma drug levels may be helpful to confirm peak levels or risk of overdose; importantly, the results must be interpreted in relation to the time of drug intake and taking into account the pharmacokinetic profile of the drug. Although the activated partial thromboplastin time and prothrombin time may provide useful information about the extent of anticoagulation with dabigatran and rivaroxaban, respectively, more specific assays to measure plasma drug levels are needed to provide more quantitative information.

Yours sincerely,

Jeffrey Weitz,
Hamilton, ON, Canada

Preparation Date: May 2015

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