An official website of the United States government
NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
Andexanet Alfa (Ondexxya): CADTH Reimbursement Review: Therapeutic area: Reversal of FXa inhibitor anticoagulant effects [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2024 Mar.
The Canadian Venous Thromboembolism Research Network (CanVECTOR) is a team of researchers, patients, healthcare professionals, and students from across Canada who work together on developing research questions to improve the quality of care for all patients affected by Venous Thromboembolism Disease (venous blood clots, such as deep vein thrombosis, DVT and pulmonary embolism, PE). This involves: deciding which areas of patient care require new research (What question should we be asking), designing the way research is done (How can we answer the question), conducting research safely and fairly (Getting the answer), and sharing the results with patients, healthcare professionals, the general public or anyone who would benefit from the answer (Sharing the answer) (from CanVECTOR Patient Partners platform).
The input included here is provided by two patient partners with the CanVECTOR network (Carol West, patient partner platform co-lead; Suzanne Dubois, patient representative on the Scientific Steering Committee) who are KT Ambassadors on an ongoing CIHR-funded research project called VTE-COS. (Establishing an International Core Outcome Set for Clinical Trials of Interventions for Venous Thromboembolism). The purpose of this project is to involve patients, caregivers, researchers, clinicians, and other stakeholders to decide together on the best outcomes for venous thromboembolism (VTE) studies. This includes input from international groups to develop a core outcome set that is applicable worldwide. A related patient-led OSSU-funded project aims to empower patient ambassadors (Carol West and Suzanne Dubois) to advocate for outcomes that are important to patients “Empowering patient ambassadors to champion research outcomes that are a priority for people who have lived experience with venous thromboembolism”.
One of the steps of the VTE-COS project was to hold interviews with patients or caregivers with VTE lived experience to identify outcomes that are meaningful to them. Thirty-three interviews have been completed with patients in seven countries, including eight from Canada. Participants all had VTE (DVT = 15, PE = 6, both DVT and PE = 12) and varied treatment experience, including warfarin, DOACs, and low molecular weight heparin, for anywhere from 1-6 months to long-term treatment (over 3 years = 16). We aimed to interview a diverse group and there is a mix of ages, education, racial identify and gender identity (results not yet published are available upon request).
Living with VTE and treatment to reduce the risk of a future blood clot means finding a balance between the risk of another clot and actual or potential side effects. For patients, bleeding is the most concerning potential side effect of treatment. Even if a patient has not experienced serious bleeding, they may live with a fear of bleeding that can impact life choices and daily activities, quality of life, and mental health.
There are several options available for treating VTE and a variety of personal factors that affect a patient’s treatment preferences. Many patients who participated in the VTE-COS study described the burden of treatment with warfarin (the inconvenience of blood monitoring, restrictions on diet or alcohol intake), or with LMWH injections (pain, bruising, discomfort with self-injections). Some patients had started on warfarin or LMWH initially and later switched to a DOAC. There were fewer burdens described with DOACs, but the lack of a reversal agent was mentioned by a few patients. It’s important to consider that some patients with a high risk of another clot will be prescribed blood thinners for the rest of their lives. For a young person with decades of treatment ahead of them this can be daunting.
“So, switching to Rivaroxaban, it really decreased my concerns. Because with INR, as you know, I had to watch for my food. Whenever I travel, I came, I should try to balance against the INR. So, it was really hectic.”
“I would say the priority is the convenience, because it really does affect your life.”
“Like taking Warfarin, the INRs, that was really hard when I had an infant. How do you make that work, right?”
Describing injections:
“At the start, I probably cried every morning taking them. Now that I’m used to taking them, I know where the spots are that don't really hurt putting them in.”
“So, however much I have my misgivings on Warfarin, Warfarin had one benefit. It was reversible. It had all the other things that were not attractive to it, but if you could make some of those things more attractive, or certainly if the new drug that would come on the market to replace or be an alternative to Apixaban, if it had a reversibility aspect to it, I think would be attractive.”
“Because in every other respect at the moment, I’m on a solid state on this drug, other than we may revisit the dose depending on how the next year of nose bleeds happens. But the reversibility aspect, certainly as I get older, and if you get other ailments, or other things, and you worry about doing that emergency ride in an ambulance to the hospital, and the medical professionals can’t do anything surgical to you for at least 24 hours from the time you took that last pill, well, there is consequences to that. And at the moment, I’m relatively healthy. I’m not dwelling on it. But certainly, as I will get older, it will be potentially a thing that will have me re-look at my choice of medication.”
“If an accident happened and the surgery is almost immediate, a reversal agent can help me with it to be going into the emergency surgery safely… Rivaroxaban, as I understand, whilst I can stop for one day, it does not have a reversal agent like warfarin which has vitamin K.”
The results of VTE-COS study will describe all the outcomes of VTE treatments that patients feel are important. Specifically, with respect to bleeding, some patients said they were not concerned about bleeding, but others described fear and changes to their daily lives to avoid the risk of bleeding.
“I’m definitely worried that I’ll have a bleed that can’t be treated, like there will be long-term permanent effects from that, specifically like a brain bleed concerns me a lot.”
“Only that I'm guiding myself not to have wounds, not to cut myself because of that, so that my blood will not gush out like that. I'm guiding myself not to cut any part of my body at all.”
“I was terrified. I did not sleep for that month, I sat up every night, waiting for the bleed…. And I spend every day terrified I’ll bleed again…”
“Yes, I am much more afraid now when I cook, it's all stupid, but to say to me that I should not cut myself…”
“I have a little hemorrhoid, and I suddenly thought to myself, I think this was you know just the very start of anticoagulation. Oh, my goodness, you know, if that hemorrhoid starts bleeding, you know, I'm prone to bleed out, or whatever, you know, obviously I didn't know anything at that point, I just thought that any bleeding might not stop.”
Not applicable.
Not applicable.
We are not advocating for or against a treatment. Our intent is to communicate about outcomes and concerns described by patients who have lived experience with VTE.
To maintain the objectivity and credibility of the CADTH reimbursement review process, all participants in the drug review processes must disclose any real, potential, or perceived conflicts of interest. This Patient Group Conflict of Interest Declaration is required for participation. Declarations made do not negate or preclude the use of the patient group input. CADTH may contact your group with further questions, as needed.
Did you receive help from outside your patient group to complete this submission? If yes, please detail the help and who provided it.
Nicole Langlois, Project Manager, VTE-COS; Senior Research Associate, Ottawa Hospital Research Institute; Manager of Clinical Research, CanVECTOR
Did you receive help from outside your patient group to collect or analyze data used in this submission? If yes, please detail the help and who provided it.
The VTE-COS Research Team was involved in data collection (participant interviews) and analysis of the transcripts from the interviews.
List any companies or organizations that have provided your group with financial payment over the past 2 years AND who may have direct or indirect interest in the drug under review.
Financial Disclosures for VTE-COS Patient Partners (Members of CanVECTOR).
An estimated 750,000 people are currently living with heart failure in Canada (Heart & Stroke Foundation, 2022). In their 2022 Report on the health of Canadians, the Heart & Stroke Foundation estimates that 100,000 Canadians are diagnosed with heart failure each year and this number is on the rise. Heart failure costs the Canadian healthcare system more than $2.8 Billion dollars per year – with the majority of those dollars being spent on acute care. Research has shown that effective patient engagement improves clinical outcomes, prevents hospitalizations, increases patient self-efficacy for managing their condition, and overall quality of life. Despite these findings, few organizations currently exist to help heart failure patients self-manage their condition, provide education and support for patients and families, and advocate for access to care and innovative treatments. The HeartLife Foundation was created in response to this need.
The HeartLife Foundation is a patient-driven charity whose mission is to transform the quality of life for people living with heart failure by engaging, educating, and empowering a global community to create lasting solutions and build healthier lives. HeartLife
Foundation is Canada’s first – and only – national patient-led Heart Failure organization. We are a Federal Charity aimed at raising public awareness of Heart Failure, engaging patients, families, and caregivers to provide education and support, facilitate access to the latest research, innovations, and treatments, and advocate better care for all.
Founded in June 2016 by Dr. Jillianne Code, a heart failure survivor and heart transplant recipient, and Mr. Marc Bains, a heart failure survivor and heart transplant recipient, HeartLife aims to drive healthcare innovation and transformation by adding patient voices to the heart failure conversation. In collaboration with Dr. Sean Virani, one of Canada’s leading heart failure specialists and promoter of patient and family centred care, we endeavour to ensure that there is an open dialogue including patients as partners with healthcare providers, government, and industry across Canada. Our members are all patients along the heart failure continuum, their families and caregivers.
Vision: To create a better everyday life for people living with heart failure.
Mission: The HeartLife Foundation is a patient-driven charity whose mission is to transform the quality of life for people living with heart failure by engaging, educating, and empowering a global community to create lasting solutions and build healthier lives.
Website: www.heartlife.ca
Review of study material and online literature.
Heart failure is a common and growing cardiovascular condition in Canada that affects 750,000 people and results in 100,000 new diagnoses each year. Heart failure is an epidemic and can be caused by anything that damages the heart. While there is no cure for heart failure, medical therapies and lifestyle changes can help manage the condition. Access to care, medical therapies, and support services vary from region to region. Patients with heart failure experience physical, social, and emotional challenges and require daily monitoring and adherence to control their symptoms. Heart failure is commonly associated with comorbidities, anxiety, depression, cognitive decline, and negative impacts on mental health.
HF is commonly associated with Atrial Fibrillation, LVAD’s and Heart Transplant, all which require invasive surgeries. As more people are surviving heart failure, there is a greater need for advanced therapies, increasing the risk of complications from surgical bleeds.
Lives of patients with HF and their family carers dramatically change upon initial diagnoses. People with heart failure experience a wide range of physical, social and emotional challenges. Individual can be born with the disease, develop it throughout their adult lives, or be diagnosed in their later years. Symptoms of heart failure vary among patients. It is a condition that requires daily monitoring, adherence and vigilance on the part of the patient in order to control the delicate balance of symptoms. These symptoms include shortness of breath, extreme fatigue, low blood pressure, dizziness, edema and bloating. Many patients also have palpitations and arrhythmia resulting in the need for ICD’s or Pacemakers. Heart Failure is commonly associated with a variety of comorbidities, anxiety, depression, a decline in cognitive ability, and can have a negative impact on mental health.
There are currently two drugs approved by the US FDA that can be used to reverse the anticoagulant effects of Factor Xa inhibitors: Andexanet alfa and Ciraparantag. Both drugs have been shown to be effective in rapidly reversing the anticoagulant effects of Factor Xa inhibitors and reducing the risk of bleeding in patients who require urgent surgery or are experiencing life-threatening bleeding.
The reversal of FXa (Factor Xa) inhibitor anticoagulants is important in emergency situations where patients taking these medications require urgent surgery or experience life-threatening bleeding. FXa inhibitors, such as rivaroxaban and apixaban, work by inhibiting the activity of Factor Xa, which is a key component of the coagulation cascade. However, this inhibition can increase the risk of bleeding, and in some cases, bleeding can become severe and potentially life-threatening. In these situations, prompt and effective reversal of the anticoagulant effect is critical to prevent further bleeding and ensure the best possible outcome for the patient.
Several reversal agents are available for FXa inhibitors, including andexanet alfa, which has been approved by regulatory authorities for use in the United States and Europe.
The reversal of FXa inhibitor anticoagulants can help patients in emergency situations where they require urgent surgery or are experiencing life-threatening bleeding. FXa inhibitors work by inhibiting the activity of Factor Xa, a key component of the coagulation cascade, and as a result, can increase the risk of bleeding. In some cases, bleeding can be severe and potentially life-threatening, and therefore prompt and effective reversal of the anticoagulant effect is critical to prevent further bleeding and ensure the best possible outcome for the patient. Reversal of FXa inhibitors can also allow for the administration of other medications or interventions that may be needed to control bleeding or manage the underlying condition. In addition, reversal agents can help reduce the need for blood transfusions, which can be associated with various risks and complications. Overall, the reversal of FXa inhibitors can play an important role in improving patient outcomes and reducing the risks associated with anticoagulant therapy for people living with heart failure.
HeartLife did not speak to patients who had experience with the drug under review.
Not applicable.
Andexanet alfa is a reversal agent used to reverse the anticoagulant effects of Factor Xa inhibitors, such as apixaban and rivaroxaban. The benefits of andexanet alfa include:
Overall, andexanet alfa is an important tool for managing patients taking Factor Xa inhibitors who require urgent surgery such as ICD’s, LVAD’s, and Heart Transplant or are experiencing life-threatening bleeding.
To maintain the objectivity and credibility of the CADTH reimbursement review process, all participants in the drug review processes must disclose any real, potential, or perceived conflicts of interest. This Patient Group Conflict of Interest Declaration is required for participation. Declarations made do not negate or preclude the use of the patient group input. CADTH may contact your group with further questions, as needed.
Did you receive help from outside your patient group to complete this submission?
No.
Did you receive help from outside your patient group to collect or analyze data used in this submission?
No.
List any companies or organizations that have provided your group with financial payment over the past 2 years AND who may have direct or indirect interest in the drug under review.
Financial Disclosures for HeartLife Foundation.
The Canadian Stroke Consortium (CSC) is Canada’s national organization for stroke neurologists, neurointerventionalists and stroke professionals. The CSC is a member organization of the Canadian Neurological Sciences Federation (CNSF), encompassing health care practitioners and providers in multiple neurological specialties. We are involved in stroke research, clinical care, and advocacy for treatment and advancement of new and emerging therapies for stroke in Canada, a field which includes the use of both factor Xa inhibitors and intracerebral hemorrhage (ICH). Further details about our organization can be found at www.strokeconsortium.ca.
Members of the Canadian Stroke Consortium have been involved in clinical trials and research programs using andexanet alfa and other therapies for reversal of hemorrhagic complications of direct oral anticoagulants, and have also been involved in the development of clinical guidelines for the use of these medications and the management of intracerebral hemorrhage, including the Heart and Stroke Foundation of Canada Stroke Best Practice Guidelines (www.strokebestpractices.ca). The information used in this submission reflects the expertise of our group as well as reviews of the current status of the literature and best practice recommendations for the management of acute intracerebral hemorrhage, including that secondary to the use of anticoagulants such as factor Xa inhibitors.
In the Canadian context, current practice patterns vary for patients who present to hospital with acute intracerebral bleeding while on anticoagulation therapy with factor Xa inhibitors (apixaban, edoxaban, and rivaroxaban). This is in part due to the absence of availability for widespread use of andexanet alfa, a specific antidote to reverse anticoagulation with these agents, combined with the lack of good evidence of efficacy with empiric use of other non-specific reversal agents, such as 4-factor prothrombin complex concentrate. Of note, while empiric use of 4-factor prothrombin complex concentrate is recommended in practice guidelines for use in patients with acute ICH associated with factor-Xa inhibitors, this remains an off-label indication of use for 4F-PCC.
Acute ICH is associated with high rates of morbidity and mortality, particularly when associated with anticoagulation use including factor Xa inhibitors. A well-known yet modifiable risk factor associated with poor outcomes in these patients is the final hematoma volume. Furthermore, it is also well-known that following the initial hematoma, patients, particularly those on anticoagulation therapy including factor Xa-inhibitors, are at risk of a secondary increase in hematoma volume (also known as hematoma expansion) in the hours following the index event. Consequently, the overall treatment goal is to rapidly reverse and revert the coagulation status of ICH patients in order to prevent or minimise the risk of hematoma expansion. The availability of a specific and targeted anti-factor Xa reversal agent may expedite reversal of anticoagulation status of acute ICH and ultimately decrease the risk of hematoma expansion as a means to improve clinical outcomes, including reduction in death and disability, in these patients.
Considering the treatment goals, please describe goals (needs) that are not being met by currently available treatments.
Currently, there is no targeted and specific reversal agents for anti-factor Xa inhibitors that can be administered in a timely fashion to decrease the risk of hematoma expansion in acute ICH. Furthermore, despite empiric use of non-specific reversal agents (such as 4-F-PCC), there is a lack of established benefit of their use for acute ICH associated with factor Xa inhibitors. As such, there is an immense gap in treatment for patients who use factor Xa inhibitors with intracerebral hemorrhage, and clinicians currently must use therapies that have no established clinical benefit, potentially leading to poorer outcomes.
How would the drug under review fit into the current treatment paradigm?
Given the emergent nature of acute ICH management, administration of andexanet alfa cannot be a complementary or add-on treatment but rather a first-line agent.
Indeed, results of the phase 3/4 open-label ANNEXA-4 study showed that use of andexanet alfa as a first-line agent in patients with acute bleeding events including acute ICH (70% of the cohort), was associated with a rapid and sustained decrease anti-Xa activity levels following bolus administration along with good or excellent hemostasis efficacy occurring in 80% of patients (Stroke 2021; 52:2096-2105). This should be considered in the context of an absence of other specific therapies for reversal of factor Xa inhibitors; therefore, andexanet-alfa would be the first and only clinically proven therapy to date for this condition and would be a first-line therapy for patients with bleeding associated with factor Xa inhibitors.
Which patients would be best suited for treatment with the drug under review? Which patients would be least suitable for treatment with the drug under review?
This therapy would be most appropriate for patients presenting with life threatening hemorrhage, including intracerebral hemorrhage, who are taking factor Xa inhibitors for indications such as prevention of cardioembolism from atrial fibrillation, or for the prevention of venous thromboembolism. This includes a large proportion of Canadian patients with atrial fibrillation, who rely on these medications for prevention of ischemic stroke, but who would be at risk of development of ICh as a result and who, until now, do not have a specific therapy available to block the action of factor Xa inhibitors in an acute situation. Eligible patients would be those who have been diagnosed with intracerebral hemorrhage on CT scan in the emergency department and who are found to have a history of use of factor Xa-inhibitors; eligibility would be determined on the basis of historical exposure to the medication, and patients would be monitored for clinical response as a stabilization in the size of the hematoma, which is currently done through clinical and radiological monitoring and which would be continued, similar to patients given idarucizumab for ICH in the context of direct thrombin inhibitors.
What outcomes are used to determine whether a patient is responding to treatment in clinical practice? How often should treatment response be assessed?
As an emergent treatment, the response to andexanet alfa would be defined initially as reduction in hematoma expansion in ICH, which is typically measured with CT scan or MRI 6-24 hours after the initial presentation. Expansion of hematoma size is a risk factor for poor outcome in ICH, and patients with larger expansion of ICH have increased risk of mortality and disability following ICH. Even a 1 ml reduction in ICH growth can have an impact on long term outcome (Neurology 2006 Apr 25;66(8):1175-81).
What factors should be considered when deciding to discontinue treatment with the drug under review?
Andexanet alfa would be used only in the hyperacute phase on initial presentation; following treatment with a bolus dose and a two-hour infusion of drug, there would be no further therapy indicated for most patients.
What settings are appropriate for treatment with [drug under review]? Is a specialist required to diagnose, treat, and monitor patients who might receive [drug under review]?
Andexanet alfa would be provided in the emergency department to patients presenting with acute ICH. Monitoring would be provided by the use of neuroimaging which is standard-of-care therapy for this condition and would be used under the supervision of a stroke neurologist or emergency room physician with appropriate input from hematologists.
It should be pointed out that andexanet alfa is approved by the United States Food and Drug Administration for this indication, and any approval by Health Canada would be bringing Canadian practice in line with established standards of clinical care for ICH in other jurisdictions.
To maintain the objectivity and credibility of the CADTH drug review programs, all participants in the drug review processes must disclose any real, potential, or perceived conflicts of interest. This conflict of interest declaration is required for participation. Declarations made do not negate or preclude the use of the clinician group input. CADTH may contact your group with further questions, as needed. Please refer to the Procedures for CADTH Drug Reimbursement Reviews (section 6.3) for further details.
Did you receive help from outside your clinician group to complete this submission?
No.
Did you receive help from outside your clinician group to collect or analyze any information used in this submission?
No.
List any companies or organizations that have provided your group with financial payment over the past two years AND who may have direct or indirect interest in the drug under review. Please note that this is required for each clinician who contributed to the input.
Name: Dylan Blacquiere
Position: Assistant Professor of Medicine (Neurology), University of Ottawa
Date: 27-03-2023
COI Declaration for Canadian Stroke Consortium — Clinician 1.
Name: Laura Gioia
Position: Assistant Professor of Medicine (Neurology), Université de Montréal
Date: 27-03-2023
COI Declaration for Canadian Stroke Consortium — Clinician 2.
Name: Dariush Dowlatshahi
Position: Professor of Medicine (Neurology), University of Ottawa
Date: 27-03-2023
COI Declaration for Canadian Stroke Consortium — Clinician 3.
Name: Andrew Demchuk
Position: Professor of Medicine, University of Calgary
Date: 26-03-2023
COI Declaration for Canadian Stroke Consortium — Clinician 4.
Name: Ghazela Basir
Position: Assistant Professor of Medicine (Neurology), University of Ottawa
Date: 27-03-2023
COI Declaration for Canadian Stroke Consortium — Clinician 5.
We are clinicians and clinician-scientists working at McMaster University-affiliated hospitals in Hamilton (Hamilton General Hospital, Juravinski Hospital, St. Joseph’s Healthcare), specializing in adult thrombosis medicine and, in particular, have considerable clinical experience dealing with anticoagulant-associated bleeding and need for urgent anticoagulant reversal in the setting of major (serious) bleeding or need for surgery. Collectively, we manage patients as part of stand-alone Thrombosis Clinical Services in which most, if not all, of anticoagulant-related bleeds and/or reversal are assessed by our service. We manage a considerable number of patients, on average 10-12 per week, who require DOAC reversal because of life-threatening bleeding or need for urgent surgery.
The response herein is based on (a) our clinical experience in managing patients with anticoagulant and, specifically, direct oral anticoagulant (DOAC)-associated bleeding, coupled with (b) our knowledge of related literature. We have not been involved in clinical trials relating to anticoagulant reversal, nor do we have financial COIs with entities that manufacture anticoagulant reversal products (PCCs, idarucizumab, andexanet-a).
In Canada, the only DOAC-specific reversal agent is idarucizumab, which can only be administered for patients who are receiving dabigatran, a DOAC that is not widely used (subjectively, we estimate in 5-10% of all DOAC users). For the vast majority of DOAC users, who are receiving a factor Xa (fXa) inhibitor (apixaban, edoxaban, rivaroxaban) there are only non-specific prohemostatic treatment options, comprising chiefly the 4-factor prothrombin complex concentrates (PCCs). It seems logical and clinically sensible that if there is a reversal agent available for warfarin (PCCs) and dabigatran (idarucizumab), such a reversal agent should be also available for oral fXa inhibitors, especially when these are, by far, the most commonly used anticoagulants.
The management of DOAC-associated bleeding, as with warfarin-associated anticoagulant bleeding, is anchored on non-drug supportive care that includes fluid administration, transfusion of packed red cells and invasive interventions (e.g., endoscopy for gastrointestinal bleeding). Although many DOAC-associated bleeds (subjective estimate is >50%) can be managed with supportive measures, DOAC-specific reversal agents would have benefit in patients with life-threatening bleeding (e.g., associated with cardiovascular collapse) or bleeding at a critical site (e.g., intracranial, spinal, pericardial).
Clinical practice guidelines support the use of DOAC-specific reversal agents (idarucizumab for dabigatran, andexanet-a for oral factor Xa inhibitors) in situations of life-threatening or critical site bleeding. Refs: Cuker A, et al. Am J Hematol 2019;94:697-709; Levy J, et al. J Thromb Haemost 2016;14:623-7; Milling T, et al. Am J Emerg Med 2020;38:1890-1903.
Current treatments for DOAC-associated bleeding in patients who are receiving oral factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) are non-specific and, in some respects, counter-intuitive. Thus, PCCs which are currently the treatment of choice for oral fXa reversal has no effect on eliminating the anticoagulant. Instead PCCs act to increase factors II, VII, IX and X to supra-physiologic levels and, in doing so, potentially overwhelming the inhibitory effect of apixaban/edoxaban/rivaroxaban on factor Xa. In such patients, levels of factors II, VII, IX and X are within normal limits and adding more of these coagulation factors (with PCCs) does not eliminate the active inhibitory action of oral fXa inhibitors and may promote a prothrombotic state. Moreover, there is limited high-quality prospective data to support the efficacy and safety of PCCs. Refs: Kimpton M, et al. Hematology Am Soc Hematol Educ Program 2019;2019:204-208.
For patients who require urgent anticoagulant reversal, the ideal treatment would directly eliminate the anticoagulant action in a drug-specific manner. Thus, PCCs are effective for warfarin-associated bleeding because they directly replace the vitamin K-dependent coagulation factors (II, VII, IX and X) whose levels have been depleted by warfarin action. Similarly, dabigatran and andexanet-a would eliminate the anticoagulant effect of dabigatran and oral fXa inhibitors, respectively.
The use of anticoagulant reversal agents, comprising PCCs, idarucizumab and andexanet-a, have been shown to rapidly reverse the anticoagulant effect of warfarin, dabigatran and oral fXa inhibitors, respectively, but evidence is lacking for all of these agents that their administration affects mortality or serious morbidity. The outcomes measured in these two-arm or single-arm trials are primarily laboratory based, reflecting anticoagulant reversal, and secondary outcomes include subjective assessment (by the treating clinician) of site-specific hemostasis in the setting of major bleeding or need for urgent surgery. Emerging evidence suggests that anticoagulant reversal in patients with intracranial hemorrhage limits hematoma expansion, with the potential to improve neurological functional outcomes in such patients.
Considering the treatment goals, please describe goals (needs) that are not being met by currently available treatments.
Although PCCs and idarucizumab are available for the management of warfarin- and dabigatran-associated bleeding, respectively, such availability is lacking for andexanet-a, which is the specific reversal agent for the most commonly used anticoagulants: apixaban (Eliquis – now generic), edoxaban (Lixiana), and rivaroxaban (Xarelto – now generic). This, in our view, represents an important missed opportunity to ensure clinicians have options for fXa reversal such that clinicians do not have to rely solely on one agent (PCC) that is non-specific, and which may have a prothrombotic effect by increasing coagulation factor levels II, VII, IX and X) to supra-physiologic levels.
In the domain of anticoagulant reversal, clinicians need to have DOAC-specific reversal agents available as a treatment option, especially for bleeding at critical sites (intracranial, spinal, pericardial) and to enable emergency/urgent surgery to safely proceed.
How would the drug under review fit into the current treatment paradigm?
The mechanism of action of andexanet-a is specific to anticoagulants that inhibit factor Xa since andexanet-a acts a decoy molecule to competitively bind to factor Xa (without inactivation), thereby rendering it inaccessible to factor Xa inhibitors. This mechanism of action has applications to reversing all anticoagulants that work through fXa inhibition, whether parenteral agents (low-molecular-weight heparins or fondaparinux) or oral agents (apixaban, edoxaban, rivaroxaban), the latter of which are most widely used.
The drug under review (andexanet-a) would be the first treatment that is specific for the reversal of anticoagulants that act through fXa inhibition. It would be used as a first-line treatment in selected patients who require urgent anticoagulant reversal in the setting of serious, life-threatening bleeding or need for urgent surgery. The drug under review would not be considered for patient’s intolerant to other anticoagulant reversal strategies but would offer clinicians the option of a specific reversal agent for selected clinical circumstances.
If the drug under review becomes available for clinical use, it is expected to shift Canadian practice algorithms and guidance documents (e.g., by Thrombosis Canada – www.thrombosiscanada.ca) so it is included as a treatment option for DOAC reversal. It is expected that its availability will shift management from administering non-specific reversal agents (PCCs), although the extent of this shift is likely to be partial. Stated differently, we expect PCCs to be used for an ‘average’ patient who needs DOAC reversal whereas andexanet-a will be used in selected patients with (a) life-threatening bleeding that does not respond to supportive management (i.e., fluids, packed red cells), (b) critical site bleeding (intracranial, spinal, pericardial), and (c) a need for emergency (within 6-8 hours) or urgent (within 12-24 hours) surgery.
The initial treatment of anticoagulant/DOAC-associated bleeding always encompasses supportive measures; however, such supportive measures are likely to be ineffective for certain types of bleeds (e.g., intracranial) and will not be relevant to patients who are not bleeding but need anticoagulant/DOAC reversal for an emergency/urgent surgery.
Which patients would be best suited for treatment with the drug under review? Which patients would be least suitable for treatment with the drug under review?
As mentioned previously, andexanet-a would be most suitable for patients who are receiving an oral fXa inhibitor (apixaban, edoxaban, rivaroxaban) and (a) have life-threatening bleeding that does not respond to initial supportive measures (fluids, pRBCs), (b) have bleeding at a critical site (intracranial, spinal, pericardial) that can lead to mortality or serious long-term morbidity, and (c) require an emergency (within 6-8 hours) or urgent (within 12-24 hours) surgery.
The decision as to whether to administer andexanet-a is a clinical decision that takes into account (a) the location and severity of the bleed, (b) the time since the last known dose of DOAC (although this is often not known), and (c) potential for improvement, accounting for patient comorbidities and goals of care. There is no widely-available and rapidly accessible laboratory test that can be used to inform this clinical decision as there are no DOAC-specific coagulation tests (as with the INR for warfarin-treated patients) that can be used as DOAC-specific tests (DOAC-calibrated anti-factor Xa levels) are not widely available and interpretation of the DOAC level is problematic. Moreover, routinely-available coagulation tests (INR, aPTT, TT), do not reliably reflect DOAC levels.
Response to treatment has been demonstrated with DOAC reversal agents using laboratory-based evidence for DOAC reversal in the case of dabigatran (normalized dilute thrombin time) and in the case of oral fXa inhibitors (normalized anti-factor Xa levels) that have been shown to occur within minutes after DOAC reversal administration, whether with idarucizumab or andexanet-a.
What outcomes are used to determine whether a patient is responding to treatment in clinical practice? How often should treatment response be assessed?
The principal outcome used to assess the response to andexanet-a is laboratory, namely measurement of anti-factor Xa levels before and after drug administration. However, as noted previously, such measurement testing is not widely available, and clinicians need to rely also on evidence of clinical stabilization of bleeding or intra- and post-operative surgical site hemostasis. In the seminal studies that investigated andexanet-a, both outcomes were measured, demonstrating a rapid and sustained effect on reduction and normalization of anti-factor Xa levels, and also demonstrating (subjectively) stabilization of hemostasis. These studies were not designed or powered to demonstrate improvements in mortality or morbidity (nor were other studies investigating idarucizumab or PCCs). In all studies, laboratory parameters (INR, dilute thrombin time, anti-fXa levels) were the primary outcome to assess efficacy.
What factors should be considered when deciding to discontinue treatment with the drug under review?
This issue does not apply to the product under review since it is administered as a one-time treatment for a short interval (2-4 hour infusion).
What settings are appropriate for treatment with [drug under review]? Is a specialist required to diagnose, treat, and monitor patients who might receive [drug under review]?
As mentioned above, the settings in which the product under review would be administered are patients with (a) life-threatening bleeding that does not respond to supportive management (i.e., fluids, packed red cells), (b) critical site bleeding (intracranial, spinal, pericardial), and (c) a need for emergency (within 6-8 hours) or urgent (within 12-24 hours) surgery.
The setting for its administration would be, typically, in the emergency department, intensive care unit or in-hospital ward.
The clinicians responsible for its administration would be emergency room, critical care, and medical-surgical specialists. In many hospitals, administration of this agent (as with use of PCCs and idarucizumab) would require approval by a specialist thrombosis or hematology service. Ideally, criteria for administration would be developed to reflect the expected case-mix at a particular hospital, for example, for tertiary trauma centers and stroke/neurosurgical referral centers.
No additional comments.
To maintain the objectivity and credibility of the CADTH drug review programs, all participants in the drug review processes must disclose any real, potential, or perceived conflicts of interest. This conflict of interest declaration is required for participation. Declarations made do not negate or preclude the use of the clinician group input. CADTH may contact your group with further questions, as needed. Please refer to the Procedures for CADTH Drug Reimbursement Reviews (section 6.3) for further details.
Did you receive help from outside your clinician group to complete this submission?
No.
Did you receive help from outside your clinician group to collect or analyze any information used in this submission?
No.
List any companies or organizations that have provided your group with financial payment over the past two years AND who may have direct or indirect interest in the drug under review. Please note that this is required for each clinician who contributed to the input.
Name: James D. Douketis MD, FRCPC, FCAHS
Position: Staff Physician, GIM and Thromboembolism Services, St. Joseph’s Healthcare Hamilton, Professor of Medicine, McMaster University
Date: 20-03-2023
COI Declaration for McMaster University Faculty in Hematology/Thromboembolism — Clinician 1.
Name: Dr. Rick Ikesaka
Position: Staff Physician, Hematology and Thromboembolism Services. St. Joseph’s Healthcare Hamilton, Assistant Professor of Medicine, McMaster University
Date: 24-03-2023
COI Declaration for McMaster University Faculty in Hematology/Thromboembolism — Clinician 2.
Name: Dr. Alfonso Iorio
Position: Staff, Thrombosis Service, Juravinski Hospital, Division of Hematology, HHS and Chair, Department of Health Research Methods, Evidence, and Impact, McMaster University
Date: 20-03-2023
COI Declaration for McMaster University Faculty in Hematology/Thromboembolism — Clinician 3.
Name: Dr. Lori Linkins
Position: Staff Physician, JH Thrombosis Service, Associate Professor of Medicine, McMaster University
Date: 21-03-2023
COI Declaration for McMaster University Faculty in Hematology/Thromboembolism — Clinician 4.
Name: Dr. Siraj Mithoowani
Position: Hematology and Thromboembolism, St. Joseph’s Healthcare, Assistant Professor of Medicine, McMaster University
Date: March 24, 2023
COI Declaration for McMaster University Faculty in Hematology/Thromboembolism — Clinician 5.
They physicians creating this submission are members of the Thrombosis and Anticoagulation Team at Dalhousie University and Nova Scotia Health. Drs. Shivakumar and Kelly are members of the Division of Hematology, and Dr. Tran is a member of the Division of General Internal Medicine.
The information in this submission is taken from publicly available publications and guidelines, as well as our own local experience.
In Canada, there are currently no antidotes for the direct Xa inhibitors. Currently, patients with life threatening bleeding or who require an urgent operation who are taking a direct Xa inhibitor have no targeted or specific therapy. Current treatment algorithms would include:
These are not targeted treatments and there is no clinical data to suggest efficacy or safety in this population.
Considering the treatment goals, please describe goals (needs) that are not being met by currently available treatments.
There are no available antidotes for FXa inhibitors. Andexanet alfa is the only targeted antidote for the FXa inhibitors. It directly affects the FXa inhibitors by the way of acting as a decoy protein. This is targeted therapy and has been shown to clearly reduce the in vitro anticoagulant effect of the FXa inhibitors. The large cohort study also found acceptable bleeding rates.
The other option that has reports of being used in patients who are on FXa inhibitors and are bleeding is prothrombin complex concentrate (PCC). This product is intended to reverse patients who are on vitamin K antagonists (VKAs), such as warfarin. VKAs work by reducing the levels of factors II, VII, IX, and X. PCC reverses this by providing these factors, which mechanistically is very logical. Using PCC or coagulation factor replacement for an inhibitor of a coagulation factor is not targeted therapy and is not as logical. In addition, other coagulation factors are being added, which may increase the thrombotic risk unnecessarily. The other potential risk associated with PCC is that there are small amounts of heparin present. Patients who have a history of heparin-induced thrombocytopenia and thrombosis (HITT) would not be able to safely have this product. There is no such concern with andexanet alfa.
There are no published, randomized comparisons between andexanet alfa and PCC. Patients who would require an antidote to FXa inhibitors would be those that are experiencing life-threatening bleeding, life-altering bleeding (e.g. intracranial hemorrhage that could result in permanent disability) or require emergency surgery. The currently available treatment (PCC) would not specifically the mechanism of FXa inhibitors, and thus, may not be improving outcomes in these very sick patients.
How would the drug under review fit into the current treatment paradigm?
Andexanet alfa would be the only treatment (and thus, first line treatment) targeted to patients who are on a FXa inhibitor and are experiencing bleeding or require emergent surgery. Andexanet alfa would be the only medication used in this setting due to the mechanisms described in the answer to 4.1. Thus, it would not make sense to have andexanet alfa be a second line treatment or to follow/combine andexanet alfa with other treatments, such as PCC. If approved, the treatment paradigm would shift to using andexanet alfa.
Which patients would be best suited for treatment with the drug under review? Which patients would be least suitable for treatment with the drug under review?
Patients who would require an antidote to FXa inhibitors would be those that are experiencing life-threatening bleeding, life-altering bleeding (e.g., intracranial hemorrhage that could result in permanent disability), or require emergency surgery, where there would not be time to wait for the FXa inhibitor’s levels to decrease to those acceptable for surgery. These patients would be quite clear clinically, based on examination findings (such as hypotension in the setting of bleeding), radiographic findings (such as hemorrhage size on CT head), or by surgeon judgment.
Patients that would be less suitable to the use of andexanet alfa would be those who last took their FXa inhibitor more than 1-2 days ago (in the presence of normal renal function), who have bleeding that is not life-threatening (e.g., normal blood pressure and heart rate), or those that can have surgery delayed for 1-2 days after their last dose of FXa inhibitor.
What outcomes are used to determine whether a patient is responding to treatment in clinical practice? How often should treatment response be assessed?
Andexanet alpha is used for patients when rapid reversal of anticoagulation is needed due to acute major bleeding, including life-threatening bleeds. A clinically meaningful response to therapy would be excellent or good hemostatic efficacy 12h after infusion. This could be assessed by various imaging modalities depending on the site of initial bleeding, or by a decrease in visible bleeding. Other outcomes that could be used to assess response include a decrease in Hemoglobin or Hematocrit by <20% as compared to baseline. Other important responses would be improvement of symptoms, decreased mortality.
What factors should be considered when deciding to discontinue treatment with the drug under review?
Reasons to discontinue treatment with Andexanet alpha may include infusion reaction, or thromboembolic events. Symptoms of potential infusion reaction can range from urticaria, flushing, or diaphoresis. Most events were defined as non-serious or mild at a rate of about 18%. Over 90% of individuals who had a reaction did not require treatment. There has been reports of thromboembolic events including cerebrovascular accident, transient ischemia attack, pulmonary embolism, deep vein thrombosis, and/or acute myocardial infarction. The median time to a thrombotic event was 7 days.
What settings are appropriate for treatment with [drug under review]? Is a specialist required to diagnose, treat, and monitor patients who might receive [drug under review]?
Andexanet alpha is used for patients when rapid reversal of anticoagulation is needed due to acute major bleeding, including life-threatening bleeds. The use of this medication would be appropriate in the hospital setting including emergency department, critical care unit, or operating room. Specialties that would be relevant in administering Andexanet alpha would include Emergency medicine, Internal medicine (Critical care, Internal medicine, Hematology), anesthesia, and surgical specialists.
Not applicable.
To maintain the objectivity and credibility of the CADTH drug review programs, all participants in the drug review processes must disclose any real, potential, or perceived conflicts of interest. This conflict of interest declaration is required for participation. Declarations made do not negate or preclude the use of the clinician group input. CADTH may contact your group with further questions, as needed. Please refer to the Procedures for CADTH Drug Reimbursement Reviews (section 6.3) for further details.
Did you receive help from outside your clinician group to complete this submission?
No.
Did you receive help from outside your clinician group to collect or analyze any information used in this submission?
No.
List any companies or organizations that have provided your group with financial payment over the past two years AND who may have direct or indirect interest in the drug under review. Please note that this is required for each clinician who contributed to the input.
Name: Sudeep Shivakumar
Position: Head, Division of Hematology
Date: 26-Mar-2023
COI Declaration for Dalhousie University Thrombosis and Anticoagulation Team — Clinician 1.
Name: Erica Kelly
Position: Hematologist, Division of Hematology
Date: 26-Mar-2023
COI Declaration for Dalhousie University Thrombosis and Anticoagulation Team — Clinician 2.
Name: Allen Tran
Position: Internist, Division of General Internal Medicine
Date: 26-Mar-2023
COI Declaration for Dalhousie University Thrombosis and Anticoagulation Team — Clinician 3.
For over 30 years, Thrombosis Canada (www.thrombosiscanada.ca) has been supporting healthcare professionals in sharing expertise to enable improved thrombosis care. From its beginnings as the Thrombosis Interest Group (TIG), led by Dr. Graham Turpie, it has grown in number of members, in the diversity of professions involved in supporting the mission, and in its impact on care. Our diverse membership includes thrombosis experts from across Canada many of whom are also considered to be global experts.
The development of up-to-date clinical guides, tools, patient materials, and resources has resulted in Thrombosis Canada becoming a driving force in improving the care of patients with or at risk for thrombosis. This is demonstrated by the yearly increases in the use of our Apps and website by individuals across Canada and internationally. The influence of our materials is also evident in the widespread feedback that we receive from users and others who reach out to us for updates when new evidence becomes available and in the number of organizations that reference our website and materials. Furthermore, our clinical guides are increasingly considered as Canadian standards of care in the areas of thrombosis and antithrombotic management.
The tools and resources that we produce are central components of our knowledge translation initiatives. We now look to ensuring that all potential users are aware of Thrombosis Canada and the valuable resources that we have to offer. It is our belief that, by increasing awareness and use of our resources, we will continue to improve the care of patients with or at risk for thrombosis. We also strive to expand the education provided to both healthcare providers and patients consistent with our vision. Where appropriate, we also endeavor to work with the community to ensure that patients have access to medications that will improve outcomes based upon research evidence.
Our vision is to improve the health of all Canadians by eliminating morbidity and mortality related to thrombotic disease.
We obtained information from thrombosis experts who manage and research anticoagulant-related bleeding, and people with lived experience of anticoagulation. Patient input was obtained through an open survey of patients on anticoagulants or their caregivers. The survey was developed by an independent team of experts and persons with lived experience from across Canada. The team convened to develop the survey questions, review the draft survey individually and provide recommendations for any changes. The survey was hosted and fielded by an independent organization, Environics Research, in both English and French. Environics distributed the survey to their patient panel and shared a link with Thrombosis Canada for distribution and promotion. Survey responses were gathered from December 12, 2022, to February 6, 2023.
Oral anticoagulants (OACs) including factor Xa inhibitors are used widely to prevent and treat cardiovascular diseases, such as stroke in patients with atrial fibrillation (AF) and venous thromboembolism (VTE). More than 40 million prescriptions for OACs are written annually in North America, including over 7 million in Canada. AF, the most common indication for their use, is associated with a 5-fold increase in the risk of ischemic stroke and affects an estimated 350,000 Canadians. Without OACs, the annual risk of ischemic stroke in AF is approximately 5%; OACs reduce the risk by about 65%. As the second most common cardiovascular disease, approximately 1-2 per 1000 persons per year will receive VTE diagnoses, and the risk of VTE increases with age. Given population aging, AF and VTE and their complications are expected to represent an even greater health problem within Canada and worldwide.
Anticoagulants are the most common cause of medication-related serious harm, in terms of emergency department visits, hospitalizations, and fatalities. Bleeding is the main complication of anticoagulation that limits its use. About 2% to 4% of patients receiving OACs experience major bleeding annually, and another 10% experience clinically relevant non-major bleeding for which they seek medical attention. Bleeding complications increase the short-term risk of death by 35-fold for intracranial bleeding and 5-fold for extracranial bleeding. Patients with OAC-related major bleeding have 30-day mortality rates up to ~10% to 40% (depending on the site of bleeding) emphasizing the need for management strategies to improve outcomes. Bleeding cessation is a clinical priority for OAC-treated patients experiencing severe bleeding complications. Reversal of anticoagulant effect is a key part of managing serious anticoagulant-related bleeding complications in conjunction with supportive measures and procedural intervention.
There are currently no agents available in Canada that reverse the anticoagulant effect of factor Xa inhibitor anticoagulants. In the absence of a specific reversal agent, and based on limited data guiding its use, 4-factor prothrombin complex concentrate (4F-PCC) is used (off-label) as a non-specific hemostatic therapy for factor Xa inhibitor treated patients with serious bleeding complications. The National Advisory Council on Blood and Blood Products Recommendations for use of Prothrombin Complex Concentrates in Canada endorses the use of 4F-PCC when specific reversal agents (e.g. andexanet alfa) are not available as follows: “Specific reversal agents for direct factor Xa inhibitors (including rivaroxaban, apixaban, and edoxaban), such as andexanet alfa, should be used, if available” (https://nacblood.ca). Other guidance from major professional societies has similar recommendations (e.g., American College of Cardiology, American Heart Association/American Stroke Association, Anticoagulation Forum).
Considering the treatment goals, please describe goals (needs) that are not being met by currently available treatments.
There are currently no approved therapies that have been shown to reverse the anticoagulant effect of factor Xa inhibitor anticoagulants. In the absence of reversal agents, 4F-PCC is used off-label to aid hemostasis in factor Xa inhibitor treated patients with serious bleeding by supplying exogenous coagulation factors. 4F-PCC contains plasma-derived inactive vitamin K–dependent coagulation factors. The effect of 4F-PCC on laboratory indices of DOAC anticoagulant effect has been studied in in vivo/ex vivo experiments, animal models, human volunteers, showing conflicting and, at best, modest effects on coagulation tests. Single-arm observational studies of factor Xa inhibitor-treated patients with major bleeding who received 4F-PCC in routine clinical practice have also been reported. Although rates of “hemostatic efficacy/effectiveness” are ~70% to 80% in these studies, rates of mortality up to ~30% and thromboembolism up to 10% are also reported. Given the lack of control group and other methodological limitations in these studies, the incremental benefit and harm of 4F-PCC in this setting are highly uncertain.
How would the drug under review fit into the current treatment paradigm?
Andexanet alfa is a modified human factor Xa variant that reverses the anticoagulant effect of factor Xa inhibitor anticoagulants. There are no other available treatments that reverse factor Xa inhibitors. Judicious use of andexanet (e.g., via institutional protocols) will ensure that it is administered to patients who are most likely to benefit including those with (i) severe/life-threatening acute bleeding, and (ii) suspected or proven clinically significant levels of anticoagulant. Use of andexanet as a first line therapy for patients with serious factor Xa inhibitor associated bleeding is endorsed by The National Advisory Council on Blood and Blood Products Recommendations for use of Prothrombin Complex Concentrates in Canada when specific reversal agents (e.g., andexanet alfa) similar to guidance from other organizations and professional societies (e.g., American College of Cardiology, American Heart Association/American Stroke Association, Anticoagulation Forum).
Which patients would be best suited for treatment with the drug under review? Which patients would be least suitable for treatment with the drug under review?
Candidates for andexanet are patients receiving factor Xa inhibitors (apixaban, rivaroxaban or edoxaban) who present with severe bleeding complications (e.g., life, limb or organ threatening) in whom clinically significant levels of drug are likely present. The presence of clinically significant drug levels can be assessed clinically based on the timing of the last dose in conjunction with estimated drug clearance (drug half-life and kidney/liver function) or based on a calibrated anti-Xa activity assay. Because there is no established threshold for clinically significant hemostatic impairment and most centers do not have factor Xa inhibitor drug levels available (at all, or with sufficiently rapid turnaround time for emergencies) treatment is usually considered based on the timing of the last dose, drug half-life and the patient’s kidney/liver function. Patients with non-serious bleeding are not suitable for andexanet.
What outcomes are used to determine whether a patient is responding to treatment in clinical practice? How often should treatment response be assessed?
Patients presenting with severe bleeding complications are managed in hospital. In clinical practice, the type of monitoring and outcomes depend on the specific site of bleeding (e.g. gastrointestinal bleeding versus intracranial bleeding). In clinical studies, “hemostatic efficacy” of andexanet and 4F-PCC (i.e. cessation of bleeding) has been determined according to site-specific and somewhat variable criteria that have not been prospectively validated. This includes clinical assessment, laboratory testing, and imaging investigations. Thrombotic events and mortality are also key outcomes monitored in clinical practice and reported in clinical studies.
What factors should be considered when deciding to discontinue treatment with the drug under review?
The drug under review is administered as an intravenous bolus followed by a 2-hour infusion. Therefore, given the limited duration of treatment, criteria for discontinuation are not relevant other than unexpected allergic reactions.
What settings are appropriate for treatment with [drug under review]? Is a specialist required to diagnose, treat, and monitor patients who might receive [drug under review]?
As eligible patients (i.e., those with severe bleeding complications) will be managed in the emergency department and/or hospital, it is not appropriate for outpatient clinic use. Andexanet is likely to be administered in an acute care setting (e.g., emergency department) by an emergency department physician. Depending on the site of bleeding, specialists may be involved in the management of these patients (e.g., neurology/neurosurgery for intracranial hemorrhage, gastroenterologists for gastrointestinal bleeding, surgeons for other types of bleeding) but their involvement should not delay the administration of andexanet for immediately life-threatening bleeding.
To assess net clinical benefit of treatments for severe acute bleeding, both the risks of bleeding and thrombosis should be considered. While underlying thrombosis risk is an important consideration, during active serious bleeding the benefit of treatments to ameliorate ongoing bleeding likely outweighs theoretical harms of thrombosis. Patients with serious anticoagulant-related bleeding are at increased risk of thrombosis due to underlying pro-thrombotic conditions, anticoagulant withdrawal, activation of endogenous hemostatic mechanisms to stop bleeding, surgeries/procedures, and prolonged hospitalization. However, these risk factors for thrombosis should not preclude the administration of anticoagulant reversal strategies for patients with actual serious bleeding. Post-bleed assessments and resumption of anticoagulation after bleeding cessation are important for mitigating thrombotic events. For example, in the ANNEXA-4 study, thrombotic events occurred only among patients who had not yet resumed any anticoagulation.
As discussed above, patients with anticoagulant-related serious bleeding are at risk of thrombosis. In a randomized trial of prothrombin complex concentrate (PCC) versus plasma for major warfarin-associated bleeding (Sarode et al, 2013), the rate of thrombotic events was similar among patients treated with plasma (6.4%) compared to those treated with PCC (7.8%). It is important to acknowledge that studies evaluating reversal strategies (idarucizumab, andexanet) or PCC for patients with direct oral anticoagulant (DOAC)-related major bleeding lacked a control arm which limits our understanding about the potential incremental harms of these treatments. The reported rate of thrombotic events among anticoagulant-treated patients with major bleeding appear similar regardless of whether they were treated with plasma, PCC, idarucizumab, or andexanet alfa (about 4% to 10%). Although these reports may suggest some variability in the frequency of thrombotic events, these results should be interpreted with caution as these studies evaluated different treatments and cannot be compared head-to-head due to significant methodological differences (e.g., study design, population, outcomes, data collection, etc.). Cohort studies that retrospectively evaluated outcomes after administration of PCC for factor Xa inhibitor bleeding in routine clinical practice did not have standardized follow-up or assessments and are at risk of ascertainment bias. Further, the rate of thrombosis is influenced by mortality which is a competing event. For example, in one cohort of patients treated with PCC for factor Xa inhibitor associated bleeding, the rate of thrombosis was 4% while the mortality rate was 32% within 30 days.
In our recent patient survey outlined above, 305 individuals responded to the survey (57% female), of whom two-thirds answered on their own behalf while one-third answered as a caregiver. Most respondents (84%) were between 18 and 64 years of age and were taking an anticoagulant for venous thromboembolism (53%), atrial fibrillation (36%) or mechanical heart valve (21%). Among 214 individuals taking oral anticoagulants, 79 (37%) were receiving warfarin, 73 (34%) were receiving apixaban, and 61 (29%) were receiving rivaroxaban. Almost one quarter (23%) of respondents indicated that they had experienced major (serious) bleeding while taking an anticoagulant and of those,15% never restarted their anticoagulant. Almost half (47%) experienced minor bleeding while on an anticoagulant. Although respondents were generally comfortable taking anticoagulation, 75% indicated that they would feel more comfortable if they knew a reversal agent could be used for major bleeding about which 44% indicated was a concern.
To maintain the objectivity and credibility of the CADTH drug review programs, all participants in the drug review processes must disclose any real, potential, or perceived conflicts of interest. This conflict of interest declaration is required for participation. Declarations made do not negate or preclude the use of the clinician group input. CADTH may contact your group with further questions, as needed. Please refer to the Procedures for CADTH Drug Reimbursement Reviews (section 6.3) for further details.
Did you receive help from outside your clinician group to complete this submission?
No.
Did you receive help from outside your clinician group to collect or analyze any information used in this submission? If yes, please detail the help and who provided it.
Environics Research.
List any companies or organizations that have provided your group with financial payment over the past two years AND who may have direct or indirect interest in the drug under review. Please note that this is required for each clinician who contributed to the input.
Thrombosis Canada has received grants from AstraZeneca who have direct interest in the drug under review.
Name: Deborah Siegal
Position: Hematologist (Thrombosis) The Ottawa Hospital; Associate Professor, Department of Medicine and School of Epidemiology and Public Health, University of Ottawa; Associate Scientist, Ottawa Hospital Research Institute
Date: 24-Mar-2023
COI Declaration for Thrombosis Canada — Clinician 1.
Name: David Airdire
Position: Executive Director, Thrombosis Canada
Date: 24-03-2023
COI Declaration for Thrombosis Canada — Clinician 2.
Journal club comprising of local ER physicians in Peel region.
Literature search for articles, and product monograph, EUSEM projects
As the chair of the journal club, I was invited to speak at the European Emergency Congress, where I was pleasantly surprised to hear that this product was already available and in use, and the preliminary experience there thus far. We have been awaiting it for a long time in Canada. With the rise and essential takeover of DOAC anticoagulants replacing Warfarin (when indicated), has caused a void in the treatment algorithm of major bleeds, and clinically significant non major bleeds. While Dabigatran has a reversal agent available, the rest of the direct oral anticoagulants do not have a specific reversal agent to treat these major bleeds. This really handicaps us in the ER as we are the first line of physicians who see and treat the major bleeds in a 24/7 active department. While we use other nonspecific treatments, these do not have any specific action against these new DOAC drugs.
Considering the treatment goals, please describe goals (needs) that are not being met by currently available treatments.
As mentioned above, most patients do not respond to the general treatments, including tranexamic acid, or PCC/activated PCC. Even surgical treatment, if indicated, is often delayed as surgeons have to be called into hospital for these emergencies. Lifesaving and disability decreasing treatment options are required and a specific reversal agent such as Andexanet Alfa would be very helpful in treating our major bleed patients on the DOAC drugs.
How would the drug under review fit into the current treatment paradigm?
Major bleeds or clinically significant non major bleeds that are not amenable for surgical/procedural intervention or where these intervention/s may be significantly delayed. It would be used to stop bleeds, and in some cases to temporize and stabilize the patients for definitive treatment.
Which patients would be best suited for treatment with the drug under review? Which patients would be least suitable for treatment with the drug under review?
Patients on Apixaban or Rivaroxaban with major bleeds presenting to the ER. Of note, the majority of patients on anticoagulation are on one of these 2 medications. Not indicated for patients on warfarin, on Dabigatran or not on anticoagulation.
Also, in patients who are on these medications who need unplanned emergent surgery or invasive procedures, this may be necessary to perform the procedure without causing excessive bleeding.
What outcomes are used to determine whether a patient is responding to treatment in clinical practice? How often should treatment response be assessed?
This will vary to a large degree on the bleeding site. Obviously, mortality, survival to discharge, disability score on discharge are all objective parameters. Even OT assessments of ADL, mobility, speech, functioning are long term outcome measures. In the ER, the measures will be to be able to stabilize the patient, stop the bleed, or at least reduce the severity of the bleeding source. In cases of an intracerebral hemorrhage a quick administration of a reversal agent could mean the difference between life and death to a previously fully functioning patient. Major GI bleeds would also be helped, and the outcome measure would be to get them to OR or GI suite for surgical intervention and definitive treatment and decreasing rate of mortality or amount of disability. Length of stays in hospital may also be a surrogate marker.
What factors should be considered when deciding to discontinue treatment with the drug under review?
This is typically given only to reverse the DOAC. It would not be continued.
What settings are appropriate for treatment with [drug under review]? Is a specialist required to diagnose, treat, and monitor patients who might receive [drug under review]?
I believe we can discuss with a hematologist on call in Emergency situations to get an approval on phone once we have discussed the case. Also, we suggest monitoring for the first year or 2 to ensure appropriate utilization of this product.
We are desperate to have these in the ER departments across Canada for all our patients who are on Rivaroxaban or Apixaban who present with major ongoing bleeds that compromise their life/limb/future disability.
To maintain the objectivity and credibility of the CADTH drug review programs, all participants in the drug review processes must disclose any real, potential, or perceived conflicts of interest. This conflict of interest declaration is required for participation. Declarations made do not negate or preclude the use of the clinician group input. CADTH may contact your group with further questions, as needed. Please refer to the Procedures for CADTH Drug Reimbursement Reviews (section 6.3) for further details.
Did you receive help from outside your clinician group to complete this submission?
No.
Did you receive help from outside your clinician group to collect or analyze any information used in this submission?
No.
List any companies or organizations that have provided your group with financial payment over the past two years AND who may have direct or indirect interest in the drug under review. Please note that this is required for each clinician who contributed to the input.
Name: Indraneel Ghosh
Position: Emergency Physician
Date: 27-03-2023
COI Declaration for ER Journal Club, GTA — Clinician 1.
Name: Dr. Brent Andruko
Position: Emergency Physician
Date: 14-03-2023
COI Declaration for ER Journal Club, GTA — Clinician 2.
Name: Dr. Daniel Shogilev
Position: Emergency Physician
Date: 14-03-2023
COI Declaration for ER Journal Club, GTA — Clinician 3.
Name: Dr. Zafar Ahmad
Position: Emergency Physician
Date: 14-03-2023
COI Declaration for ER Journal Club, GTA — Clinician 4.
Name: Dr. Thomas Campbell
Position: Emergency Physician
Date: 14-03-2023
COI Declaration for ER Journal Club, GTA — Clinician 5.
Copyright © 2024 - Canadian Agency for Drugs and Technologies in Health. Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial- NoDerivatives 4.0 International licence (CC BY-NC-ND).
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