Al Raizah

Initially, 29 statements were developed by the survey development committee and were emailed to the experts for the first voting round. Of them, ten statements reached the consensus level, eight were rephrased without second-round voting, and one was removed. The remaining ten statements were rephrased during the expert meeting and reached the consensus level after the second round of voting. Thus, the present consensus was composed of 28 statements.
I. Trends of NOAC utilization and incidence of major bleeding:
Three statements about the trend of NOAC use in the GCC countries reached the consensus level (Table 1).

Table 1. Experts' Consensus Statements on NOACs Use and Risk of Major Bleeding.

The last decade has witnessed a significant shift in the OACs landscape, characterized by a growing preference for NOACs over traditional VKAs. The experts agreed that the utilization of NOACs over VKAs has significantly increased in the GCC over the last decade (Statement 1). This decision runs in line with global statistics showing a significant increase in NOAC utilization rate from 5% to nearly 30-48% over the past 15 years.[23,24] In the GCC region, published data indicated a dramatic increase in NOAC utilization since 2013 (Figure 1).[17-19,25-28]

Figure 1. Rates of OACs Utilization in Real-world Practice in the GCC Countries.

Several reasons can explain the trends of increased NOAC use in the GCC region. One of the primary drivers of this shift has been the pharmacological advantages that NOACs offer over VKAs. In addition, the increasing prevalence of conditions such as AF and VTE, which are key indications for OACs, has also likely contributed to the growing use of NOACs.[14,29] The patient population in the GCC countries is diverse, with varying comorbidities, age groups, and risk factors,[30,31] which increase the probability of receiving prophylactic OACs.
As the use of NOACs continues to rise in the GCC countries, emergency departments (EDs) are anticipated to encounter cases of NOAC-associated major bleeding increasingly. In previous retrospective studies from Saudi Arabia, the overall rate of major bleeding ranged from 1.1% to 3.9% in NVAF and VTE patients receiving rivaroxaban or apixaban, while the rate of fatal bleeding was 0.2%.[20,32,33] Another study showed that the rate of intracranial hemorrhage (ICH) in patients receiving rivaroxaban in Saudi Arabia was 0.58%.[34] Therefore, the healthcare system must anticipate and prepare for the increased encounters of NOAC-associated major bleeding in the GCC region by adopting local recommendations and guidelines for clinical care pathways and management of NOAC-associated major bleeding.
The type and indication of NOACs, as well as patient-specific factors, appear to play a role in the risk of bleeding.[35] The experts agreed that the risk of major bleeding varies for different types of NOACs in clinical practice (Statement 2). Thus, clinicians must consider these differences, along with patient-specific factors (e.g., renal function, concomitant medications, and bleeding history), when selecting the most appropriate anticoagulant for each patient.
Despite the growing number of published guidelines,[36-39] there is no universal agreement on the definition of major bleeding. The experts agreed on adopting the definition of the 2020 American College of Cardiology (ACC) consensus.[12] The ACC consensus defines NOAC-associated major bleeding as bleeding that fulfills one or more of the following: bleeding in a critical site; bleeding causes hemodynamic instability; and/or bleeding that causes hemoglobin drop ≥ 2g/dL or transfusion of ≥ 2 units of packed red blood cells (Statement 3).
II. Clinical Care Pathway:
Eight statements about the clinical care pathway for the management of NOAC-associated bleeding reached the consensus level (Table 2).

Table 2. Experts' consensus statements on recommendations for clinical care pathway for major bleeding.

The identification of early signs of major bleeding can positively impact the clinical care pathway and patient outcome.[40,41] Thus, educating patients and their caregivers about the signs and symptoms of major bleeding can empower them to recognize potentially life-threatening events early and seek timely medical intervention (Statement 4).
Several simple and easy-to-use scores have been developed to identify early signs of stroke and ensure rapid access to medical care.[42] The BEFAST (Balance, Eyes, Face, Arm, Speech, Time) criteria were developed to improve the diagnostic accuracy of the original FAST tool in patients with signs of a stroke.[43] In the GCC setting, when paramedics recognize stroke or major bleeding using BEFAST criteria, they are required to activate pre-hospital notifications and transfer patients to the nearest qualified hospital. The decision to use the specific reversal agents then depends on the presence of an emergency medicine consultant or a hematologist (Figure 2).

Figure 2. Patient Journey of NOAC-associated Major Bleeding in the GCC Countries.

Thus, the experts agreed that the Emergency Medical Services (EMS) staff should be aware of the BEFAST stroke assessment criteria. The EMS should Identify the available referral centers clearly and follow a standardized protocol to determine the symptom onset, duration, site, and severity (Statement 5). The EMS staff should be trained to activate pre-hospital notifications and transfer patients with suspected life-threatening bleeding to the nearest qualified hospital (Statement 6).
The initial assessment of bleeding severity, medication history, and clinical presentation in patients treated with NOACs is essential for treatment decisions (Statement 7). The current international guidelines indicate that the management of bleeding complications depends primarily on the severity and location of the bleeding.[12,13] Thus, the ED personnel should be aware of the approved NOACs, their complications, side effects, and antidotes (Statement 8).
Alongside the initial assessment, several laboratory measures have been recommended to assess patients with suspected NOAC-associated bleeding, mainly the coagulation profile, including prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen level.[44] However, the PT and aPTT are limited when used for qualitative assessment of NOAC activities.[45] Previous reports suggested that PT and aPPT prolongation is not exclusively associated with NOAC over-dosage and may lead to misleading results.[46-48] In contrast, certain conditions may be associated with normal limits despite elevated NOAC concentrations.[49] Thus, it has been previously advocated that PT and aPTT should not be used alone.[50]
Quantitative assessment of NOAC levels is crucial to determine the serum concentration of the NOAC. Specialized assays, such as the anti-factor Xa assay (for rivaroxaban and apixaban) and the diluted thrombin time (dTT) or ecarin clotting time (ECT) for dabigatran, can be used to measure the specific NOAC levels.[51-53] One of the critical advantages of measuring NOAC plasma concentrations is the ability to ascertain whether bleeding events are attributable to over-dosage, and that is particularly relevant in acute settings where rapid decision-making is crucial. Establishing the presence of excessive anticoagulation can guide the administration of specific reversal agents, ensuring targeted and efficient management of bleeding complications.[49,54] Moreover, patients experiencing recurrent thrombosis while on NOAC therapy may benefit from plasma concentration testing to evaluate under-dosage or inadequate anticoagulation.[55] While not routinely recommended, adjusting the dosage based on plasma levels could be considered in such cases to optimize anticoagulation and prevent further thrombotic events. Additional clinical scenarios where NOAC plasma concentration testing is valuable include before initiating treatment, in preparation for surgical or invasive procedures, and before thrombolytic therapy for acute ischemic stroke.[50] Qualitative assays can also provide information on the NOAC activity in the case of normal PT or aPTT.[56] Plasma NOAC assays are also commercially available and easy to operate, with comparable results between laboratories.[50]
Despite the benefits and availability of NOAC plasma concentration testing, a notable barrier to its widespread adoption is physician reluctance. This hesitance may stem from a lack of familiarity with the tests, uncertainty about interpreting results, or concerns over the impact of testing on clinical workflow.[12] Addressing these concerns through education and evidence-based guidelines could enhance the utilization of NOAC testing in appropriate clinical scenarios.
Currently, there is significant variability in the laboratory assessment of patients with NOAC-associated major bleeding. Different institutions may have different protocols, and not all laboratories have the capacity to perform specialized NOAC assays. This lack of standardization can lead to variability in patient care and may affect outcomes. Therefore, the ED should be well-equipped with standardized protocols to manage patients with major NOAC-induced bleeding (Statement 9).
All patients receiving NOAC therapy with any neurological manifestation should perform a computed tomography (CT) scan (Statement 10). For patients with life-threatening bleeding, NOACs should be stopped (Statement 11).
III. Management of NOAC-associated Major Bleeding:
In the present consensus, 13 recommendations were developed regarding management approaches for patients with NOAC-associated major bleeding (Table 3).

Table 3. Experts' consensus statements on the management of NOAC-associated major bleeding.

The current guidelines emphasize the importance of a structured and systematic approach to the management of NOAC-associated bleeding. The initial management step is to stabilize the patient's hemodynamics in case of hemodynamic instability.[57-60] The experts agreed that patients with NOAC-associated bleeding should be continuously monitored in the intensive care unit (ICU) with special consideration to the bleeding extent/size, hemodynamic stability, airway management, and consciousness level (Statement 12).
For patients with severe or life-threatening bleeding, activation of a massive transfusion protocol may be necessary.[61] However, previous trials demonstrated better survival and lower risk of recurrent bleeding with restrictive rather than massive transfusion.[62] Additionally, massive transfusion can be associated with life-threatening consequences, such as coagulopathy, transfusion-related acute lung injury, and transfusion-associated circulatory overload.[63] The decision for massive transfusion in NOAC-associated major bleeding should be individualized in patients on NOACs who require a massive blood transfusion with a 1:1:1 ratio of packed RBCs, platelets, and fresh frozen plasma (FFP) (Statements 13 and 14).
In the setting of NOAC-associated bleeding, a comprehensive understanding of concomitant medications and comorbidities is essential. Concurrent use of antiplatelet medications with DOACs can significantly increase the risk of bleeding events.[64] Renal impairment is another critical consideration, as most NOACs, particularly dabigatran, are partially excreted by the kidneys; thus, renal dysfunction can lead to longer half-lives and an increased risk of bleeding.[65] In case of renal impairment, desmopressin acetate or cryoprecipitate may be beneficial in correcting uremia-associated platelet dysfunction.[66,67] Liver disorders, often associated with coagulopathy due to decreased synthesis of clotting factors, can further complicate the bleeding risk and the approach to reversal and hemostasis.[12] Therefore, intensive care specialists must thoroughly know the patient's medication profile and comorbid conditions (Statement 15).
The introduction of specific reversal agents has significantly improved the outcomes of bleeding complications of NOACs and provided a new horizon for better utilization of NOACs in clinical practice. Idarucizumab is a humanized monoclonal antibody fragment (Fab) that binds specifically and with high affinity to dabigatran, neutralizing its anticoagulant effect.[68,69] The pivotal REVERSE AD trial showed that idarucizumab effectively restored normal hemostatic activity in 88 to 98% of the patients with life-threatening/uncontrolled bleeding due to dabigatran. Similar findings were in patients who needed urgent surgery.[70] In 2018, the FDA fully approved idarucizumab as the first reversal agent for restoring hemostasis in dabigatran users with life-threatening/uncontrolled bleeding or needing urgent surgery.[71]
Andexanet alfa is a recombinant modified human factor Xa protein that acts as a decoy receptor for factor Xa inhibitors. It binds to these drugs, reducing their ability to inhibit endogenous factor Xa and reversing their anticoagulant effects.[72] In the ANNEXA-A and ANNEXA-R studies, which evaluated and examined alfa in healthy volunteers, anti-factor Xa activity was reduced by 92-94%, and the thrombin generation was restored in 100% of the patients.[73] In the pivotal phase III/IV ANNEXA-4 trial, which recruited patients with acute major bleeding due to apixaban or rivaroxaban, Overall, 82% of the patients had adequate restoration of homeostasis within 12 hours, while the median reduction in the anti-factor Xa activity was 92% within 18 hours. Within 30 days of follow-up, 10% of the patients had thromboembolic events. The overall mortality rate was 14%.[11] Based on these findings, andexanet alfa was granted accelerated approval by the FDA in 2018 as the first specific reversal agent for apixaban and rivaroxaban-treated patients.[74]
The experts agreed that, in the case of NOAC-induced life-threatening bleeding, specific reversal agents are recommended. Thus, ER personnel should have rapid access to these agents in coordination with the attending hematologist to facilitate quick management decisions and ensure administration within the accepted window of opportunity. If not received in the ED, reversal agents should be administered in the ICU as soon as possible (Statements 16 and 17). Idarucizumab and andexanet alfa are recommended in patients with life-threatening bleeding due to factor IIa and Xa inhibitors, respectively (Statements 18 and 19). The accepted window to administer and examine alfa depends on the NOAC dosage received and pharmacokinetics and can be up to 18 hours after the last dose of the FXa inhibitor (Statement 20). Patients on dabigatran, especially those with renal insufficiency, may benefit from hemodialysis;[12] thus, hemodialysis could be considered (Statement 18). In case the major bleeding etiology [spontaneous versus traumatic bleeding] could not be assessed, immediate reversal of anticoagulation is indicated regardless of the bleeding site unless there is an absolute contraindication (Statement 21).
Measuring plasma concentrations of NOAC before the administration of a specific reversal agent should be considered whenever possible.[50] Although the pivotal clinical trials evaluating the reversal agents did not include the measurement of NOAC concentrations before administrating the reversal agents, post-hoc analyses of registration trials for idarucizumab and andexanet alfa revealed that approximately 30% of patients treated had relatively low NOAC concentrations at the time of antidote administration.[70,75] These findings raise important questions about the necessity and efficacy of administering antidotes without significant NOAC levels, suggesting that some patients may receive treatment without a clear pharmacological need. Measuring NOAC levels before administering antidotes could help identify patients who would most benefit from reversal agents, thereby enhancing the clinical value of antidote administration and preventing unnecessary use.[50] However, in the case of life-threatening bleeding, point-of-care NOAC assessment can be used. The NOAC assays require standardization and calibration for specific NOACs, and the performance and interpretation of these tests require a specialist.[76] Hence, most of the guidelines highlighted the importance of the clinical history of the patient and only using the test of NOACs if the test is available and the results will be ready within less than 20 minutes.[77]
When specific reversal agents are not available, 4-factor PCC, which contains the vitamin K-dependent coagulation factors II, VII, IX, and X, can be used to reverse the effects of NOACs (Statements 18 and 19). Observation studies showed that 4-factor PCC restored the hemostatic efficacy in nearly two-thirds of the patients with major bleeding due to apixaban or rivaroxaban.[78,79] In a recent meta-analysis, it was concluded that it is difficult to determine whether 4F-PCC, in addition to cessation of direct oral FXa inhibitor, is more effective than cessation of direct oral FXa inhibitor alone in patients with direct FXa inhibitor-related major bleeding.[80]
Activated charcoal is a highly porous substance with a large surface area that can bind to various drugs and toxins, thereby reducing systemic absorption. In the context of NOAC-associated bleeding, activated charcoal is considered a potential intervention to limit further drug absorption, especially when the NOAC has been recently ingested.[81] Activated charcoal could be considered with known recent (2-4 hours) ingestion of NOACs (Statement 22). On the other hand, FFP is not recommended due to the lack of supporting evidence and the potential risk of transfusion (Statement 23).
A growing number of studies indicated that NOAC stoppage increased the risk of ischemic events in NVAF patients who experienced major bleeding.[82] Restarting NOAC demonstrated safety and feasibility without increasing the risk of future bleeding.[83] Notably, restarting NOAC was found to be associated with a reduced risk of long-term disability.[84] Nonetheless, limited evidence is available regarding the factors that guide NOAC restarting decision. For instance, conflicting results exist regarding the impact of ICH location (lobar versus subarachnoid), the presence of aneurysm or hematoma, and patient-specific factors (e.g., age, history of thromboembolic events) on the recurrence risk after resuming NOACs.[85-88] The experts agreed that restarting anticoagulants in patients with NOAC-induced major bleeding requires a multidisciplinary team to weigh the risks versus benefits of anticoagulation reintroduction (Statement 24).
IV. Unmet Medical Needs in the GCC Countries:
Four statements about the recommendations to address the current gaps in NOAC-associated bleeding reached the consensus level (Table 4).

Table 4. Experts' consensus statements on the unmet needs for the management of NOAC-associated major bleeding.

The experts agreed on the importance of conducting real-world studies in the GCC to understand the characteristics and outcomes of NOAC-associated major bleeding in the region (Statement 25). Local real-world evidence is vital in the GCC countries, where healthcare systems and patient demographics may differ significantly from those in Western countries.[43] Such evidence can provide insights into patient adherence to NOACs, the incidence and management of major bleeding events, and patient outcomes following such events. It can also help identify potential gaps in healthcare services, such as the need for more widespread availability of reversal agents or more extensive education on NOAC use and bleeding management.[89,90]
The experts agreed on the need for standardized definitions of major and life-threatening bleeding in the GCC setting to allow proper assessment and standardized treatment plans (Statement 26). The lack of standardized definitions for major and life-threatening bleeding can lead to variability in clinical practice, making it challenging to compare data across different studies or healthcare settings.[91] A standardized definition would enable clinicians in the GCC countries to assess the severity of bleeding events uniformly, guide treatment decisions, and allow for more meaningful data comparisons across different healthcare institutions. This standardization could, in turn, lead to more standardized and evidence-based treatment plans for patients experiencing NOAC-associated major bleeding.[92]
In addition, national and institutional guidelines are needed to aid all stakeholders involved in NOAC-associated bleeding management (Statement 27). The development of national and institutional guidelines in the GCC countries can provide an evidence-based and standardized approach to managing NOAC-associated bleeding.
The experts also agreed that cross-specialty collaboration can improve communication, decisions, and outcomes of patients with NOAC-associated bleeding (Statement 28). The management of NOAC-associated major bleeding is complex and often requires the involvement of multiple healthcare professionals, including emergency physicians, hematologists, intensivists, and pharmacists. In the GCC context, fostering cross-specialty collaboration is essential. Such collaboration can facilitate more effective communication among healthcare professionals, leading to quicker and more informed decision-making. It can also promote a more holistic approach to patient care, considering all aspects of a patient's condition and treatment needs.[93,94]

Clinical Care Pathway and Management of Major Bleeding Associated with Nonvitamin K Antagonist Oral Anticoagulants: A Modified Delphi Consensus from Saudi Arabia and UAE