Reversal of Oral Anticoagulants: A Survey of Contemporary Practice Trends (ReACT)

Abstract

This study evaluated practice patterns and factors influencing treatment decisions regarding urgent or emergent reversal of oral anticoagulants (OACs). A 30-question survey was electronically distributed to anticoagulation members of the Anticoagulation Forum. Questions were designed to capture practice trends in the reversal of warfarin, factor Xa inhibitors, and factor IIa inhibitors. Continuous and categorical data were analyzed to generate descriptive statistics. Open-ended questions were summarized by thematic categories. 173 responses were collected most from US-based pharmacists with direct patient care responsibilities. The majority of the respondents’ institutions (90.2%) utilized a guideline or protocol for OACs reversal. Vitamin K (91.3%), activated charcoal (80.4%), and fresh frozen plasma (72.8%) were the most common reversal agents on formulary without restrictions. Most institutions (87.0%) reported having 4-factor prothrombin complex concentrate (4F-PCC) and idarucizumab on formulary, but most commonly (52.2%) with restrictions. Andexanet alfa was only reported on formulary at 35.9% of institutions. In contrast to current guideline recommendations, vitamin K (98.8%) was preferred over 4F-PCC and 4F-PCC (71.6%) was preferred over andexanet alfa as first-line agents used to reverse warfarin and factor Xa inhibitors, respectively. Weight-based dosing strategies for 4F-PCC were commonly utilized for different reversals (41.2%-59.4%). Cost, efficacy, and safety of 4F-PCC were identified as top facilitators and barriers for 4F-PCC adoption in practice. Our findings revealed that guideline recommendations for reversal of warfarin and factor Xa and IIa inhibitors are not followed by a majority of institutions. Studies are needed to investigate strategies to overcome barriers for implementing and following guideline recommendations.

Introduction

Oral anticoagulants (OACs) are the cornerstone for the treatment and prevention of thromboembolic complications for various indications, including acute coronary syndrome, heart valve replacement, venous thromboembolism, and other coagulation disorders. Vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) are the two most commonly used oral anticoagulant classes in the United States (US). Since dabigatran was first approved in 2010, DOACs have overtaken VKAs (eg, warfarin) as the most commonly used OACs due to superior efficacy, safety, and/or convenience. ¹ DOACs include dabigatran (factor IIa inhibitor) and the direct factor Xa inhibitors apixaban, betrixaban, edoxaban, and rivaroxaban. Although effective, OACs are associated with an increased risk of bleeding, including events causing chronic debilitation or death. In clinical practice, the annual incidence rate of VKA-related and DOAC-related major bleeding is estimated to be between 1.5% and 3.5%.^2,3 When major bleeding occurs or an unplanned invasive procedure is approaching, rapid reversal of anticoagulation may be necessary and reversal agents for OACs are often needed.

Several reversal agents are available, including vitamin K, four-factor prothrombin complex concentrate (4F-PCC), three-factor prothrombin complex concentrate (3F-PCC), factor VIII inhibitor bypassing activity (FEIBA), andexanet alfa, idarucizumab, activated charcoal, and recombinant factor VIIa. Vitamin K and 4F-PCC are approved by the Food and Drug Administration (FDA) for warfarin reversal, while idarucizumab is FDA-approved for reversal of dabigatran and andexanet alfa for reversal of apixaban and rivaroxaban. While several clinical guidelines provide recommendations for the use of reversal agents, inconsistencies exist among these recommendations.^4–8 For example, among the guidelines that recommend 4F-PCC for reversal, some suggest using a fixed dosing strategy,^5,6 while others recommend using weight-based dosages.^4,7,8 The inconsistencies in current recommendations may lead to variations in prescribers’ practice. Given the lack of literature describing practice patterns of reversal agents, the purpose of this survey is to evaluate practice patterns for the reversal of OACs and identify factors influencing healthcare providers’ decisions regarding the use of these therapies. Due to inconsistencies in guideline recommendations for 4F-PCC use, a secondary objective of this survey was to investigate practice patterns related to OAC reversal using 4F-PCC.

Methods

A three-section questionnaire (Appendix S1) was developed, and included 28 closed-ended and 2 open-ended questions. The questionnaire comprised 8 questions focused on the demographics of the respondents, 13 questions focused on current practice patterns related to reversal agents for OACs and factors influencing these practices, and 9 questions addressed barriers and facilitators to using 4F-PCC. While many questions were optional to answer, forced responses were incorporated where appropriate to enhance logic among questions. Before release, the survey was piloted by three graduate students who had expertise in survey design and analyses, and three clinical pharmacists with expertise in anticoagulant management. The respondents for the pilot individually reviewed the survey for content clarity, logic among questions, response option format, and ease of completion. Revisions were made based on the feedback received. The survey was developed and distributed through Qualtrics XM (Qualtrics Inc., Provo, Utah).

The survey was electronically distributed to anticoagulation specialists affiliated with the Anticoagulation Forum (AC Forum), the largest peer organization of anticoagulation professionals. ⁹ It was first distributed through email, in the format of a newsletter post, on August 6^th, 2020, followed by a reminder email sent four weeks later. The survey was available for eight weeks in total. All responses were anonymous. The respondents were provided with an option to enter their contact information at the end of the survey to draw a $100 Amazon gift card to incentivize participation. By voluntarily completing and submitting the online survey, consent was implied to participate in this study. This study was approved by the University of Illinois Chicago Institutional Review Board.

Data from submitted surveys were coded and entered into spreadsheets using Microsoft Excel (Microsoft Excel 2016 for Windows; Microsoft Corp., Redmond, WA). Continuous and categorical data were analyzed to generate descriptive statistics. For questions regarding the importance of facilitators or barriers in 4F-PCC utilization, weighted rankings were created by assigning weights to the answer options in the opposite order as the response rankings (eg, the second top facilitator in response to a question with 7 answer options would weigh as 6). ¹⁰ Then, mean weighted scores (MWSs) were calculated by averaging the weighted rankings from all responses. Qualitative analysis was conducted for the open-ended questions and responses were summarized by thematic categories. The dosing patterns of 4F-PCC were compared to current guideline recommendations for different reversal indications.^3–8 The number of respondents for each survey question served as the denominator when calculating response rates.

Results

Demographic and Clinical Characteristics

A total of 173 individuals opened the online survey, 115 answered at least one question (66.5%), and 70 (40.5%) completed the survey in its entirety. The majority of respondents (78.9%) were pharmacists (Table 1), 76.1% were direct patient care providers (79.6% of whom were pharmacists), and 84.3% were based in the US. The majority of respondents practiced in an anticoagulation clinic (39.4%), intensive care unit (26.7%), or emergency department (12.7%). Most respondents practiced at non-profit (47.1%) or academic (32.9%) institutions of moderate (100-499 beds, 50.0%) to large size (>500 beds, 37.1%). Most respondents (88.6%) had more than five years of practice experience, including 62.9% with 10 or more years of experience.

Table 1.

Demographic Information for Survey Respondents.

Characteristics	Overall (N)	Percentage %
Profession (N = 71)
Pharmacist	56	78.9%
Physician	12	16.9%
Other	3	4.2%
Role in the Anticoagulation Department (N = 71) a
Direct patient care provider	54	76.1%
Indirect patient care provider	37	52.1%
Administrator	7	9.9%
Other	5	7.0%
Practice Setting (N = 71) a
Anticoagulation Clinic	28	39.4%
Medical/Surgical Intensive Care Unit	12	16.9%
Emergency Department	9	12.7%
Neurosurgical Intensive Care Unit	4	5.6%
Trauma Center Intensive Care Unit	3	4.2%
Other	16	22.5%
Type of Institution (N = 70)
Non-profit	33	47.1%
Academic	23	32.9%
Governmental	9	12.9%
For-profit	5	7.1%
Capacity of the Institution (N = 70)
<100 beds	9	12.9%
100–499 beds	35	50.0%
> 500 beds	26	37.1%
Years of Practicing (N = 70)
<5	8	11.4%
≥5 and <10	18	25.7%
≥10 and <20	28	40.0%
≥20	16	22.9%

^a More than one options could be selected by the respondents.

Current Practice Patterns of Reversal Agents

The top indications for OAC reversals were intracranial hemorrhage (ICH) (93.9%; Table 2), need for urgent or invasive procedures (87.8%), major bleeding involving airway (71.3%), and spinal hemorrhage (67.8%). Most institutions (84.8%) assessed the outcomes of patients who required OAC reversal. Major bleeding events (92.7%), post-OAC reversal thromboembolism (83.6%), and anticoagulant-related mortality (78.2%) were commonly evaluated outcomes. The majority (90.2%) of respondents reported their institutions had a guideline or protocol for emergent OAC reversals. Among the institutions that had a guideline or protocol, the majority updated their protocol in the past three years to include recommendations for the use of 4F-PCC for OAC reversals. The 2019 Anticoagulation Forum Guideline on Reversal of Direct Oral Anticoagulants (68.9%) and 2017 American College of Cardiology (ACC) Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants (55.7%) were the guidelines most commonly used to inform institutional protocols. A minority of responders reported their institutional protocol for OAC reversal incorporates consultation with hematologists (or hematology team, 28.3%) or pharmacists (22.8%).

Table 2.

Prescribing Patterns of Oral Anticoagulant Reversal Agents at Respondents’ Institutions. ^a

	Overall (N)	Percentage %
Indications for Reversal of OACs (N = 115)
Intracranial hemorrhage	108	93.9%
Need for urgent or emergent surgery or invasive procedure	101	87.8%
Major bleeding involving airway (including posterior epistaxis)	82	71.3%
Intra- or extra-axial spinal hemorrhage	78	67.8%
Other non-major bleeding not mentioned above (eg, gastrointestinal, intra-abdominal)	72	62.6%
Pericardial tamponade	60	52.2%
Intraocular hemorrhage	54	47.0%
Intentional or unintentional overdose of an oral anticoagulant	36	31.3%
Coagulopathy without major bleeding	23	20.0%
Other	2	1.7%
Practice Guide Utilized (N = 92)
Guideline/protocol for reversal agents	83	90.2%
Recommend the use of 4F-PCC for OA reversal b	73	94.8%
Consultation with hematologist or hematology consult team by mandate	26	28.3%
Consultation with pharmacist by mandate	21	22.8%
Outcomes Assessed (N = 55)
The incidence of major bleeding events	51	92.7%
The incidence of thromboembolism	46	83.6%
The incidence of anticoagulant related mortality	43	78.2%
Other	4	7.3%
Top Criteria for 4F-PCC Utilization (N = 78)
Bleed at a critical site (eg Intracerebral hemorrhage, cardiac tamponade, etc)	66	84.6%
Hemodynamic instability	61	78.2%
Consultation with hematologist or hematology consult team by mandate	46	59.0%
Clinically overt bleeding with a hemoglobin decrease of ≥ 2 g/dl and/or administration of ≥ 2 units of packed red blood cells	39	50.0%

OAC = oral anticoagulant, 4F-PCC = four-factor prothrombin complex concentrate.

^a More than one options could be selected by the respondents.

^b 77 participants responded to this question.

Reversal agent formulary status summary at the institutions is provided in Figure 1. Vitamin K (91.3%), activated charcoal (80.4%), and fresh frozen plasma (72.8%) were generally reported as being on formulary without restrictions. While 4F-PCC (87.0%), idarucizumab (78.3%), and recombinant factor VIIa (72.8%) were on most formularies, the majority of institutions (>50%) restricted their use. A minority of institutions had FEIBA, andexanet alfa, or 3F-PCC on their formularies. In fact, at many institutions, 3F-PCC (63.0%), andexanet alfa (60.9%), and FEIBA (44.6%) were not on formulary nor available for use.

Figure 1.

Oral anticoagulant reversal agent formulary Status at participants’ institutions (N = 92). 4F-PCC = four-factor prothrombin complex concentrate, 3F-PCC = three-factor prothrombin complex concentrate, FEIBA = factor VIII inhibitor bypassing activity.

The preferred reversal agents and dosing practice for reversal of each OAC class are summarized in Table 3. Vitamin K (98.8%) and 4F-PCC (61.5%) were the preferred first-line agents for urgent or emergency reversal of warfarin, whereas 4F-PCC (71.6%) and idarucizumab (82.5%) were preferred first-line agents for reversing factor Xa and IIa inhibitors, respectively. For VKA reversals with 4F-PCC, 59.4% utilized weight-based dosing strategies and 10.9% used fixed dosing strategies recommended by current guidelines and/or the FDA.^6–8,11 For factor Xa inhibitor reversal with 4F-PCC, less than half of respondents reported using weight-based dosing (41.2%) or a fixed-dose (20.6%) strategy recommended by guidelines.^4–8 Similarly, when used for factor IIa inhibitor reversal, only 44.4% of the respondents reported utilizing weight-based dosing of 4F-PCC recommended by guidelines.^4–8

Table 3.

First-Line Agents and 4F-PCC Dosages Used in Urgent or Emergent Oral Anticoagulant Reversal. ^a

	Reversal of warfarin (N = 83)	Reversal of factor Xa inhibitors (N = 81)	Reversal of factor IIa inhibitors (N = 80)
First-line agents	Vitamin K (98.8%) 4F-PCC (61.5%) Plasma (12.2%) Activated charcoal (6.0%) Recombinant factor VIIa (2.4%) 3F-PCC (2.4%)	4F-PCC (71.6%) Activated Charcoal (28.4%) Andexanet Alfa (19.75%) Plasma (6.2%) 3F-PCC (2.5%) FEIBA (1.2%)	Idarucizumab (82.5%) Activated Charcoal (23.8%) 4F-PCC (7.5%) Plasma (6.25%) 3F-PCC (3.8%)
	Reversal of warfarin (N = 75)	Reversal of factor Xa inhibitors (N = 68)	Reversal of factor IIa inhibitors (N = 27)
4F-PCC dosages	Recommended by FDA and guidelines6,7,8,11: Wt-based dose according to INR b (59.4%) Fixed-dose: 1500 units for ICH, 1000 units for all other (10.9%)	Recommended by guidelines5–8: Wt-based dose: 50 units/kg (41.2%) Fixed-dose: 2000 units for all (20.6%)	Recommended by guidelines5–8: Wt-based dose: 50 units/kg (44.4%)
4F-PCC dosages	Dosing strategies not approved by FDA nor recommended by guidelines Fixed-dose: 1500 units for all (15.6%) Fixed-dose: 1000 units for all (3.1%) Fixed-dose: 500 units for all (1.6%) Other (26.6%) Wt-based doses for ICH and fixed-doses for other indications; other weight-based dosages according to INR; fixed dosages with a different dose	Dosing strategies not recommended by guidelines Wt-based dosage 25 units/kg (8.8%) Fixed-dose: 1500 units for ICH, 1000 units for all other (7.4%) Fixed-dose: 500 units for all (2.9%) Fixed-dose: 1500 units for all (1.5%) Fixed-dose: 1000 units for all (1.5%) Other (25.0%) Wt-based dose for ICH and fixed-doses for others; other weight-based dosages according to INR	Dosing strategies not recommended by guidelines Fixed dose: 1500 units for ICH, 1000 units for all other (14.8%) Fixed-dose: 1500 units for all (11.1%) Fixed-dose: 1000 units for all (3.7%) Fixed-dose: 500 units for all (3.7%) Other (22.3%) Fixed-dose 2000 units for all; one rescue dose of 1500 units as needed; Wt-based dosage 25 units/kg only

4F-PCC = four-factor prothrombin complex concentrate, 3F-PCC = three-factor prothrombin complex concentrate, FEIBA = factor VIII inhibitor bypassing activity, FDA  =  the Food and Drug Administration in the United States, INR = International Normalized Ratio, ICH  =  intracranial hemorrhage, Wt  =  weight.

^a More than one options could be selected by the respondents.

^b 25 units/kg for INR 2–4, 35 units/kg for INR 4–6, 50 units/kg for INR > 6.^5,8

In the past three years, the majority of institutions using 4F-PCC (59.5%) reported an overall increase in its usage. Among patients who required OAC reversal in the past year, 50.6% estimated that the majority (>50%) of patients requiring OAC reversal were appropriate candidates for 4F-PCC. Similarly, among patients treated with 4F-PCC in the past year, 51.3% estimated that the majority (>50%) of patients treated with 4F-PCC were appropriate candidates. However, more than one-third of respondents felt that few patients (≤25%) requiring OAC reversal were good candidates for 4F-PCC and, likewise, few patients (≤25%) treated with 4F-PCC were good candidates.

Factors Influencing 4F-PCC Use

Potential facilitators and barriers to 4F-PCC use are listed in Figure 2. The top criteria for 4F-PCC utilization included bleeding at a critical site (84.6%), hemodynamic instability (78.2%), consultation with hematology experts (59.0%), and clinically overt bleeding (50.0%). Based on the mean weighted scores (MWSs), the top facilitators for 4F-PCC use were efficacy and safety compared to other reversal therapies, recommendations from national consensus guidelines and/or statements, cost relative to other reversal agents, and the institutional guidelines or protocol for OAC reversals. Cost of 4F-PCC was the dominant barrier influencing the use of 4F-PCC. Other important factors included inconsistencies in efficacy and safety data in 4F-PCC, concern for thromboembolic complications, and inconsistencies between national consensus guidelines and/or statements.

Figure 2.

Weighted ranking of facilitators and barriers for the use of 4F-PCC (N = 77)^a.4F-PCC = four-factor prothrombin complex concentrate. ^a Weights were assigned to each option in the same order as ranking; higher number = stronger facilitator and/or barrier.

Discussion

Anticoagulant reversal plays a key role in managing bleeding that is life-threatening, occurs in a critical site, or is refractory to supportive measures.^3–8 However, as new oral anticoagulants (eg, DOACs) and target-specific reversal agents (eg, andexanet alpha) have been approved, our study highlights important variations in practice patterns related to the clinical use of OAC reversal agents.

Our findings suggest that the use of reversal agents are often inconsistent with recommendations from evidence-based guidelines. Although most recent guidelines.^3,4,6–8 recommend the concurrent use of 4F-PCC with IV vitamin K as the first-line therapy for VKA reversal, nearly 40% of institutions use vitamin K alone or alternatives to 4F-PCC. While we found general accordance between the reported practice and guidelines for factor IIa inhibitor reversal, some inconsistencies existed in the reversal of factor Xa inhibitors. Andexanet alfa, a factor Xa-specific reversal agent, was first approved by the FDA in 2018. While all guidelines published after 2018 recommend using andexanet alfa to reverse factor Xa inhibitors as first-line therapy,^5,6 most respondents reported using 4F-PCC as their first-line option for reversal.

Interestingly, our study evaluated factors influencing the utilization of 4F-PCC and identified that cost, efficacy, and safety of 4F-PCC compared to other reversal agents were both top facilitators and obstacles of its adoption in practice. Not surprisingly, cost was the top-ranked barrier identified in our survey. The average wholesale cost per dose of 4F-PCC to reverse OACs was estimated to be 90 times greater than that of vitamin K and idarucizumab in 2021.^12–14 Thus, the cost of 4F-PCC is likely a barrier to use when VKA reversal is necessary. In contrast, Peled et al estimated the cost of andexanet alfa to be $20,000 to $53,100 higher per treatment compared to 4F-PCC, ¹⁵ which likely explains why cost was a facilitator for 4F-PCC use to reverse factor Xa inhibitors and a deterrent for adding andexanet alfa to the majority of respondents’ institutional formularies. The importance of cost among reversal agents confirms the findings from Faine et al, who found product cost, along with the knowledge of drug availability and product shelf-lives, are strongly associated with the availability and utilization of the reversal agent. ¹⁶ The manufacturer recently reduced the acquisition cost by more than 50%, which may influence future practice patterns.^17,18 Despite this, some have suggested that the relative lack of comparative efficacy and safety profile to 4F-PCC remains a barrier, consistent with our observations. ¹⁹ Our findings suggest discrepancies between 4F-PCC dosing strategies used in practice and recent guideline recommendations. These discrepancies are likely due to uncertain evidence and a lack of consensus on dosing strategies.^4,6,20–23 For VKA reversal, most recent guidelines suggest either a weight-based dose according to INR or fixed-dose based on indications. However, a systematic review from the Netherlands comparing 4F-PCC reversal strategies, including both weight-based and fixed-dose regimens, found no evidence that one dosing strategy was superior to another when a treatment protocol was followed in the practice site. ²⁰ The evidence of dosage for factor Xa and IIa inhibitors is limited, contributing to dosing variations. Nevertheless, our data suggest that for factor Xa reversal, many institutions are not only abstaining from using the preferred agent (andexanet alpha) but using doses of 4F-PCC that are inconsistent with guidelines, which collectively may increase the risk of adverse events.

The discordance between the clinical management of reversal agents and current guideline recommendations is consistent with a survey of anesthesiologists that revealed only 32% of institutions had an emergency anticoagulant reversal protocol. ¹⁹ Although not indicated as a first-line agent by recent guidelines, this survey demonstrated that fresh frozen plasma was widely used for emergent VKA reversal and commonly used for emergent DOAC reversals. Additionally, 4F-PCC was only used in one-third of VKA reversals. Only 26% of the anesthesiologists consulted or coordinated with a hematologist regarding OAC reversal management before reversal agent prescribing, which is consistent with our findings.

There are potential limitations to this study. The survey was limited to the members of the AC Forum. Although the AC Forum is one of the largest organizations of anticoagulation specialists, some practitioners manage reversal agents but are not affiliated with the AC Forum and, therefore, did not have the opportunity to participate. Since not all AC Forum members are active clinicians, they may have been unaware of practice patterns at their sites, limiting their participation. Our study is subject to selection bias; those who chose to complete the survey may differ in their expertise and opinions compared to those who did not participate. To improve our survey response rate, we provided incentives and sent out reminder emails. However, the sample size was still limited; response rates for individual questions ranged from 40% (n  =  70) to 66% (n  =  115), which reduced the generalizability of our results. In addition, practice differences between US-based practitioners and non-US practitioners were not able to be assessed due to the study sample size. Nevertheless, by engaging anticoagulation experts from the AC Forum, we believe the richness of our data adds to the current understanding of OAC reversal practices and the contributing. Additional studies are needed to investigate clinical practices that deviate from guidelines and also investigate strategies to overcome barriers for following guideline recommendations.

Conclusion

Guideline recommendations for the reversal of warfarin and factor Xa and IIa inhibitors are not followed by many institutions. For 4F-PCC, we found considerable variation in dosing strategies, which may be related to uncertain evidence and inconsistent consensus recommendations.