Skip to main content
Skip main navigationClose Drawer MenuOpen Drawer Menu

Meta-Analysis of Reversal Agents for Severe Bleeding Associated With Direct Oral AnticoagulantsFree Access

Original Investigation

J Am Coll Cardiol, 77 (24) 2987–3001
Sections

Central Illustration

Abstract

Background

Direct oral anticoagulants (DOACs) have shown a positive benefit-risk balance in both clinical trials and real-world data, but approximately 2% to 3.5% of patients experience major bleeding annually. Many of these patients require hospitalization, and the administration of reversal agents may be required to control bleeding.

Objectives

The aim of this study was to investigate clinical outcomes associated with the use of 4-factor prothrombin complex concentrates, idarucizumab, or andexanet for reversal of severe DOAC-associated bleeding.

Methods

The investigators systematically searched for studies of reversal agents for the treatment of severe bleeding associated with DOAC. Mortality rates, thromboembolic events, and hemostatic efficacy were meta-analyzed using a random effects model.

Results

The investigators evaluated 60 studies in 4,735 patients with severe DOAC-related bleeding who were treated with 4-factor prothrombin complex concentrates (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936). The mortality rate was 17.7% (95% confidence interval [CI]: 15.1% to 20.4%), and it was higher in patients with intracranial bleedings (20.2%) than in patients with extracranial hemorrhages (15.4%). The thromboembolism rate was 4.6% (95% CI: 3.3% to 6.0%), being particularly high with andexanet (10.7%; 95% CI: 6.5% to 15.7%). The effective hemostasis rate was 78.5% (95% CI: 75.1% to 81.8%) and was similar regardless of the reversal agent considered. The rebleeding rate was 13.2% (95% CI: 5.5% to 23.1%) and 78% of rebleeds occurred after resumption of anticoagulation. The risk of death was markedly and significantly associated with failure to achieve effective hemostasis (relative risk: 3.63; 95% CI: 2.56 to 5.16). The results were robust regardless of the type of study or the hemostatic scale used.

Conclusions

The risk of death after severe DOAC-related bleeding remains significant despite a high rate of effective hemostasis with reversal agents. Failure to achieve effective hemostasis strongly correlated with a fatal outcome. Thromboembolism rates are particularly high with andexanet. Comparative clinical trials are needed.

Introduction

Approximately 1% to 2% of the population in Western countries is on long-term anticoagulation (1). Direct oral anticoagulants (DOACs) have overtaken vitamin K antagonists in market share, currently being prescribed in 68% to 79% of new anticoagulated patients in the European Union and the United States (2,3).

Despite being safer than vitamin K antagonists, the introduction of DOACs has been paradoxically associated with an increase in the number of urgent admissions for bleeding complications in some countries, probably due to the increase in the number of candidates for anticoagulation (4).

Adequate supportive care and discontinuation of the DOACs are essential for management of these bleeding complications, whereas additional measures, such as the administration of procoagulants and/or specific antidotes, may be needed to control bleeding (5). Various procoagulant agents, mainly 4-factor prothrombin complex concentrates (4PCC) and others have been tested for the treatment of DOAC-related bleeding with variable success, but can cause thromboembolic events (TEs) (5). Two specific agents for DOAC reversal are currently available: idarucizumab and andexanet alfa (6,7). These new agents are effective in neutralizing the anticoagulant effects of the DOAC, but no prospective trials in comparison with 4PCC are currently available.

We conducted a systematic review and meta-analysis to investigate the clinical outcomes associated with the use of nonspecific reversal of DOAC with 4PCC and specific reversal of DOAC with idarucizumab (for dabigatran) or andexanet (for oral direct FXa inhibitors) in patients with severe or uncontrolled major bleeding.

Methods

Protocol and registration

The protocol was registered in the International Prospective Register of Systematic Reviews PROSPERO, registration number: CRD42018100252.

Eligibility criteria

We included studies evaluating 4PCC, idarucizumab, or andexanet for the treatment of severe/uncontrolled bleeding associated with DOAC use (e.g., potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise; major bleeding associated with a fall in hemoglobin >2 g/dl; or bleeding in a critical area or organ). Case-series with <10 patients were excluded. We excluded subgroups of patients who did not receive a reversal agent, those treated with other less common reversal modalities (e.g., activated prothrombin complex concentrate, recombinant factor VIIa, tranexamic acid, and/or vitamin K) and those in which the administration of the reversal agent was not indicated to treat a major bleeding (see also Supplemental Appendix 4).

Study identification and data collection

We used Medline and CENTRAL for the main literature search (from January 1, 2010, to December 1, 2020). We conducted additional gray literature searches on Google Scholar, websites of regulatory agencies, clinical trial registries, and relevant conference proceedings (see also Supplemental Appendix 1). No language restrictions were applied. Two investigators separately assessed the studies for eligibility (A.G.-O. and A.I.T.-F.), data extraction (A.-G.-O. and P.A.), and risk of bias (A.-G.-O. and G.C.-R.). We contacted the principal investigators by email for additional information or clarification if necessary.

Study characteristics and quality assessment

The following data were collected: type of study, inclusion and exclusion criteria, patient characteristics, type of DOAC, indication for anticoagulation, type and dose of the reversal agent, and duration of the hospital stay and follow-up period.

The quality of nonrandomized studies was assessed using the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS) (8). Inter-rater agreement was assessed with the Kappa statistic using GraphPad QuickCalcs software (9,10). In case of disagreement, we used the worst score of the 2 evaluations.

Outcome measures

Main outcome was all-cause death. A descriptive analysis of the causes of death was also performed.

Total TEs were investigated as a secondary safety outcome. An additional analysis was performed separately for venous thromboembolism (VTE), and arterial thromboembolism (ATE).

Effective hemostasis was also investigated and defined as “excellent/good” hemostasis using the Sarode scale and the Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXA Inhibitors (ANNEXA-4) scale and effective hemostasis “yes” in the International Society on Thrombosis and Haemostasis (ISTH) scale or assessed by other means (using other scales or through the clinical judgment of the investigators) (see Supplemental Table 1 for complete definitions) (11–13).

Rebleeding after initial control of the bleeding episode was also investigated as a secondary outcome. We also collected data on disability after DOAC-related intracranial hemorrhage (ICH).

Quantitative data synthesis

This review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (14). We used the intent-to-treat population and the longest observation period for which data were available. The Freeman–Tukey double-arcsine transformation was performed before data pooling to stabilize the variance of the proportion of events in each study (15). We also performed a comparative meta-analysis of the relative risk (RR) of death in patients who did not achieve effective hemostasis after administration of the reversal agent compared to patients who did achieve effective hemostasis. We used the random effects method in both meta-analyses (proportions and RR) (16). Pooled proportions and RR were presented together with 95% confidence intervals (CIs). Heterogeneity was defined as Higgins index I2 >50% (17). Categorical variables were reported as numbers and percentage, and continuous variables were reported as mean ± SD and range.

Subgroup analyses were performed according to: 1) study duration; 2) reversal agent; 3) type of bleeding; 4) type of study; 5) risk of bias; 6) presence/absence of significant exclusion criteria; 7) hemostatic scale used; and 8) study sponsorship. Meta-regression techniques as well as the aforementioned subgroup analyses were used to analyze potential heterogeneity in the results. All analyses were performed with the OpenMetaAnalyst software version for Windows 10 (18).

Results

Study selection

The bibliographic search identified 1,997 articles and 18 reports from other sources for a total of 2,015 reports (Figure 1, Supplemental Appendix 1). Of these, 1,888 reports were excluded after review of the title and abstract and 67 additional references were excluded after checking of full text (see Supplemental Appendix 2 for the list of excluded reports and causes of exclusion).

Figure 1
Figure 1

Flow Chart of Study Selection

Recommended flow chart in the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” statement (14).

Study design and risk of bias

Sixty studies met the inclusion criteria (19–78). The majority were retrospective cohorts (n = 48), followed by prospective cohorts (n = 10) and clinical trials (n = 2) (Table 1).

Table 1 Characteristics of Studies

First Author, Year (Ref. #) (Study Acronym)Total PatientsTreatmentsType of StudyFollow-Up, DaysMain Effectiveness OutcomeHemostasis Definition?Risk of Bias (RoBANS Scale)Significant Exclusion Criteria
Grandhi, 2015 (19)184PCCRSC90ICH progression on repeated CT scanNoHighNo
Beynon, 2015 (20)554PCC, no reversalRSC30RebleedingNoHighNo
Purrucker, 2016 (21) (RASUNOA ICH)614PCC, no reversalPMC90Hematoma expansionNoModerateNo
Yoshimura, 2017 (22) (SAMURAI-NVAF)104PCCPMC7Hematoma expansion, rebleedingNoModerateNo
Majeed, 2017 (23) (UPRATE)844PCCPMC30Effective hemostasisISTHModerateYes
Schenk, 2018 (24)134PCCPSC30Difference in thrombin generation vs. baselineNoModerateYes
Tao, 2018 (25)434PCCRSC14Continued bleeding despite PCCClinical judgementHighNo
Schulman, 2018 (26)664PCCPMC30Effective hemostasisSarodeModerateYes
Harrison, 2018 (27)424PCCRMC7 (hospital stay)Hemorrhagic expansionNoHighNo
Gerner, 2018 (28) (RETRACE II)1464PCC, no reversalRMC90Hematoma enlargementNoHighNo
Testa, 2018 (29) (START-SSC Events)1174PCC, no reversalPMC180NoneNoModerateYes
Santibanez, 2018 (30)2124PCCRMC14Effective hemostasisOtherHighNo
Arachchillage, 2019 (31)3444PCCRSC30Effective hemostasisOtherHighNo
Smith, 2019 (32)314PCCRSC7Effective hemostasisSarodeHighYes
Müller, 2019 (33)3464PCCRSC5 (hospital stay)NoneNoHighNo
Zada, 2019 (34)534PCCRSC26 (hospital stay)NoneNoHighNo
Dybdahl, 2019 (35)624PCC, no reversalRMC6 (hospital stay)NoneNoHighNo
Frontera, 2020 (36)464PCCRSC30Effective hemostasisSarodeHighYes
Lindhoff-Last, 2020 (37) (RADOA)1934PCC, no reversalPMC30MortalityNoModerateNo
Castillo, 2020 (38)674PCC, aPCCRMC5 (hospital stay)Effective hemostasisANNEXA-4HighYes
Wilsey, 2020 (39)994PCCRSC30Effective hemostasisANNEXA-4,HighNo
Panos, 2020 (40)6634PCC, aPCCRMC30Effective hemostasisSarodeModerateNo
Bavalia, 2020 (41)1224PCC, IDARU, no reversalRMC30Effective hemostasisISTH, SarodeModerateNo
Korobey, 2020 (42)594PCCRSC30Effective hemostasisANNEXA-4HighYes
Allison, 2020 (43)334PCCRSC7 (hospital stay)Effective hemostasisClinical judgementHighNo
Zheng, 2020 (44)244PCCRSC45NoneNoHighNo
Lipari, 2020 (45)1194PCCRMCHospital stayEffective hemostasisANNEXA-4HighNo
Reynolds, 2020 (46)314PCCRSC7Effective hemostasisISTHHighNo
Highsmith, 2020 (47)384PCCRSC30Effective hemostasisISTHHighNo
Nguyen, 2019 (48)224PCC, ADXRSC30Effective hemostasisANNEXA-4HighNo
Johal, 2019 (49)1214PCC, ADXRSC8 (hospital stay)Good outcome in GOSNoHighNo
Ammar, 2019 (50)294PCC, ADXRSCHospital stayICH stability on tomographyNoHighNo
Coleman, 2020 (51)30304PCC, ADX, FFP, other,§ no reversalRMC5 (hospital stay)NoneNoHighNo
Barra, 2020 (52)294PCC, ADXRSC5 for deaths and 30 for TEEffective hemostasisANNEXA-4HighNo
Pollack, 2017 (53) (RE-VERSE AD)503IDARUCT30 and 90Confirmed bleeding cessation within 24 hClinical judgementLowNo
Brennan, 2019 (54)23IDARURSCHospital stayEffective hemostasisClinical judgementHighNo
Sheikh-Taha, 2019 (55)13IDARURSC7 (hospital stay)Effective hemostasisISTHHighNo
van der Wall, 2019 (56)88IDARURMC90Effective hemostasisISTHModerateNo
Okishige, 2019 (57)21IDARURMC7 (hospital stay)Effective hemostasisBleeding cessationHighYes
Wheeler, 2019 (58)80IDARU, no reversalRSC30NoneNoHighNo
Küpper, 2019 (59) (MR REPAIR)32IDARUPMC90NoneNoHighNo
Gendron, 2020 (60)87IDARURMC90Effective hemostasisISTHHighNo
Sarmento, 2020 (61)33IDARURSC30 for deaths and 60 for TENoneNoHighNo
Abdulrehman, 2019 (62)25IDARURMC12 (hospital stay)NoneNoHighNo
Singh, 2020 (63)266IDARURMC8 for deaths and 30 for TENoneNoModerateYes
Yasaka, 2020 (64)262IDARUPSC28NoneNoModerateNo
Kermer,2020 (65)120IDARURMCHospital stayNoneNoHighNo
Vene, 2020 (66)16IDARURMCHospital stayNoneNoHighNo
Haastrup, 2020 (67)46IDARURMC30Effective hemostasisISTHHighNo
Magan, 2020 (68)37IDARURSC30 and 90Bleeding cessationClinical judgementModerateNo
Lombardi, 2020 (69)47IDARURMC30NoneNoHighNo
Connolly, 2019 (70) (ANNEXA-4)352ADXCT30Effective hemostasisANNEXA-4LowYes
Stevens, 2019 (71)13ADXRSC30Effective hemostasisANNEXA-4HighNo
Giovino, 2020 (72)39ADXRSC5 for deaths and 30 for TEEffective hemostasisANNEXA-4HighNo
Brown, 2020 (73)25ADXRMC30Effective hemostasisANNEXA-4HighNo
Nederpelt, 2020 (74)21ADXRMC9 (hospital stay)Effective hemostasisANNEXA-4HighNo
Asad, 2020 (75)14ADXPSC7 (hospital stay)Effective hemostasisANNEXA-4HighNo
Girgis, 2020 (76)11ADXRSC14Effective hemostasisISTHHighNo
Vestal, 2020 (77)19ADXRSC30NoneNoHighNo
Santarelli, 2020 (78)15ADXRSC30NoneNoHighNo

4PCC = 4-factor prothrombin complex concentrate (Beriplex, Octaplex, Kcentra); ADX = andexanet; ANNEXA-4 = Prospective, Open-Label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor Who Have Acute Major Bleeding; aPCC = activated prothrombin complex concentrate (FEIBA: factor eight bypassing agent); CT = clinical trial; FFP = fresh frozen plasma; GOS = Glasgow Outcome Scale; ICH = intracranial hemorrhage; IDARU = idarucizumab; ISTH = International Society of Thrombosis and Hemostasis; PMC = prospective multicenter cohort; PSC = prospective single-center cohort; RADOA = Reversal Agent use in patients treated with Direct Oral Anticoagulants or vitamin K antagonists; RASUNOA ICH = Registry of Acute Stroke Under New Oral Anticoagulants Intracranial Hemorrhage substudy; RETRACE II = German-Wide Multicenter Analysis of Oral Anticoagulation-Associated Intracerebral Hemorrhage II; RE-VERSE AD = REVERSal Effects of Idarucizumab in Patients on Active Dabigatran; RMC = retrospective multicenter cohort; RoBANS = Risk of Bias Assessment Tool for Nonrandomized Studies; RSC = retrospective single-center cohort; SAMURAI-NVAF = Stroke Acute Management with Urgent Risk-factor Assessment and Improvement in patients with non-valvular atrial fibrillation; START-SCC = Survey on anTicoagulated pAtients RegisTer by the Scientific and Standardization Committee (SSC) Control of Anticoagulation of the International Society of Thrombosis and Haemostasis; TE = thromboembolism.

∗ Exclusion criteria potentially affecting death and/or thromboembolic rates: “do not resuscitate order,”“life expectancy of <3 days,” “only comfort measures,” “patients receiving palliative care,” “intracranial bleeding with hematoma >60 ml,” “initial Glasgow coma scale <7,”, “died before repeat imaging,” “history of transplant, or severe valve heart disease,” “recent history of thromboembolic events.” The full list of exclusion criteria is included in Supplemental Table 2 and Supplemental Appendix 5.

† For major bleeds with ICH, hemostatic effectiveness was achieved if the first neuroimaging result within 24 h of 4PCC administration showed no change or an improvement in hematoma volume. For patients experiencing any other type of major bleed, hemostatic effectiveness was achieved if hemoglobin did not decrease by >20% from baseline within 24 h of 4PCC administration.

‡ 4PCC treatment was considered as effective if there was no recurrent bleeding within 48 h of administering 4PCC at the time of presentation with major bleeding or patient did not die directly related to major bleeding. If the patient died as a result of major bleeding or had recurrent bleeding within 48 h of first administering 4PCC was considered as ineffective.

§ “Other” category includes aPCC, 3-factor PCCs, recombinant factor VIIa, tranexamic acid, and/or vitamin K.

The 60 studies included 8,636 patients, of which 4,735 had severe bleeding related to DOAC treated with 4PCC (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936) (see Supplemental Appendix 4 for excluded patients and causes for exclusion).

Interrater agreement on the assessment of the risk of bias of individual studies was high (Kappa = 0.81; 95% CI: 0.65 to 0.96), indicating near-perfect agreement (see also Supplemental Appendix 3). A total of 45 studies were at high risk of bias, 13 were at moderate/unclear risk of bias, and only 2 were at low risk of bias (Table 1).

Ten studies had exclusion criteria potentially altering the rates of death and/or TE (Table 1, Supplemental Table 2).

Patient and treatment characteristics

A total of 4,735 patients were analyzed. The mean age was 77 ± 3.5 years (range: 68 to 86 years), 57% were males and 55% had ICH as the index event (Table 2). The reason for anticoagulation with DOAC was atrial fibrillation (82%), VTE (14%), or other pathologies (4%), and the DOAC type was rivaroxaban (36%), followed by apixaban (32%), dabigatran (31%), and edoxaban (1%) (Table 2).

Table 2 Characteristics of Patients

First Author, Year (Ref. #) (Study Acronym)Assessable Patients, nAge, yrsMales, %ICH, %GIB, %Other, %DOAC Type, %DOAC Indication, %
4PCC
 Grandhi, 2015 (19)18805610000R, 89; A, 11AF, 89; VTE, 6; Other, 6
 Beynon, 2015 (20)31786210000R, 79; A, 13; D, 8AF, 84; VTE; 15, Other, 2
 Purrucker, 2016 (21) (RASUNOA ICH)35766310000R, 77; A, 11; D, 11AF, 100
 Yoshimura, 2017 (22) (SAMURAI-NVAF)10746090100R, 70; A, 20; D, 10AF, 100
 Majeed, 2017 (23) (UPRATE)847557701514R, 54; A, 46AF, 79; VTE, 21
 Schenk, 2018 (24)13806277815R, 100NA
 Tao, 2018 (25)437453374023R, 49; A, 51AF, 77; VTE; 21; Other, 2
 Schulman, 2018 (26)667767552421R, 56; A, 44AF, 86; VTE; 12; Other, 2
 Harrison, 2018 (27)14744310000NAAF, 71; VTE, 18; Other, 12
 Gerner, 2018 (28) (RETRACE II)103775310000R, 79; A, 12; D, 9NA
 Testa, 2018 (29) (START-SSC Events)32796278139R, 50; A, 19; D, 31AF, 85; VTE, 15; Other 0
 Santibanez, 2018 (30)367455NANANAR, 53; A, 36; D, 11NA
 Arachchillage, 2019 (31)807665583013R, 50; A, 50AF, 83; VTE; 15; Other, 3
 Smith, 2019 (32)31747458339R, 45; A, 55AF, 90; VTE, 10
 Müller, 2019 (33)74776161327R, 91; A, 7; E, 1; D, 1AF, 65; VTE, 18; Other, 18
 Zada, 2019 (34)407958433325R, 51; A, 47; E, 2NA
 Dybdahl, 2019 (35)35793710000R, 51; A, 49AF, 89; VTE, 11
 Frontera, 2020 (36)46797470247R, 67; A, 33AF, 96; VTE, 4
 Lindhoff-Last, 2020 (37) (RADOA)468153701120R, 48; A, 43; E, 5; D, 4AF, 79; VTE, 6; Other, 14
 Castillo, 2020 (38)37805910000R, 59; A, 41AF, 86; VTE, 8; Other, 5
 Wilsey, 2020 (39)99725359437R, 60; A, 40AF, 71; VTE, 26; Other, 3
 Panos, 2020 (40)514NA5410000R, 45; A, 55AF, 79; VTE, 17; Other, 4
 Bavalia, 2020 (41)707558NANANAR, 71; A, 21; E, 8AF, 84; VTE, 12; Other, 4
 Korobey, 2020 (42)59795610000R, 32; A, 68AF, 60; VTE, 20; Other, 21
 Allison, 2020 (43)3373459136R, 82; A, 18AF, 73; VTE, 18; Other, 9
 Zheng, 2020 (44)22684659365R, 46; A, 54AF, 79; VTE, 21
 Lipari, 2020 (45)1197755711118R, 41; A, 59AF, 76; VTE, 16; Other, 8
 Reynolds, 2020 (46)317748552323R, 55; A, 45AF, 71; VTE, 19; Other, 10
 Highsmith, 2020 (47)387650533216R, 34; A, 66AF, 68; VTE, 32
 Nguyen, 2019 (48)22NANA10000NANA
 Johal, 2019 (49)121NANA412636NANA
 Ammar, 2019 (50)29NANA10000NAAF, 79; VTE, 21
 Coleman, 2020 (51)1,07570NA224137R, 41; A, 51; E, 8NA
 Barra, 2020 (52)29716610000R, 73; A, 27AF, 73; VTE, 27
  Subtotal3,1357656592120R, 54; A, 43; E, 1; D, 2AF, 79; VTE, 16; Other, 5
IDARU
 Pollack, 2017 (53) (RE-VERSE AD)3017957334622D, 100AF, 96; VTE, 2; Other, 3
 Brennan, 2019 (54)187757114444D, 100AF, 100
 Sheikh-Taha, 2019 (55)117991551827D, 100AF, 100
 van der Wall, 2019 (56)537860343828D, 100AF, 98; VTE, 2
 Okishige, 2019 (57)21732900100D, 100AF, 100
 Wheeler, 2019 (58)11755545459D, 100AF, 92; VTE, 8
 Küpper, 2019 (59) (MR REPAIR)20786985150D, 100AF, 100
 Gendron, 2020 (60)618161335116D, 100AF, 96; VTE, 2; Other, 2
 Sarmento, 2020 (61)20NANANANANAD, 100NA
 Abdulrehman, 2019 (62)228160272350D, 100AF, 96; Other, 4
 Singh, 2020 (63)265765742580D, 100NA
 Yasaka, 2020 (64)1787865472825D, 100NA
 Kermer,2020 (65)40777010000D, 100AF, 100
 Vene, 2020 (66)108140602020D, 100AF, 100
 Haastrup, 2020 (67)207674501535D, 100AF, 95; Other, 5
 Magan, 2020 (68)147493432136D, 100AF, 93; Other, 7
 Lombardi, 2020 (69)308157NANANAD, 100NA
  Subtotal1,0957860414019D, 100AF, 96; VTE, 2; Other, 2
ADX
 Connolly, 2019 (70) (ANNEXA-4)3527753642610R, 39; A, 58; E, 3; D, 0AF, 80; VTE, 17; Other, 3
 Stevens, 2019 (71)13695446054R, 31; A, 69AF, 62; VTE, 38
 Giovino, 2020 (72)39826210000R, 28; A, 69; E, 3AF, 79; VTE, 18; Other, 3
 Brown, 2020 (73)227741591823R,23; A,77AF, 64; VTE, 36
 Nederpelt, 2020 (74)21736202476R, 33; A, 67AF, 76; VTE, 24
 Asad, 2020 (75)1486NA10000NANA
 Girgis, 2020 (76)11NANA55045NANA
 Vestal, 2020 (77)19NANA10000NANA
 Santarelli, 2020 (78)147267432136R, 67; A, 33AF, 80; VTE, 20
  Subtotal5057754652014R, 37; A, 60; E, 2AF, 79; VTE, 19; Other, 3
Total4,7357757552619R, 36; A, 32; E, 1; D, 31AF, 82; VTE, 14; Other, 4

A = apixaban; AF = atrial fibrillation; D = dabigatran; DOAC = direct-acting oral anticoagulants; E = edoxaban; GIB = gastrointestinal bleeding; MR REPAIR = Munich Registry of Reversal of Pradaxa in clinical routine; NA = not available; Other = comprises a variety of indications for anticoagulation other than AF or VTE (i.e., stroke, lupus anticoagulant, venous bypass graft, unknown, etc.); R = rivaroxaban; UPRATE = Unactivated Prothrombin complex concentrates for the Reversal of Anti-factor TEn inhibitors; VTE = venous thromboembolism; other abbreviations as in Table 1.

∗ Assessable patients are those patients with DOAC-associated major bleeding and reversal with 4PCC, idarucizumab or andexanet.

† Mean was used if available. Median values were used only if mean values were not available.

‡ The type of bleeding (i.e., intracranial, gastrointestinal, other) was not specified in the publication.

The type of bleeding was reported in 4,579 patients (96.7%): 2,537 (55%) patients had an ICH and 2,042 (45%) had other types of bleeding (Table 2).

The 4PCC dose was high (50 U/kg or ≥35 U/kg) or mostly high (>50% of patients receiving a high dose) in 15 studies, and low (25 U/kg or <35 U/kg) or mostly low (>50% of patients receiving a low dose) in 14 studies (see Supplemental Table 3). In 18 studies with idarucizumab, patients received a fixed 5-g idarucizumab dose, and 10 patients received 2 or more doses. In 10 studies with andexanet, 77.3% of patients received the low dose of andexanet (400-mg bolus in 15 min followed by 4 mg/min for 120 min [480 mg]), and 21.7% of patients were treated with a high dose (800-mg bolus in 15 min followed by 8 mg/min for 120 min [960 mg]) (Supplemental Table 3).

The mean time from the last dose of DOAC to administration of the reversal agent was 13.8 ± 3.6 h (range: 8 to 21 h) (data available from only 9 studies). Anticoagulation was resumed after controlling the bleeding event in 57% of patients (range: 25% to 73% in studies), and time to resumption was 11 days (range: 5 to 27 days in studies) (Supplemental Table 3).

Concomitant use of hemostatic adjuncts or interventional procedures was reported in 32 studies. Hemostatic adjuncts included packed red blood cells (range: 2.6% to 53%), fresh frozen plasma (range: 2.1% to 35%), tranexamic acid (range: 0.7% to 35.7%), and platelet concentrates (range: 1.6% to 35.7%). Invasive procedures (range: 4.3% to 67%) included neurosurgery, endoscopy, embolization, pericardiocentesis, and others (Supplemental Table 4).

Outcomes

Mortality

There were 623 deaths in 4,169 patients evaluable for mortality (rate: 17.7%; 95% CI: 15.1% to 20.4%) with significant heterogeneity between trials (I2 = 71.3%) (Figure 2). Study duration was a covariate significantly correlated with mortality rates in meta-regression analyses (p < 0.001) (Supplemental Figure 1). Mortality rate was higher in studies lasting ≥30 days (19.7%) than in studies <30 days (13.4%) (Table 3). Heterogeneity still persisted within each subgroup, so other sources of heterogeneity were also investigated. The type of bleeding also contributed to heterogeneity in mortality rates, which were higher in ICH patients (20.2%; 95% CI: 17.2% to 23.3%; I2 = 45.1%) than in patients with extracranial bleeding (15.4%; 95% CI: 11.9% to 19.2%; I2 = 78%) (Table 3). In addition, studies with significant exclusion criteria resulted in lower mortality rates (13.3%; 95% CI: 8.8% to 18.6%; I2 = 73.6%) than studies without such exclusion criteria (19.2%; 95% CI: 16.2% to 22.2%; I2 = 70.8%) (Table 3).

Figure 2
Figure 2

Proportions of Deaths

The proportions of deaths are expressed as a decimal. Data obtained from 58 studies using a random effects meta-analysis of proportions with the Freeman–Tukey double-arcsine transformation performed before data pooling. Two of 60 studies, from Frontera et al. (36) and Panos et al. (40), are not included because they were not assessable for mortality, as the number of deaths in patients receiving the reversal agent (4-factor prothrombin complex concentrate) was not reported, but they were assessable for thrombotic events and hemostatic efficacy. CI = confidence interval.

Table 3 Summary of Subgroup Analyses

DeathThromboembolismEffective Hemostasis
N% (95% CI)I2N% (95% CI)I2N% (95% CI)I2
All patients416917.7 (15.1 to 20.4)71.33,0924.6 (3.3 to 6.0)44.71,89078.5 (75.1 to 81.8)60.8
By study duration
 ≥30 days1,76219.7 (16.7 to 22.7)52.52,0745.7 (4.2 to 7.4)43.41,40976.9 (72.8 to 80.9)62.1
 <30 days2,40713.4 (10.6 to 16.1)64.71,0184.3 (2.6 to 6.4)43.348180.6 (74.9 to 85.7)52.3
By reversal agent
 4PCC2,12517.4 (14.0 to 21.1)73.11,5504.3 (3.2 to 5.5)7.51,10380.1 (75.9 to 84.2)64.8
 Idarucizumab1,10817.4 (13.5 to 21.8)56.71,0113.8 (2.3 to 5.5)25.040576.7 (68.5 to 85.0)67.9
 Andexanet93618.9 (12.1 to 26.7)80.853110.7 (6.5 to 15.7)37.938280.7 (73.5 to 87.9)50.2
By type of hemorrhage
 Intracranial hemorrhage1,56720.2 (17.2 to 23.3)45.11,7124.8 (3.5 to 6.3)25.41,05879.6 (76.6 to 82.5)15.8
 Extracranial hemorrhage1,66415.4 (11.9 to 19.2)789015.6 (4.3 to 7.2)35.637378.1 (70.5 to 84.9)58.3
By type of study
 Prospective1,21917.3 (13.7 to 21.2)55.31,1846.1 (4.3 to 8.1)35.173173.4 (65.9 to 80.3)75.8
 Retrospective2,95018.1 (15.0 to 21.4)73.11,9084.8 (3.5 to 6.4)41.0115980.6 (75.1 to 81.8)60.8
By risk of bias
 RoBANS low/moderate1,51616.3 (12.8 to 20.1)65.31,9635.1 (3.3 to 7.4)69.4104674.1 (67.9 to 79.8)75.2
 RoBANS high2,65318.6 (15.3 to 22.1)72.91,1295.2 (3.7 to 6.8)27.184480.8 (76.8 to 84.4)44.8
By presence of significant exclusion criteria
 Yes96013.3 (8.8 to 18.6)73.69744.9 (2.2 to 8.6)76.159380.7 (75.4 to 85.4)50.4
 No3,20919.2 (16.2 to 22.2)70.82,1185.0 (3.8 to 6.3)22.41,29777.7 (73.3 to 81.8)62.7
By hemostatic scale used
 ISTH37620.4 (15.1 to 26.2)41.43764.0 (2.2 to 6.3)5.836072.4 (66.6 to 77.8)26.3
 Sarode9714.4 (8.2 to 22.1)06574.1 (2.0 to 6.9)29.145879.6 (75.8 to 83.1)0
 ANNEXA-482617.0 (12.2 to 22.5)65.48267.5 (4.3 to 11.5)65.571181.2 (76.1 to 85.9)54.3
 Other54616.9 (9.6 to 25.7)77.65464.1 (2.6 to 5.9)036180.5 (70.0 to 89.2)74.6
 None2,32418.3 (14.5 to 22.3)73.06875.3 (3.0 to 8.3)40.8NANANA
By sponsorship
 Industry2,26515.7 (11.8 to 20.0)78.91,1586.2 (4.1 to 8.6)48.071575.6 (67.4 to 82.9)80.0
 Public grant research22417.4 (8.1 to 29.3)69.73710.4 (0.5 to 30.6)62.51376.9 (51.3 to 94.8)NA
 No funding97316.6 (12.7 to 20.9)59.71,3604.0 (2.4 to 5.9)47.682580.8 (76.0 to 85.2)53.7
 Not specified70721.0 (16.4 to 25.9)55.05375.1 (3.4 to 7.1)033778.4 (72.7 to 83.6)31.4
By type of hemorrhage and reversal agent
 Intracranial hemorrhage
  4PCC81122.0 (17.2 to 27.2)61.151,0133.5 (2.4 to 4.7)073880.1 (76.1 to 83.9)28.8
  Idarucizumab33418.0 (13.0 to 23.4)20.13574.6 (2.5 to 7.5)12.1NANANA
  Andexanet42215.9 (12.0 to 20.2)9.43429.6 (6.7 to 12.9)026480.9 (74.3 to 86.7)16.6
 Extracranial hemorrhage
  4PCC73314.0 (5.3 to 25.9)85.11385.7 (2.5 to 10.0)021381.5 (69.4 to 91.1)76.19
  Idarucizumab49213.6 (8.1 to 20.3)59.25983.5 (2.2 to 5.1)0.342176.2 (56.2 to 91.5)NA
  Andexanet43910.3 (2.6 to 22.3)85.2516511.1 (3.7 to 21.8)50.310977.2 (48.0 to 96.4)84.6
By risk of bias and reversal agent
 RoBANS low-moderate
  4PCC33718.1 (11.9 to 25.3)58.67844.3 (2.6 to 6.4)15.751675.1 (66.2 to 83.0)73.7
  Idarucizumab82714.9 (10.4 to 17.7)63.88274.5 (2.0 to 7.8)66.028166.9 (61.3 to 72.3)0%
  Andexanet35213.9 (10.5 to 17.7)NA3529.7 (6.8 to 13.0)NA24981.9 (76.9 to 86.4)NA
 RoBANS high risk
  4PCC1,78817.3 (13.3 to 21.6)75.417664.4 (3.0 to 6.1)8.9158781.4 (76.3 to 86.0)53.1
  Idarucizumab28119.4 (13.5 to 26.2)43.21842.9 (1.0 to 5.7)212482.0 (73.2 to 89.3)22.6
  Andexanet58419.9 (11.3 to 30.2)81.217911.3 (5.8 to 18.3)43.813378.6 (67.5 to 87.9)50.6

CI = confidence interval; I2 = Higgins percentage of heterogeneity not explained by chance (a value >50% represents significant heterogeneity between studies); other abbreviations as in Table 1.

∗ Studies that included any of the following exclusion criteria: “Do not resuscitate order” “Life expectancy of <3 days” “Only comfort measures” “Patients receiving palliative care” “Intracranial bleeding with hematoma > 60 ml” “Initial Glasgow coma scale < 7” “Died before repeat imaging” “History of transplant or severe valve heart disease” “Recent history of thromboembolic events” (Supplemental Table 2, Supplemental Appendix 5).

No relevant differences were found in death rates depending on the reversal agent used, the type of study, risk of bias, or study sponsorship (Table 3 and Supplemental Appendix 6).

Causes of death were available only for 146 cases. Of them, 99 (67.8%) were adjudicated to the underlying index bleeding event, only 2 (1.4%) were adjudicated to TE, and 45 (30.2%) were attributed to other causes: sepsis/multiorgan failure (n = 18), heart failure/cardiac arrest (n = 8), cancer (n = 4), and other (n = 15).

Thromboembolic events

TEs occurred in 159 of 3,092 patients (rate: 4.6%; 95% CI: 3.3% to 6.0%; I2 = 44.7%) (Table 3, Supplemental Figure 2). The risk was high with andexanet (10.7%; 95% CI: 6.5 to 15.7%; I2 = 37.9%) and relatively low with 4PCC (4.3%) and idarucizumab (3.8%), and the results were consistent regardless of the type of bleeding, the type of study, the risk of study bias, and the duration of the study (Table 3, Supplemental Appendix 6).

Pooled rates of VTE and ATE were 1.8% and 2.2%, respectively (Supplemental Figure 4). The risk was relatively high for andexanet (VTE 5.5% and ATE 5.0%) and lower with 4PCC (VTE 2.4% and ATE 2.2%) and idarucizumab (VTE 1.7% and ATE 3.3%) (Supplemental Appendix 6).

Effective hemostasis and rebleeding

Effective hemostasis was achieved in 1,469 of 1,890 patients (rate: 78.5%; 95% CI: 75.1% to 81.8%) (Table 3, Supplemental Figure 5), and there was heterogeneity between studies (I2 = 60.8%). The use of different definitions of effective hemostasis was the main source of heterogeneity, with the results being homogeneous between studies that applied the ISTH definition (I2 = 26.3%) and the Sarode definition (I2 = 0%) (11,13). Heterogeneity remained significant between studies that used the ANNEXA-4 definition (I2 = 54.3%) or other definitions (I2 = 74.6%) (Supplemental Figure 6) (12). Heterogeneity within studies that used the ANNEXA-4 definition disappeared after the removal of 1 outlier study (I2 reduced from 54.3% to 16.63%) (74). The reason that study found a very low rate of hemostatic efficacy with andexanet (47.6%; 10 of 21 patients) remains unclear (74). The use of the ISTH definition tended to yield more conservative results on effective hemostasis (72.4%) than those obtained by applying the Sarode definition (79.6%) or the ANNEXA-4 definition (81.2%) (Table 3, Supplemental Appendix 6).

The rate of hemostatic efficacy was high with 4PCC (80.1%; 95% CI: 75.9% to 84.2%), idarucizumab (76.7%; 95% CI: 68.5% to 85%), and andexanet (80.7%; 95% CI: 73.5% to 87.9%) (Table 3, Supplemental Appendix 6, Central Illustration). Retrospective studies, those with high risk of bias, and those with significant exclusion criteria tended to produce more optimistic estimates of effective hemostasis (80.6%, 80.8%, and 80.7%, respectively) than prospective studies, those with low-moderate risk of bias, and those that did not apply significant exclusion criteria (73.4%, 74.1%, and 77.7%, respectively) (Table 3, Supplemental Appendix 6).

Central Illustration
Central Illustration

Deaths, Thromboembolism, and Effective Hemostasis, Total and by Reversal Agent

Data obtained from 60 studies in patients with severe DOAC-related bleeding who were treated with 4PCC, idarucizumab, or andexanet. Pooled events rates were obtained using a random effects meta-analysis. 4PCC = 4-factor prothrombin complex concentrate (Beriplex, Octaplex, Kcentra); ADX = andexanet; DOAC = direct oral anticoagulant; IDARU = idarucizumab.

A total of 28 of the 232 evaluable patients from only 6 studies experienced rebleeding (rate 13.2%; 95% CI: 5.5% to 23.1%; I2 = 68.19%) (Supplemental Figure 7). The mean time to rebleeding was 13.4 ± 9.3 days (range: 5 to 34 days) and 78% of rebleeds occurred after resumption of anticoagulation. A rebleeding event was described as an ICH in 82% of cases.

Correlation between failure to achieve effective hemostasis and risk of death

Failure to achieve effective hemostasis resulted in a more than a 3-fold increase of death compared to achieving effective hemostasis (RR: 3.63; 95% CI: 2.56 to 5.16; I2 = 0%) (data from 12 studies) (Figure 3). The results were robust regardless of study type, risk of bias, hemostatic scale, and type of reversal (Supplemental Figures 53, 54, 55, and 56, Supplemental Appendix 6).

Figure 3
Figure 3

All-Cause Death in Patients With and Without Effective Hemostasis

Data obtained from 12 studies using a random effect meta-analysis and expressed as risk ratio. M-H = Mantel-Haenszel; other abbreviation as in Figure 2.

Disability-related outcomes

A total of 96 of 160 evaluable patients from 4 studies had moderate-severe disability at discharge (modified Rankin Scale [mRS]: 3 to 5) (rate: 52.6%; 95% CI: 26.6% to 77.9%; I2 = 86.94%) (Supplemental Figure 8).

Five studies reported a good outcome (mRS 0–3) or bad outcome (mRS 4 to 6: moderate to severe disability or death). A total of 54 of 198 patients experienced a good outcome (33.8%; 95% CI: 12.1% to 59.6%; I2 = 90.38%) (Supplemental Figure 9), whereas the remaining 144 patients experienced a poor outcome (66.2%; 95% CI: 40.4% to 87.9%; I2 = 90.38%) (Supplemental Figure 10).

A total of 67 of 229 patients in 6 studies were discharged to a rehabilitation center (27.9%; 95% CI: 17.2% to 39.9%; I2 = 68.28%) (Supplemental Figure 11).

Discussion

Our meta-analysis shows a relatively high risk of death (18%) in patients with severe bleeding associated with DOAC despite the administration of a reversal agent. The risk of death varied between studies, with the duration of the study (between 5 to 180 days) being the main determinant of this variability. The effective hemostasis rate was high (79%), being this the main predictor of survival. In fact, the death rate was more than 3 times higher in patients in whom effective hemostasis was not achieved. Therefore, a plausible conclusion is that, in the event of insufficient response, additional attempts and/or combination with other treatment modalities aimed at achieving effective hemostasis should be considered.

The bleeding site is important in decision-making as the different types of bleeds vary in their treatment and outcome. We found a mortality rate of 20.2% in patients with ICH related to DOAC, which compares favorably with the ICH case fatality rate of 37.5% to 49% reported 10 years ago during the main trials with DOAC when the use of reversal agents was anecdotal (79,80).

There was a high rate of patients (52.6%) who had moderate/severe disability at discharge (mRS: 3 to 5), and a 66.2% of patients with poor outcomes (mRS: 4 to 6). Therefore, although the mortality rates from DOAC-related ICH appear to have decreased with the introduction of reversal agents over the past decade, the rates of moderate/severe disability and poor prognosis remain very high.

The overall rate of TE in our review was 4.6%, which was particularly high with andexanet (10.7%), but in the absence of a direct prospective comparison with other reversal strategies it should be considered only as a signal that deserves to be confirmed in further studies. A prothrombotic rebound effect cannot be ruled out with andexanet within the first days after reversal since andexanet has shown to transiently increase thrombin generation (81). TE is generally manageable and most episodes are probably related to a return to baseline risk of thromboembolism when anticoagulation with DOAC is withdrawn in the context of an incomplete and late resumption of anticoagulation. A recent consensus paper recommends resumption of anticoagulation after major bleeding as soon as the thrombotic risk exceeds the rebleeding risk, in most cases within 1 week (82). In our review, anticoagulation was resumed on average 11 days after admission. The rebleeding rate was 13.2%, and 78% of rebleeds occurred after resumption of anticoagulant therapy. Eighty-two percent of rebleeds were described as an ICH. Therefore, caution with anticoagulant resumption is advised.

The main strength of this review is that the results are based on a large sample size of more than 4,700 patients from 60 studies, half of them published in 2020, which were identified through an exhaustive systematic search. Four previous reviews focused on the safety and effectiveness of 4PCC or and andexanet and idarucizumab, but they had limitations, as the sample size was small or did not analyze patients with major bleeding separately from other indications (83–85,86).

Study limitations

The main limitation of our review is that 47 of the 60 studies were retrospective cohorts and 45 had a high risk of bias. Retrospective studies and those at high risk of bias tended to report more optimistic hemostatic effectiveness results than prospective studies and studies at low-moderate risk of bias, but the analysis of deaths and TE yielded similar results regardless of the type of study and risk of bias. A limitation of the analysis of mortality in patients with and without effective hemostasis is that it is based in a selected population of patients with an assessment of effective hemostasis within 48 h, and it may not be available in patients who die early (11–14). Another limitation is that, in general, there was poor reporting of some important clinical data in the studies (e.g., time from the last dose of anticoagulant to reversal that is difficult to obtain in practice, the administered dose of the reversal agent, post-bleeding anticoagulation management, exclusion criteria, etc.), implying caution in interpretation. A comparative clinical trial of andexanet versus standard is currently being conducted in patients with ICH associated with oral FXa inhibitors (n = 900) ( NCT03661528).

The arrival of DOAC-specific antidotes meets an unmet need and will increase confidence in the safe use of the DOAC. Some recent guidelines favor the use of specific reversal agents based on expert consensus and surrogate evidence from biomarkers (87). However, 4PCC may be associated to similar rates of effective hemostasis than specific antidotes and low rates of TE, and therefore could be a valuable treatment when a specific antidote is not available.

Conclusions

Our systematic review shows a high rate of effective hemostasis, around 80%, with 4PCC or specific reversal agents and a relatively high rate of deaths (17.7% in average). Failure to achieve hemostatic efficacy was correlated with a more than 3-fold increase in mortality. TEs occurred with a high frequency with andexanet. In the absence of prospective comparative trials, it cannot be determined whether specific reversal agents are more effective and/or safer than nonspecific reversal with 4PCC. Comparative studies are needed.

Perspectives

COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: In patients with severe bleeding, particularly intracranial hemorrhage, during treatment with DOACs, failure to achieve effective hemostasis after administration of either 4PCC or specific reversal agents (idarucizumab or andexanet alfa) is associated with considerable mortality. Thromboembolic events occur more frequently with andexanet than with 4PCC or idarucizumab.

TRANSLATIONAL OUTLOOK: Further studies are necessary to determine whether specific DOAC reversal agents offer greater safety and efficacy than 4PCC.

Funding Support and Author Disclosures

Dr. Lecumberri has received personal fees from Boehringer Ingelheim and Bristol Myers Squibb outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Abbreviations and Acronyms

4PCC

4-factor prothrombin complex concentrates

ATE

arterial thromboembolism

CI

confidence interval

DOAC

direct oral anticoagulant

ICH

intracranial hemorrhage

ISTH

International Society of Thrombosis and Hemostasis

mRS

modified Rankin Scale

RoBANS

Risk of Bias Assessment Tool for Nonrandomized Studies

RR

relative risk

TE

thromboembolism

VTE

venous thromboembolism

References

  • 1. Morgan A., Joshy G., Schaffer A., et al. "Rapid and substantial increases in anticoagulant use and expenditure in Australia following the introduction of new types of oral anticoagulants". PLoS One 2018;13:e0208824.

    CrossrefGoogle Scholar
  • 2. Llisterri Caro J.L., Cinza-Sanjurjo S., Polo Garcia J., et al. "Use of direct-acting oral anticoagulants in Primary Care in Spain. Positioning statement by SEMERGEN on the current situation [In Spanish]". Semergen 2019;45:413-429.

    CrossrefMedlineGoogle Scholar
  • 3. Zhu J., Alexander G.C., Nazarian S., et al. "Trends and variation in oral anticoagulant choice in patients with atrial fibrillation, 2010–2017". Pharmacotherapy 2018;38:907-920.

    CrossrefMedlineGoogle Scholar
  • 4. Alfirevic A., Downing J., Daras K., et al. "Has the introduction of direct oral anticoagulants (DOACs) in England increased emergency admissions for bleeding conditions? A longitudinal ecological study". BMJ Open 2020;10:e033357.

    CrossrefMedlineGoogle Scholar
  • 5. Gómez-Outes A., Suarez-Gea M.L., Lecumberri R., et al. "Specific antidotes in development for reversal of novel anticoagulants: a review". Recent Pat Cardiovasc Drug Discov 2014;9:2-10.

    CrossrefMedlineGoogle Scholar
  • 6. Proietti M., Boriani G. "Use of idarucizumab in reversing dabigatran anticoagulant effect: a critical appraisal". Ther Clin Risk Manag 2018;14:1483-1488.

    CrossrefMedlineGoogle Scholar
  • 7. Heo Y.A. "Andexanet alfa: first global approval". Drugs 2018;78:1049-1055.

    CrossrefMedlineGoogle Scholar
  • 8. Kim S.Y., Park J.E., Lee Y.J., et al. "Testing a tool for assessing the risk of bias for nonrandomized studies showed moderate reliability and promising validity". J Clin Epidemiol 2013;66:408-414.

    CrossrefMedlineGoogle Scholar
  • 9. Landis J.R., Koch G.G. "The measurement of observer agreement for categorical data". Biometrics 1977;33:159-174.

    CrossrefMedlineGoogle Scholar
  • 10. "GraphPad QuickCalcs software". Available at: https://www.graphpad.com/quickcalcs/kappa1/. Accessed January 11, 2021.

    Google Scholar
  • 11. Sarode R., Milling T.J., Refaai M.A., et al. "Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study". Circulation 2013;128:1234-1243.

    CrossrefMedlineGoogle Scholar
  • 12. Connolly S.J., Milling T.J., Eikelboom J.W., et al. "Andexanet alfa for acute major bleeding associated with factor Xa inhibitors". N Engl J Med 2016;375:1131-1141.

    CrossrefMedlineGoogle Scholar
  • 13. Khorsand N., Majeed A., Sarode R., et al. "Assessment of effectiveness of major bleeding management: proposed definitions for effective hemostasis: communication from the SSC of the ISTH". J Thromb Haemost 2016;14:211-214.

    CrossrefMedlineGoogle Scholar
  • 14. Liberati A., Altman D.G., Tetzlaff J., et al. "The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration". BMJ 2009;339:b2700.

    CrossrefMedlineGoogle Scholar
  • 15. Freeman M.F., Tukey J.W. "Transformations related to the angular and the square root". Ann Math Stat 1950;21:607-611.

    CrossrefGoogle Scholar
  • 16. DerSimonian R., Laird N. "Meta-analysis in clinical trials revisited". Contemp Clin Trials 2015;45:139-145.

    CrossrefMedlineGoogle Scholar
  • 17. Higgins J.P., Thompson S.G., Deeks J.J., et al. "Measuring inconsistency in meta-analyses". BMJ 2003;327:557-560.

    CrossrefMedlineGoogle Scholar
  • 18. Wallace B.C., Dahabreh I.J., Schmid C.H., et al. "Modernizing the systematic review process to inform comparative effectiveness: tools and methods". J Comp Eff Res 2013;2:273-282.

    CrossrefMedlineGoogle Scholar
  • 19. Grandhi R., Newman W.C., Zhang X., et al. "Administration of 4-factor prothrombin complex concentrate as an antidote for intracranial bleeding in patients taking direct factor Xa inhibitors". World Neurosurg 2015;84:1956-1961.

    CrossrefMedlineGoogle Scholar
  • 20. Beynon C., Sakowitz O.W., Störzinger D., et al. "Intracranial haemorrhage in patients treated with direct oral anticoagulants". Thromb Res 2015;136:560-565.

    CrossrefMedlineGoogle Scholar
  • 21. Purrucker J.C., Haas K., Rizos T., et al. "Early clinical and radiological course, management, and outcome of intracerebral hemorrhage related to new oral anticoagulants". JAMA Neurol 2016;73:169-177.

    CrossrefMedlineGoogle Scholar
  • 22. Yoshimura S., Sato S., Todo K., et al. "Stroke Acute Management with Urgent Risk-factor Assessment and Improvement (SAMURAI) Study Investigators. Prothrombin complex concentrate administration for bleeding associated with non-vitamin K antagonist oral anticoagulants: the SAMURAI-NVAF study". J Neurol Sci 2017;375:150-157.

    CrossrefMedlineGoogle Scholar
  • 23. Majeed A., Ågren A., Holmström M., et al. "Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study". Blood 2017;130:1706-1712.

    CrossrefMedlineGoogle Scholar
  • 24. Schenk B., Goerke S., Beer R., et al. "Four-factor prothrombin complex concentrate improves thrombin generation and prothrombin time in patients with bleeding complications related to rivaroxaban: a single-center pilot trial". Thromb J 2018;16:1.

    CrossrefMedlineGoogle Scholar
  • 25. Tao J., Bukanova E.N., Akhtar S. "Safety of 4-factor prothrombin complex concentrate (4F-PCC) for emergent reversal of factor Xa inhibitors". J Intensive Care 2018;6:34.

    CrossrefMedlineGoogle Scholar
  • 26. Schulman S., Gross P.L., Ritchie B., et al. "Prothrombin complex concentrate for major bleeding on factor Xa Inhibitors: a prospective cohort study". Thromb Haemost 2018;118:842-851.

    CrossrefMedlineGoogle Scholar
  • 27. Harrison S.K., Garrett J.S., Kohman K.N., et al. "Comparison of outcomes in patients with intracranial hemorrhage on factor Xa inhibitors versus vitamin K antagonists treated with 4-factor prothrombin complex concentrate". Proc Bayl Univ Med Cent 2018;31:153-156.

    CrossrefGoogle Scholar
  • 28. Gerner S.T., Kuramatsu J.B., Sembill J.A., et al. "Association of prothrombin complex concentrate administration and hematoma enlargement in non–vitamin K antagonist oral anticoagulant–related intracerebral hemorrhage". Ann Neurol 2018;83:186-196.

    CrossrefMedlineGoogle Scholar
  • 29. Testa S., Ageno W., Antonucci E., et al. "Management of major bleeding and outcomes in patients treated with direct oral anticoagulants: results from the START-Event registry". Intern Emerg Med 2018;13:1051-1058.

    CrossrefMedlineGoogle Scholar
  • 30. Santibanez M., Lesch C.A., Lin L., et al. "Tolerability and effectiveness of 4-factor prothrombin complex concentrate (4F-PCC) for warfarin and non-warfarin reversals". J Crit Care 2018;48:183-190.

    CrossrefMedlineGoogle Scholar
  • 31. Arachchillage D.R.J., Alavian S., Griffin J., et al. "Efficacy and safety of prothrombin complex concentrate in patients treated with rivaroxaban or apixaban compared to warfarin presenting with major bleeding". Br J Haematol 2019;184:808-816.

    CrossrefMedlineGoogle Scholar
  • 32. Smith M.N., Deloney L., Carter C., et al. "Safety, efficacy, and cost of four-factor prothrombin complex concentrate (4F-PCC) in patients with factor Xa inhibitor-related bleeding: a retrospective study". J Thromb Thrombolysis 2019;48:250-255.

    CrossrefMedlineGoogle Scholar
  • 33. Müller M., Eastline J., Nagler M., et al. "Application of prothrombin complex concentrate for reversal of direct oral anticoagulants in clinical practice: indications, patient characteristics and clinical outcomes compared to reversal of vitamin K antagonists". Scand J Trauma Resusc Emerg Med 2019;27:48.

    CrossrefMedlineGoogle Scholar
  • 34. Zada I., Wang S., Akerman M., et al. "Four-factor prothrombin complex concentrate for the reversal of direct oral anticoagulants". J Intensive Care Med 2021;36:58-62.

    CrossrefMedlineGoogle Scholar
  • 35. Dybdahl D., Walliser G., Chance Spalding M., Spalding M.C., Pershing M., Kincaid M. "Four-factor prothrombin complex concentrate for the reversal of factor Xa inhibitors for traumatic intracranial hemorrhage". Am J Emerg Med 2019;37:1907-1911.

    CrossrefMedlineGoogle Scholar
  • 36. Frontera J.A., Bhatt P., Lalchan R., et al. "Cost comparison of andexanet versus prothrombin complex concentrates for direct factor Xa inhibitor reversal after hemorrhage". J Thromb Thrombolysis 2020;49:121-131.

    CrossrefMedlineGoogle Scholar
  • 37. Lindhoff-Last E., Herrmann E., Lindau S., et al. "Severe hemorrhage associated with oral anticoagulants". Dtsch Arztebl Int 2020;117:312-319.

    MedlineGoogle Scholar
  • 38. Castillo R., Chan A., Atallah S., et al. "Treatment of adults with intracranial hemorrhage on apixaban or rivaroxaban with prothrombin complex concentrate products". J Thromb Thrombolysis 2021;51:151-158.

    CrossrefMedlineGoogle Scholar
  • 39. Wilsey H.A., Bailey A.M., Schadler A., et al. "Comparison of low- versus high-dose four-factor prothrombin complex concentrate (4F-PCC) for factor Xa inhibitor–associated bleeding: a retrospective study". J Intensive Care Med 2021;36:597-603.

    CrossrefMedlineGoogle Scholar
  • 40. Panos N.G., Cook A.M., John S., et al. "Factor Xa inhibitor–related intracranial hemorrhage: results from a multicenter, observational cohort receiving prothrombin complex concentrates". Circulation 2020;141:1681-1689.

    CrossrefMedlineGoogle Scholar
  • 41. Bavalia R., Abdoellakhan R., Brinkman H.J.M., et al. "Emergencies on direct oral anticoagulants: management, outcomes, and laboratory effects of prothrombin complex concentrate". Res Pract Thromb Haemost 2020;4:569-581.

    CrossrefMedlineGoogle Scholar
  • 42. Korobey M.J., Sadaka F., Javed M., et al. "Efficacy of 4-factor prothrombin complex concentrates in factor Xa inhibitor-associated intracranial bleeding". Neurocrit Care 2021;34:112-120.

    CrossrefMedlineGoogle Scholar
  • 43. Allison T.A., Lin P.J., Gass J.A., et al. "Evaluation of the use of low-dose 4-factor prothrombin complex concentrate in the reversal of direct oral anticoagulants in bleeding patients". J Intensive Care Med 2020;35:903-908.

    CrossrefMedlineGoogle Scholar
  • 44. Zheng Y., Tormey C.A. "The use of 4F-PCC to correct direct oral anticoagulant-induced coagulopathy: an observational analysis". Transfus Med 2020;30:304-307.

    CrossrefMedlineGoogle Scholar
  • 45. Lipari L., Yang S., Milligan B., Blunck J. "Emergent reversal of oral factor Xa inhibitors with four-factor prothrombin complex concentrate". Am J Emerg Med 2020;38:2641-2645.

    CrossrefMedlineGoogle Scholar
  • 46. Reynolds T.R., Gilbert B.W., Hall K.M. "Utilization of 4-factor prothrombin complex concentrate for reversal of oral factor Xa inhibitor-associated acute major bleeding: a case series". J Pharm Pract 2020Feb24. [E-pub ahead of print].

    CrossrefMedlineGoogle Scholar
  • 47. Highsmith E.A., Morton C., Varnado S., et al. "Outcomes associated with 4-factor prothrombin complex concentrate administration to reverse oral factor Xa inhibitors in bleeding patients". J Clin Pharmacol 2021;61:598-605.

    CrossrefMedlineGoogle Scholar
  • 48. Nguyen K., Hurley M., Wdowiarz K., et al. "Andexanet alfa versus four-factor prothrombin complex concentrate (4F-PCC) for the reversal of intracranial hemorrhage (ICH) associated with rivaroxaban and apixaban: a retrospective comparative study". Neurocrit Care 2019;31:S25.

    Google Scholar
  • 49. Johal J., Castro-Apolo R., Laskosky J., et al. "Comparing outcomes with andexanet and 4F-PCC in factor Xa inhibitor–related bleeding". Neurocrit Care 2019;31:S23.

    Google Scholar
  • 50. Ammar A.A., Ammar M.A., Kirsh E., et al. "Factor Xa inhibitors reversal with andexanet alfa versus four-factor prothrombin complex concentrate in intracranial hemorrhage". Neurocrit Care 2019;31:S223.

    Google Scholar
  • 51. Coleman C.I., Dobesh P.P., Danese S., et al. "Real-world management of oral factor Xa inhibitor-related bleeds with reversal or replacement agents including andexanet alfa and four-factor prothrombin complex concentrate: a multicenter study". Future Cardiol 2021;17:127-135.

    CrossrefMedlineGoogle Scholar
  • 52. Barra M.E., Das A.S., Hayes B.D., et al. "Evaluation of andexanet alfa and four-factor prothrombin complex concentrate (4F-PCC) for reversal of rivaroxaban- and apixaban-associated intracranial hemorrhages". J Thromb Haemost 2020;18:1637-1647.

    CrossrefMedlineGoogle Scholar
  • 53. Pollack C.V., Reilly P.A., van Ryn J., et al. "Idarucizumab for dabigatran reversal — full cohort analysis". N Engl J Med 2017;377:431-441.

    CrossrefMedlineGoogle Scholar
  • 54. Brennan Y., Favaloro E.J., Pasalic L., et al. "Lessons learnt from local real-life experience with idarucizumab for the reversal of dabigatran". Intern Med J 2019;49:59-65.

    CrossrefMedlineGoogle Scholar
  • 55. Sheikh-Taha M. "Idarucizumab for reversal of dabigatran: single-center real-world experience". Am J Cardiovasc Drugs 2019;19:59-64.

    CrossrefMedlineGoogle Scholar
  • 56. van der Wall S.J., van Rein N., van den Bemt B., et al. "Performance of idarucizumab as antidote of dabigatran in daily clinical practice". Europace 2019;21:414-420.

    CrossrefMedlineGoogle Scholar
  • 57. Okishige K., Yamauchi Y., Hanaki Y., et al. "Clinical experience of idarucizumab use in cases of cardiac tamponade under uninterrupted anticoagulation of dabigatran during catheter ablation of atrial fibrillation". J Thromb Thrombolysis 2019;47:487-494.

    CrossrefMedlineGoogle Scholar
  • 58. Wheeler M., Borrie A., Dookia R., Carter J. "Idarucizumab for dabigatran reversal: the first 6 months in a tertiary centre". Intern Med J 2019;49:1316-1320.

    CrossrefMedlineGoogle Scholar
  • 59. Küpper C., Feil K., Klein M., et al. "Idarucizumab administration in emergency situations: the Munich Registry of Reversal of Pradaxa® in clinical routine (MR REPAIR)". J Neurol 2019;266:2807-2811.

    CrossrefMedlineGoogle Scholar
  • 60. Gendron N., Chocron R., Billoir P., et al. "Dabigatran level before reversal can predict hemostatic effectiveness of idarucizumab in a real-world setting". Front Med 2020;7:599626.

    CrossrefGoogle Scholar
  • 61. Sarmento A., Pinto B.I., Cibele D., et al. "Idarucizumab for dabigatran reversal — a single-center analysis of two years' experience". Vox Sanguinis 2019;114:S1: 16(abstr A-S01-05).

    Google Scholar
  • 62. Abdulrehman J., Lindsay D., Elbaz C., et al. "A retrospective analysis of the real world use of idarucizumab at two tertiary care centres in Toronto, Canada". Res Pract Thromb Haemost 2019;3:suppl 1: 733(abstr PB1063).

    Google Scholar
  • 63. Singh S., Nautiyal A., Belk K.W. "Real world outcomes associated with idarucizumab: population-based retrospective cohort study". Am J Cardiovasc Drugs 2020;20:161-168.

    CrossrefMedlineGoogle Scholar
  • 64. Yasaka M., Yokota H., Suzuki M., et al. "Idarucizumab for emergency reversal of anticoagulant effects of dabigatran: interim results of a Japanese post-marketing surveillance study". Cardiol Ther 2020;9:167-188.

    CrossrefMedlineGoogle Scholar
  • 65. Kermer P., Eschenfelder C.C., Diener H.C., et al. "Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany — updated series of 120 cases". Int J Stroke 2020;15:609-618.

    CrossrefMedlineGoogle Scholar
  • 66. Vene N., Mavri A., Božič-Mijovski M., et al. "Idarucizumab for dabigatran reversal in daily clinical practice: a case series". Eur J Anaesthesiol 2020;37:874-878.

    CrossrefMedlineGoogle Scholar
  • 67. Haastrup S.B., Hellfritzsch M., Nybo M., et al. "Real-world experience with reversal of dabigatran by idarucizumab". Thromb Res 2020;197:179-184.

    CrossrefMedlineGoogle Scholar
  • 68. Magan C. "Antidote spécifique du dabigatran: expérience du CHU de Montpellier. Sciences Pharmaceutiques 2020;dumas-02978167". Available at: https://dumas.ccsd.cnrs.fr/dumas-02978167/document. Accessed December 5, 2020.

    Google Scholar
  • 69. Lombardi N., Brilli V., Crescioli G., et al. "Patterns and trends of idarucizumab use in an Italian region: a probabilistic record-linkage approach in a real-life setting". Eur Heart J 2020;41:suppl 2: ehaa946.3364.

    MedlineGoogle Scholar
  • 70. Connolly S.J., Crowther M., Eikelboom J.W., et al. "Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors". N Engl J Med 2019;380:1326-1335.

    CrossrefMedlineGoogle Scholar
  • 71. Stevens V.M., Trujillo T., Mueller S.W., et al. "Coagulation factor Xa (recombinant), inactivated-zhzo (andexanet alfa) hemostatic outcomes and thrombotic event incidence at an academic medical center". Clin Appl Thromb Hemost 2019;25:1076029619896619.

    CrossrefGoogle Scholar
  • 72. Giovino A., Shomo E., Busey K.V., et al. "An 18-month single-center observational study of real-world use of andexanet alfa in patients with factor Xa inhibitor associated intracranial hemorrhage". Clin Neurol Neurosurg 2020;195:106070.

    CrossrefMedlineGoogle Scholar
  • 73. Brown C.S., Scott R.A., Sridharan M., et al. "Real-world utilization of andexanet alfa". Am J Emerg Med 2020;38:810-814.

    CrossrefMedlineGoogle Scholar
  • 74. Nederpelt C.J., Naar L., Sylvester K.W., et al. "Evaluation of oral factor Xa inhibitor–associated extracranial bleeding reversal with andexanet alfa". J Thromb Haemost 2020;18:2532-2541.

    CrossrefMedlineGoogle Scholar
  • 75. Asad S.D., Lombardi S.R., Staff I., et al. "Safety and efficacy of andexanet alfa in patients with life threatening intracerebral hemorrhage: a single center experience". Stroke 2020;51:suppl 1: abstr TP352.

    MedlineGoogle Scholar
  • 76. Girgis J., Adler A., O'Brien K., et al. "Evaluating the safety and effectiveness of andexanet alfa at a tertiary academic medical center". Crit Care Med 2020;40:244.

    CrossrefGoogle Scholar
  • 77. Vestal M., Hodulik K., Mando-Vandrick J., et al. "Coagulation factor Xa ([recombinant] Andexxa®) for reversal of apixaban and rivaroxaban in patients diagnosed with intracranial hemorrhage". Res Pract Thromb Haemost 2020;4:suppl 1: abstr PB0413.

    Google Scholar
  • 78. Santarelli A., Dietrich T., Sprague R., et al. "Real world utilization of andexanet alfa at a community hospital". Am J Emerg Med 2020Nov24. [E-pub ahead of print].

    CrossrefMedlineGoogle Scholar
  • 79. Hart R.G., Diener H.C., Yang S., et al. "Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial". Stroke 2012;43:1511-1517.

    CrossrefMedlineGoogle Scholar
  • 80. Hankey G.J., Stevens S.R., Piccini J.P., et al. "Intracranial hemorrhage among patients with atrial fibrillation anticoagulated with warfarin or rivaroxaban: the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation". Stroke 2014;45:1304-1312.

    CrossrefMedlineGoogle Scholar
  • 81. Ondexxya (andexanet alfa). "EU Summary of Product Characteristics". Available at: https://www.ema.europa.eu/en/documents/product-information/ondexxya-epar-product-information_en.pdf. Accessed January 12, 2020.

    Google Scholar
  • 82. Halvorsen S., Storey R.F., Rocca B., et al. "Management of antithrombotic therapy after bleeding in patients with coronary artery disease and/or atrial fibrillation: expert consensus paper of the European Society of Cardiology Working Group on Thrombosis". Eur Heart J 2017;38:1455-1462.

    MedlineGoogle Scholar
  • 83. Udayachalerm S., Rattanasiri S., Angkananard T., et al. "The reversal of bleeding caused by new oral anticoagulants (NOACs): a systematic review and meta-analysis". Clin Appl Thromb Hemost 2018;24:suppl 9: 117S-126S.

    CrossrefMedlineGoogle Scholar
  • 84. Piran S., Khatib R., Schulman S., et al. "Management of direct factor Xa inhibitor–related major bleeding with prothrombin complex concentrate: a meta-analysis". Blood Adv 2019;3:158-167.

    CrossrefMedlineGoogle Scholar
  • 85. Costa O.S., Baker W.L., Roman-Morillo Y., et al. "Quality evaluation of case series describing four-factor prothrombin complex concentrate in oral factor Xa inhibitor–associated bleeding: a systematic review". BMJ Open 2020;10:e040499.

    CrossrefGoogle Scholar
  • 86. Rodrigues A.O., David C., Ferreira J.J., et al. "The incidence of thrombotic events with idarucizumab and andexanet alfa: a systematic review and meta-analysis". Thromb Res 2020;196:291-296.

    CrossrefMedlineGoogle Scholar
  • 87. Milling T.J., Pollack C.V. "A review of guidelines on anticoagulation reversal across different clinical scenarios — is there a general consensus?". Am J Emerg Med 2020;38:1890-1903.

    CrossrefMedlineGoogle Scholar

Footnotes

Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.