What evidence supports Kcentra for direct oral anticoagulant (DOAC) reversal in intracranial hemorrhage?

Comment by InpharmD Researcher

Overall, there are mixed data regarding the use of Kcentra® in direct oral anticoagulant (DOAC) reversal. The 2019 Anticoagulation Forum guidance suggests treatment with four-factor prothrombin complex concentrate (4F-PCC) 2000 units when andexanet alfa is unavailable. The optimal dosing and timing of Kcentra® remain unestablished, with comparisons between 25 IU/kg and 50 IU/kg reporting mixed results.

Background

The Anticoagulation Forum 2019 guidelines for the reversal of direct oral anticoagulants (DOAC) recommend against the routine use of reversal agents in patients with DOAC overdose without bleeding. Reversal agents may be considered in situations where a patient is judged to be at high risk of DOAC-associated catastrophic bleeding. These agents should be administered when a patient experiences life-threatening bleeding into a critical organ or bleeding is not controlled by maximal supportive measures, provided with a reasonable expectation that the patient has plasma DOAC levels of clinical significance. The encompassing recommendation is that traditional DOAC reversal agents, such as andexanet alfa (AA) for direct factor Xa inhibitors and idarucizumab for dabigatran, be used when available. A four-factor prothrombin complex concentrate (4F-PCC) such as Kcentra® should be initiated at 2000 units for rivaroxaban- or apixaban-associated major bleeding if AA is unavailable. 4F-PCC 2000 units or AA may also be administered off-label in patients with edoxaban- or betrixaban-associated major bleeding in whom a reversal agent is indicated. The onset of action of 4F-PCC in DOAC patients is unknown, and the timing of 4F-PCC for DOAC reversal was not discussed within the guidelines. [1]

A 2022 meta-analysis evaluated 36 studies (N= 1832) to determine the outcomes associated with DOAC reversal agents in intracranial hemorrhage (ICH), focusing on 4F-PCC, AA, and idarucizumab. A direct retrospective comparison of 4F-PCC and AA showed no differences in the rates of anticoagulation reversal, proportional mortality, or thromboembolic events. The findings of the analysis showcased that 4F-PCC had a 77% success rate in anticoagulation reversal (95% confidence interval [CI], 72% to 82%), AA with a 75% success rate (95% CI, 67% to 81%), and idarucizumab with an 82% success rate (95% CI, 55% to 95%). The authors concluded that the overall anticoagulation reversal, mortality, and thromboembolic event rates with 4F-PCC appear similar to AA and idarucizumab for managing ICH in adult patients treated with a DOAC. In addition to these results, the study's authors highlighted the importance of considering the availability of DOAC reversal agents, specifically in the community setting, where 4F-PCC may be the only available and cost-effective reversal agent. Despite this, further research is still necessary to improve patient-centered approaches and outcomes in patients requiring ICH reversal therapy. [2]

The RETRACE II study, a 2018 German retrospective cohort study, evaluated the use of 4F-PCC in 146 patients with DOAC-related ICH over a 5-year period, of which 131 received rivaroxaban or apixaban and 15 received dabigatran. The hemostatic treatment consisted primarily of administration of PCC at a median dosage of 2,000 (1,500-3,000) IU in all patients, followed by vitamin K, platelet concentrates, fresh frozen plasma, tranexamic acid, desmopressin, and antithrombin III. The study defined hemostatic intervention as the administration of PCC prior to follow-up cranial imaging. The results showed that the PCC administration prior to follow-up imaging was not significantly associated with a reduced rate of hematoma enlargement, the primary outcome, neither in overall NOAC-related ICH nor in patients with factor-Xa-inhibitor intake (RR [95%CI]: NOAC 1.150 [0.632-2.090]; factor-Xa-inhibitor: 1.057 [0.565-1.977]), regardless of PCC-dosage given or time interval until imaging or treatment. As PCC administration did not yield a reduced rate of hematoma enlargement in NOAC-related ICH, the authors suggest exploring alternative strategies for patients with factor-Xa-inhibitor-related ICH. [3]

References:

[1] Cuker A, Burnett A, Triller D, et al. Reversal of direct oral anticoagulants: Guidance from the Anticoagulation Forum. Am J Hematol. 2019;94(6):697-709. doi:10.1002/ajh.25475
[2] Chaudhary R, Singh A, Chaudhary R, et al. Evaluation of Direct Oral Anticoagulant Reversal Agents in Intracranial Hemorrhage: A Systematic Review and Meta-analysis. JAMA Netw Open. 2022;5(11):e2240145. doi:10.1001/jamanetworkopen.2022.40145
[3] Gerner ST, Kuramatsu JB, Sembill JA, 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(1):186-196. doi:10.1002/ana.25134
Literature Review

A search of the published medical literature revealed 8 studies investigating the researchable question:

What evidence supports Kcentra for direct oral anticoagulant (DOAC) reversal in intracranial hemorrhage?

Please see Tables 1-8 for your response.

 

Andexanet Alfa Versus Four-factor Prothrombin Complex Concentrate for the Reversal of Apixaban or Rivaroxaban-associated Intracranial Hemorrhages

Design

A multicenter, retrospective chart review 

N= 109

Objective

To compare the efficacy and safety of andexanet alpha (AA) versus four-factor prothrombin complex concentrate (4F-PCC) for the reversal of apixaban- or rivaroxaban-associated intracranial hemorrhage (ICH)

Study Groups

AA (n= 47)

4F-PCC (n= 62)

Inclusion Criteria

Adults taking apixaban or rivaroxaban prior to admission, had radiographical evidence of ICH, and received either AA or 4F-PCC as a reversal agent

Exclusion Criteria

Under 18 years of age or received both AA and 4F-PCC

Methods

In this study, AA was dosed according to the product labeling for life-threatening bleeding associated with factor Xa inhibitors. The 4F-PCC dosing protocol was standardized to 50 units/kg (maximum 5000 units) for one dose across all hospitals. The criteria for AA use varied between the hospitals. When evaluating a multi-center healthcare system, AA was restricted to adult patients with acute, severe neurologic intracranial or spinal bleeding emergencies. In comparison, a stand-alone hospital restricted AA to patients 18 years and older with confirmed acute, life-threatening bleeding, specific usage of apixaban or rivaroxaban within the past 18 hours, and an ICH score of 1 to 4.

Duration

June 2016 to December 2020

Outcome Measures

Primary outcome: level of excellent hemostasis achieved

Secondary outcomes: thromboembolism event, myocardial infarction (MI), stroke, deep vein thrombosis (DVT), pulmonary embolism (PE), inpatient mortality  

Baseline Characteristics

  

AA

(n= 47)

4F-PCC

(n= 62)

    

Age, years (IQR)

  77 (70-86)  81 (71-86)    

Male

  31 (66.0%)  32 (51.6%)    

Race

African American

Asian

Caucasian

Hispanic 

Other 

 

7 (14.9%)

0 (0.0%)

36 (76.6%)

2 (4.3%)

2 (4.3%)

 

4 (6.5%)

1 (1.6%)

51 (82.3%)

0 (0.0)

6 (9.7%)

    

Weight, kg

  85.0 (68.1, 96.9)  75.3 (67.5, 89.6)    

INR at presentation

  1.3 (1.1, 1.5)  1.2 (1.1, 1.3)    

Results

Endpoint

AA

(n= 47)

4F-PCC

(n= 62)

Mean Difference (95% CI)

p-value

Hemostasis Scale

Excellent 

Good

Poor

 

27 (71.1%)

4 (10.5%)

7 (18.4%%)

 

41 (70.7%)

5 (8.6%)

12 (20.7%)

 

0.4 (−18.2–18.9)

0.4 (−18.2–18.9)

−2.3 (−18.4–13.9)

 

1

0.737

1

Thromboembolism event

 4 (8.5%) 6 (9.7%) −1.2 (−12.0, 9.7) 1

MI

 1 (2.1%) 0 (0.0%) 2.1 (−2.0, 6.3) 0.431

Stroke

 0 (0.0%) 0 (0.0%) 0 (0, 0) 1

DVT

 3 (6.4%)  5 (8.1%) −1.7 (−11.4, 8.1) 1

PE

 0 (0.0%)  1 (1.6%) −1.6(−4.7, 1.5) 1

Inpatient mortality 

 16 (34.0%) 13 (21.0%) 13.1(−3.8, 30.0) 0.134

CI = confidence interval 

Adverse Events

N/A

Study Author Conclusions

No significant difference was found in efficacy or safety between AA and 4F-PCC when used for ICH. There is insufficient evidence to recommend one reversal agent over the other for patients with ICHs associated with the use of apixaban or rivaroxaban. Further studies with a larger patient population to assess whether there is truly a difference between AA and 4F-PCC in hemostatic efficacy are needed.

InpharmD Researcher Critique

Retrospective chart reviews rely on the accuracy of existing medical records, which could potentially introduce bias and affect the overall accuracy of the results. Additionally, a larger sample size in the study may have provided more robust findings.

 

References:

Pham H, Medford WG, Horst S, et al. Andexanet alfa versus four-factor prothrombin complex concentrate for the reversal of apixaban- or rivaroxaban-associated intracranial hemorrhages. Am J Emerg Med. 2022;55:38-44. doi:10.1016/j.ajem.2022.02.029

 

Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study

Design

Multicenter, prospective study 

N= 84

Objective

To assess the efficacy and safety of 4-factor prothrombin complex concentrates (PCCs) for the reversal of the anticoagulant effect of rivaroxaban and apixaban

Study Groups

Apixaban (n= 39)

Rivaroxaban (n= 45) 

Inclusion Criteria

Patients on rivaroxaban or apixaban who required a PCC to manage acute and active major bleeding (defined by the International Society of Thrombosis and Hemostasis); administration of the last dose of either rivaroxaban or apixaban was within 24 hours

Exclusion Criteria

Patients with a drop of hemoglobin without an evident source of bleeding; preoperative reversal of rivaroxaban or apixaban; acute coronary syndrome or ischemic stroke within the past 30 days; received other hemostatic agents

Methods

Patients were recruited from 25 hospitals in Sweden and referred to the Coagulation Unit at Karolinska University Hospital. According to the hospital protocol, a flat dose of 1,500 IU of 4-factor PCCs was given to patients < 65 kg and 2,000 IU to patients ≥ 65 kg. A second dose of a PCC could be administered at the treating physician's discretion if patients were still bleeding. Patients' medical interventions, laboratory results, and outcomes were retrieved from their medical records. 

Two coagulation specialists assessed the effectiveness of bleeding management in each case and reached an agreement by discussion. 

Duration

Study enrollment: January 1, 2014, and October 1, 2016

Follow-up: 30 days post-treatment 

Outcome Measures

Duration of hospital stay, discharge destinations, and effectiveness of bleeding management

For non-intracranial hemorrhage (ICH): changes in the hemoglobin level, transfusion of blood products, intervention or surgery to stop the bleeding, and the administration of other hemostatic agents

For ICH: follow-up computed tomography (CT) within 24 hours, change in neurological status, and surgical intervention

Safety outcome: occurrence of arterial or venous thromboembolism and death

Baseline Characteristics

  

Apixaban (n= 39)

Rivaroxaban (n= 45) 

 p-value  

Median age, years (interquartile range [IQR])

77 (7 to 81)

 73 (68 to 84) 0.52  

Female

 17 (43.4%) 19 (42.2%) 1  

Median body weight, kg

75 (67 to 89)

75 (65 to 80)

 0.97  

Indication for anticoagulation

SPAF

VTE

Both

 

34 (87.2%)

2 (5.1%)

3 (7.7%)

 

29 (64.4%)

1 (2.2%)

15 (33.3%)

0.01

--

--

--

  

History of stroke

11 (28.2%)

 10 (22.2%) 0.62  

Concomitant medications 

Antiplatelet 

NSAID

 

7 (17.9%)

2 (5.1%)

 

3 (6.7%)

0

 

0.22

0.21

  

Baseline laboratory results

INR 

APTT

Creatinine

 

1.2 (1.1 to 1.3)

35 (32 to 39)

77 (61 to 83)

 

1.3 (1.1 to 1.5)

41 (36 to 49)

79.5 (63.5-99.5)

 

0.04

0.01

0.39

  

Bleeding location

ICH 

GI bleeding 

Visceral 

Genitourinary 

Musculoskeletal 

 

29 (74.4%)

5 (12.8%)

2 (5.1%)

2 (5.1%)

1 (2.6%)

 

30 (66.7%)

8 (17.8%)

3(6.7%)

2 (4.4%)

2 (4.4%)

0.95

--

--

--

--

--

  

SPAF, stroke prevention in patients with atrial fibrillation; VTE, venous thromboembolism; NSAID, nonsteroidal anti-inflammatory drug; INR, international normalized ratio; APTT, activated partial thromboplastin time; GI, gastrointestinal 

Results

Management given

Apixaban (n= 39)

Rivaroxaban (n= 45) 

p-value

  

Median PCC dose, IU factor IX

Total dose

Dose, IU/kg 

 

2000 (2000 to 2000)

26.7 (22 to 29.9)

 

2000 (1500 to 2000)

26.7 (20.8 to 29.4)

 

0.26

0.62

  

Transfusions given

Red blood cell concentrate

Plasma

Platelet

 

9 (23.1%)

2 (5.1%)

2 (5.1%)

 

11 (24.4%)

8 (17.8%)

8 (17.8%)

 

1

0.1

0.1

  

Outcome of management

 Apixaban (n= 39) Rivaroxaban (n= 45)
Effective  Ineffective Effective Ineffective

Bleeding location

ICH

GI

Visceral

Genitourinary

Musculoskeletal

 

21 (72.4%)

3 (60%)

0 

1 (50%)

1 (100%)

 

8 (27.6%)

2 (40%)

2 (100%)

1 (50%)

0 

 

22 (73.3%)

5 (62.5%)

1 (33.3%)

2 (100%)

2 (100.0%)

 

8 (26.7%)

3 (37.5%)

2 (66.7%)

0 

0 

Hemoglobin drop  

2 (33.3%)

 4 (66.7%)

3 (37.5%)

5 (62.5%)

Any invasive procedure 

None

Craniotomy

Gastroscopy

Embolization

Fasciotomy

Laparotomy

Thoracotomy

 

17 (68%)

5 (71.4%)

3 (75.1%)

0 

1 (100%)

0 

0 

 

8 (32%)

2 (28.6%)

1 (25%)

2 (100%)

0

0

0

 

23 (74.2%)

6 (100%)

1 (33.3%)

1 (50%)

0 

1 (50%)

0

 

1 (25%)

0 

2 (66.7%)

1 (50%)

0

1 (50%)

1 (100%)

Median length of hospital stay, days 

7 (3 to 15)

 4.5 (2 to 7)

9 (4 to 16)

2.5 (2 to 5)

Discharge destination

Home

Rehabilitation facility

Other hospital

Deceased

 

14 (93.3%)

7 (63.6%)

2 (66.7%)

3 (33.3%)

 

1 (6.7%)

4 (36.4%)

1 (33.3%)

6 (66.7%)

 

10 (90.9%)

13 (92.9%)

1 (100%)

5 (35.7%)

 

1 (9.1%)

1 (7.1%)

0 

9 (64.3%)

PCCs were administered 6 hours after the estimated bleeding time (2 to 10 hours). 

Most patients with ineffective hemostasis with PCC had ICH (n = 16; 61.5%).

Adverse Events

Occurrence of arterial or venous thromboembolism: ischemic stroke (n= 2) and pulmonary embolism (n= 1)

Study Author Conclusions

The study found that the majority of patients treated with PCCs for the management of major bleeding events (MBEs) on rivaroxaban or apixaban achieved effective bleeding control, with few observed thromboembolic events.

Based on the study results, the authors would suggest giving patients with MBEs on rivaroxaban or apixaban an initial PCC dose of 2000 IU, which may be repeated if the effect is suboptimal. Such an approach seems to be associated with an acceptable balance between efficacy and safety of PCCs.

InpharmD Researcher Critique

The use of flat dosing of PCCs in this study led to an overall effective anticoagulant reversal when administered within a couple of hours of bleeding onset with a low risk of thromboembolism. However, the applicability of the study results of using flat doses of PCCs as reversal agents for rivaroxaban or apixaban may be limited by the absence of a control group.

 

References:

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(15):1706-1712. doi:10.1182/blood-2017-05-782060

 

Evaluation of andexanet alfa and four-factor prothrombin complex concentrate (4F-PCC) for reversal of rivaroxaban- and apixaban-associated intracranial hemorrhages

Design

Retrospective, single-center, observational study

N= 29

Objective

To evaluate the clinical and hemostatic outcomes of patients with oral FXa inhibitor-associated intracranial hemorrhage (ICH) treated with andexanet alfa or 4F-PCC and describe the operational procedures associated with each therapeutic agent

Study Groups

Andexanet alfa (n= 18)

4F-PCC (n= 11)

Inclusion Criteria

Age ≥ 18 years; on rivaroxaban or apixaban therapy at baseline; received andexanet alfa (Andexxa) or 4F-PCC (Kcentra) for reversal of ICH

Exclusion Criteria

Received andexanet alfa or 4F-PCC antithrombotic reversal for any reason other than reversal for ICH

Methods

Consecutive patients, using a medication dispense report, who received andexanet alfa or 4F-PCC for rivaroxaban- and apixaban-associated traumatic or spontaneous ICH admitted to a Level 1 trauma center. Andexanet alfa was administered to patients meeting eligibility criteria for ANNEXA-4 clinical trial enrollment or to patients presenting with an acute ICH with last known administration of apixaban or rivaroxaban within 18 hours.

4F-PCC was dosed 25 to 50 units/kg, dosed per treating clinician discretion, with a maximum dose of 5000 units. The low-dose andexanet alfa regimen was 400 mg intravenous bolus administered over 15 minutes followed by 480 mg infused over 2 hours while the high-dose andexanet alfa regimen was 800 mg intravenous bolus over 30 minutes followed by 960 mg infused over two hours. Re-treatment with andexanet alfa was not recommended.

Duration

April 1, 2016 to April 30, 2019

Outcome Measures

Primary: percentage of patients with good or excellent hemostasis on repeat imaging within 24 hours of antithrombotic

Secondary: incidence of good functional outcome at hospital discharge (defined as a Glasgow Outcome Score [GOS]> 3); the incidence of thromboembolic events within 30 days

Baseline Characteristics

  

4F-PCC (n= 11)

Andexanet alfa (n= 18)

Age (range), years

 71.0 (68.6 to 73.2) 83.4 (70.3 to 88.8)

Female

 2 (18.2%) 8 (44.4%)

Creatine clearance (range), ml/min

 56.7 (37.8 to 72.3) 52.8 (30.7 to 77.5)

Liver disease

 1 (9.1%) 2 (11.1%)

Apixaban use at baseline

Dose (range), mg/day

Time since last dose, hours

< 8 

8-18 

> 18 

3 (27.3%)

10 (5 to 10)

 

1 (33.3%)

1 (33.3%)

1 (33.3%)

15 (83.3%)

5 (5 to 10)

 

5 (33.3%)

4 (26.7%)

0 

Rivaroxaban use at baseline

Dose (range), mg/day

Time since last dose, hours

< 8 

8-18 

> 18 

8 (72.7%)

20 (20 to 20)

 

1 (12.5%)

0

3 (37.5%)

3 (16.7%)

15 (10 to 20)

 

1 (33.3%)

0

0

Concurrent antiplatelet therapy

Aspirin

P2Y12 inhibitor

Dual antiplatelet therapy

 

4 (36.4%)

0

0

 

3 (16.7%)

2 (11.1%)

0

Coagulation parameters on presentation

PT, seconds

PTT, seconds

INR

Platelets, K/μL

 

16.5 (15 to 18.8)

30.3 (26.5 to 32.3)

1.4 (1.2 to 1.6)

197 (180 to 262)

 

14.8 (14 to 16.3)

33.2 (27.3 to 38.9)

1.2 (1.1 to 1.3)

175 (127 to 222) 

Prothrombin complex concentrate

Dose, units/kg

Dose, units

11 (100%)

26.9 (21.8 to 43.7)

2,500 (2,364 to 3,231)

1 (5.6%)

9.4

500

Andexaanet alfa

High dose regimen

Low dose regimen

 

-

-

 

0

18 (100%)

Results

Endpoint

4F-PCC (n= 11)

Andexanet alfa (n= 18)

Hemostatic effectiveness

Excellent

Good

Poor

 

6 (60.0%)

0

4 (40.0%)

 

14 (77.8%)

2 (11.1%)

2 (11.1%)

Discharge functional status

Glasgow Outcome Score (range)

 

1 (1 to 3)

 

4 (3 to 4)

Incidence of new thrombosis

1 (9.1%)

3 (16.7%)

Adverse Events

N/A

Study Author Conclusions

Higher rates of occurrence of good or excellent hemostasis and GOS > 3 were observed on hospital discharge and increased incidence of thrombosis in patients who received andexanet alfa compared to 4F-PCC for oral factor Xa inhibitor reversal. However, patients receiving 4F-PCC had lower pre-reversal Glasgow Coma Scale (GCS) scores and larger pre-reversal ICH volume.

InpharmD Researcher Critique

Since this study was limited based on the retrospective nature, single-center design and a small heterogenous patient population of both traumatic and spontaneous hemorrhage, a direct comparison of treatments was not possible. Additionally, patients who received 4F-PCC at an outside hospital and then transferred to the institution were not taken into consideration. 

 

References:

Barra ME, Das AS, Hayes BD, 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(7):1637-1647. doi:10.1111/jth.14838

 

Andexanet alfa and four‐factor prothrombin complex concentrate for reversal of apixaban and rivaroxaban in patients diagnosed with intracranial hemorrhage

Design

Retrospective, single-center, observational study

N= 56

Objective

To evaluate clinical outcomes of four‐factor prothrombin complex concentrate (4F-PCC) and andexanet alfa for the reversal of intracranial hemorrhage (ICH) associated with oral factor Xa inhibitors

Study Groups

Andexanet alfa (n= 21)

4F-PCC (n= 35)

Inclusion Criteria

Age ≥ 18 years; diagnosed with ICH; anticoagulated with apixaban or rivaroxaban prior to presentation; received either andexanet alfa or 4F-PCC 

Exclusion Criteria

Received either andexanet alfa or 4F-PCC for non-ICH indication; reversal of anticoagulants other than apixaban or rivaroxaban; received both andexanet alfa and 4F-PCC; or received alternative dosing of 4F-PCC

Methods

Eligible patients received either andexanet alfa or 4F-PCC in either the Emergency Department or Neuroscience Intensive Care Unit (ICU). Based on provider consensus (when the factor Xa inhibitor drug, dose, and/or timing of the last dose is unknown), if rivaroxaban level returns as > 0.15 ug/mL or an apixaban level > 200 ng/mL, then an additional low dose bolus is ordered, and infusion rate is increased to match the high-dose regimen of andexanet alfa.

Duration

Andexanet alfa: July 1, 2018 to September 1, 2019

4F-PCC: July 1, 2013 to September 1, 2019

Outcome Measures

Hematoma expansion, 30-day all-cause mortality, time from presentation to the administration of reversal agent, ICU length of stay, hospital length of stay, and 30-day readmission rate

Baseline Characteristics

  

Andexanet alfa (n= 21)

 4F-PCC (n= 35)

Age, years

 73.29 ± 11.97 74.51 ± 13.37

Male

 15 (71.4%) 14 (40.0%)

White

 17 (80.9%) 28 (80.0%)

DOAC

Apixaban

Rivaroxaban

 

14 (66.7%)

7 (33.3%)

 

20 (57.1%)

15 (42.9%)

Timing of last DOAC dose

< 8 h

≥ 8 h to < 18 h

≥ 18 h

 

4 (19.0%)

6 (28.6%)

6 (28.6%)

 

1 (2.9%)

6 (17.1%)

1 (2.9%)

Apixaban dosing

2.5 mg BID

5 mg BID

10 mg BID

 

4 (19.0%)

10 (47.6%)

0 

 

8 (22.9%)

11 (31.4%)

1 (2.9%)

Rivaroxaban dosing

15 mg once daily

15 mg BID

20 mg once daily

 

1 (4.8%)

0 

6 (28.6%)

 

2 (5.7%)

1 (2.9%)

11 (31.4%)

Admission laboratory results (interquartile range [IQR])

Apixaban assay level, ng/mL

Rivaroxaban assay level, μg/mL

Prothrombin time, seconds

INR

Activated partial thromboplastin time, seconds

Platelets (×109/L)

 

104 (88.5 to 149.5)

0.16 (0.10 to 0.24)

14.4 (13.0 to 15.7)

1.2 (1.1 to 1.3)

30.2 (27.5 to 34.2)

213 (151 to 272)

 

 43 (41.5 to 44.5)

0.21 (0.16 to 0.26)

14.3 (13.4 to 17.0)

1.2 (1.2 to 1.5)

29.2 (26.6 to 32.0)

226 (200 to 268)

Hemorrhage location

Intracerebral

Subdural

Subarachnoid

Multicompartmental

 

17 (81.0%)

2 (9.5%)

2 (9.5%)

0 

 

18 (51.4%)

1 (2.9%)

6 (17.1%)

10 (28.6%)

Dosing

Andexanet alfa

400 mg IV bolus + 480 mg infusion

800 mg IV bolus + 960 mg infusion

4F-PCC

Units

Units/kg

 

 

20 (95.2%)

1 (4.8%)

 

--

--

 

 

--

--

 

3,920.34 ± 940.48

48.25 ± 4.41

Results

Endpoint

Andexanet alfa (n= 21)

4F-PCC (n= 35)

Hematoma expansion

Yes

No

 

6 (35.3%)

11 (64.7%)

 

14 (45.2%)

17 (54.8%)

30-day all-cause mortality

 6 (30.0%)  14 (45.2%)

Time from presentation to the administration of reversal agent, hours (IQR)

2.67 (1.75 to 4.13)

1.73 (1.21 to 3.55)

Length of stay, days (IQR)

ICU 

Hospital

 

3.78 (2.54 to 6.69)

7.75 (4.64 to 15.87)

 

2.29 (1.37 to 5.83)

5.02 (2.72 to 8.56)

30-day readmission

  2/18 (11.1%) 2/22 (9.1%)

Study Author Conclusions

In this cohort, patients with ICH anticoagulated with apixaban or rivaroxaban, hemostatic efficacy rates differed between andexanet alfa and 4F-PCC. Additionally, 4F-PCC was found to have a higher rate of thrombotic events and mortality compared to andexanet alfa in this cohort of patients.

InpharmD Researcher Critique

This study is subject to limitations inherent to retrospective analysis, single-center, observational nature and historical bias. Additionally, patients receiving 4F-PCC were noted to have a lower GCS on admission and a high ICH score, thus limiting the ability to perform a direct comparison of the two reversal agents.

 

References:

Vestal ML, Hodulik K, Mando-Vandrick J, et al. Andexanet alfa and four-factor prothrombin complex concentrate for reversal of apixaban and rivaroxaban in patients diagnosed with intracranial hemorrhage [published online ahead of print, 2021 Jun 8]. J Thromb Thrombolysis. 2021;10.1007/s11239-021-02495-3. doi:10.1007/s11239-021-02495-3

 

Andexanet Alfa Versus 4-Factor Prothrombin Complex Concentrate for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage

Design

Retrospective, single-center, observational study

N= 44

Objective

To describe the experience with andexanet alfa (AA) or four-factor prothrombin complex concentrate (4F-PCC) in patients with oral reverse factor Xa inhibitors (FXi)-related traumatic and spontaneous intracranial hemorrhage (ICH)

Study Groups

Andexanet alfa (n= 28)

4F-PCC (n= 16)

Inclusion Criteria

Patients with life-threatening traumatic or spontaneous intraparenchymal, subarachnoid, subdural hemorrhages, and other intracranial bleeds after receiving apixaban or rivaroxaban; treated with at least one dose of AA or 4F-PCC

Exclusion Criteria

 Received both AA and 4F-PCC

Methods

Patients that required reversal of FXi received either AA dosed according to the product labeling for life-threatening bleeding associated with factor Xa inhibitors or 4F-PCC dosed with 25 units/kg up to 2,500 units per dose.

Duration

 Data collection period: July 2018 to April 2019

Outcome Measures

 Primary: ICH stability based on head computer tomography scans (CT) were defined as similar amount of blood from the initial scan at the onset of ICH to subsequent scans at 6 and 24 hours of treatment

Baseline Characteristics

  

Andexanet alfa (n= 28)

4F-PCC (n= 16)

 p-value

Age, years

 78 80 0.88

Female

 11 (39%) 5 (31%) 0.84

White

 24 (86%) 13 (81%) 0.84

Past medical history

Atrial fibrillation

Myocardial infarction

Stroke

 

20 (71%)

8 (29%)

8 (29%)

 

10 (62%)

1 (6%)

1 (6%)

 

0.74

0.12

0.12

Anticoagulant received

Apixaban

Rivaroxaban

 

19 (68%)

9 (32%)

 

12 (75%)

4 (25%)

 

0.74

0.74

Hemorrhage type

Spontaneous intracranial hemorrhage

Traumatic intracranial hemorrhage

Multicompartmental

Subdural hemorrhage

Contusions

 

20 (71%)

8 (29%)

7 (25%)

0

1 (4%)

 

8 (50%)

8 (50%)

5 (31%)

3 (19%)

0

0.20

Results

Endpoint

Andexanet alfa (n= 28)

4F-PCC (n= 16)

p-value

ICH stability based on CT scan

6 hours

24 hours

 

78%

88%

 

71%

60%

 

0.71

0.15

Incidence of thromboembolic events

 7% 0 0.53

Study Author Conclusions

In this limited sample of patients, no difference was found in neuroimaging stability, functional outcome, and thrombotic events when comparing AA and 4F-PCC in patients with FXi-related ICH. Since the analysis is likely underpowered, a multi-center collaborative network devoted to this question is warranted.

InpharmD Researcher Critique

 As mentioned, the small sample size likely leads to an underpowered result which remains speculatory at best. The p-value may be reporting false negatives despite the potential for andexanet alfa to be more beneficial to 4F-PCC as seen in the results.

 

References:

Ammar AA, Ammar MA, Owusu KA, et al. Andexanet Alfa Versus 4-Factor Prothrombin Complex Concentrate for Reversal of Factor Xa Inhibitors in Intracranial Hemorrhage. Neurocrit Care. 2021;35(1):255-261. doi:10.1007/s12028-020-01161-5

 

Retrospective review of Andexanet Alfa versus 4-Factor Prothrombin Complex Concentrate for reversal of DOAC-Associated Intracranial Hemorrhage

Design

Retrospective, single-center, observational, cohort study

N= 46

Objective

 To determine if there was a difference in hemostatic efficacy of andexanet alfa (AA) and 4-factor prothrombin complex concentrate (4F-PCC) in patients with a factor Xa inhibitor-related intracranial hemorrhage

Study Groups

4F-PCC (n= 15)

AA (n= 31)

Inclusion Criteria

 Aged ≥18 years; diagnosis of intracranial hemorrhage (ICH); received either AA or 4F-PCC for reversal of apixaban or rivaroxaban

Exclusion Criteria

 Received andexanet alfa or 4FPCC for an indication other than ICH

Methods

This was a retrospective chart review of patients admitted for ICH between September 2017 to March 2021 at a single hospital in San Francisco. Prior to andexanet alfa's FDA approval in 2018, the hospital protocol was to give 4F-PCC via rapid IV infusion at a dose of 50 units/kg up to 5000 units with a maximum infusion rate of 8.4 mL/min.

Andexanet alfa dose was based on the factor Xa inhibitor dose and timing of last administration, per the prescribing information. Low dose factor Xa inhibitor would lead to AA 400 mg IV bolus, followed by 4 mg/min IV infusion for up to 120 min (480 mg); high dose patients were given AA 800 mg IV bolus, followed by 8 mg/min IV infusion for up to 120 min (960 mg).

Duration

 September 2017 to March 2021

Outcome Measures

Primary: hemostatic efficacy (per computed tomography scan readings)

Secondary: time from order entry to administration of treatment, thrombotic event within 30 days, survival to discharge

Baseline Characteristics

  

4F-PCC (n= 15)

AA (n= 31)

 p-value

Age, years (interquartile range)

 69 (67-75) 77 (71.5-85) 0.013

Male

 60% 58.1% 1

Anticoagulant indication

Atrial fibrillation

Deep vein thrombosis

Pulmonary embolism

Other

 

60%

26.7%

0

13.3%

 

67.7%

12.9%

12.9%

6.5%

 0.30

Apixaban

Rivaroxaban

53.3%

46.7%

80.6%

19.4%

 0.11

Concomitant antiplatelet use*

26.7%

19.4%

 0.94

Glasgow Coma Score

10.6 ± 5.2

12.5 ± 3.9

 0.23

International Normalized Ratio

1.31 ± 0.43

1.46 ± 1.37

 0.58

*aspirin was the only antiplatelet used concomitantly in these patients

Results

Endpoint

4F-PCC (n= 15)

AA (n= 31)

p-value

Hemostatic efficacy

Excellent

Good

Poor

Not reported

 

60%

13.3%

6.7%

13.3%

 

51.6%

22.6%

16.1%

6.5%

 0.61

First INR after reversal (interquartile range)

 1.50 (1.18-1.85) 1.30 (1.20-1.60) 0.74

Packed red cells administered, units

 2.36 ± 0.745 2.77 ± 0.504 0.078

Time from order to medication administration, minutes

 35.3 47.8 0.054

Survival to discharge

 60% 83.9% 0.19

New thrombosis within 30 days

 0 6.5% 0.83

Adverse Events

 N/A

Study Author Conclusions

 This study found no difference in hemostatic efficacy between andexanet alfa and 4FPCC. At this time, clinicians should choose an agent based on individual patient presentation and resource availability. Further research will help clarify the role of each agent in the management of DOAC-related intracranial hemorrhage.

InpharmD Researcher Critique

Limitations of this study include the single-center and retrospective design with a small sample size. These results may be confounded by no standard on when CT scans were conducted following reversal agent administration. Even though the baseline characteristics reported all 46 patients, the results sometimes did not count 1 patient per group for an unknown reason; this occurred even when "not reported" could be counted.

Three patients received both medications, AA first then 4F-PCC; these patients were counted in the AA group. The one instance of new thrombus within 30 days was a patient who received both reversal agents.



References:

Troyer C, Nguyen W, Xie A, Wimer D. Retrospective review of Andexanet Alfa versus 4-Factor Prothrombin Complex Concentrate for reversal of DOAC-Associated Intracranial Hemorrhage. J Thromb Thrombolysis. 2023;55(1):149-155. doi:10.1007/s11239-022-02715-4

 

Low-dose versus standard-dose four-factor prothrombin complex concentrate for factor-Xa inhibitor reversal in spontaneous and traumatic intracranial hemorrhage

Design

Multicenter, retrospective, cohort study

N= 93

Objective

To compare hemostatic efficacy in low-dose 25 IU/kg versus standard-dose 50 IU/kg four-factor prothrombin complex concentrate (4PCC) for factor Xa inhibitors (FXaI) reversal in spontaneous and traumatic intracranial hemorrhage (ICH) bleed

Study Groups

25 IU/kg (n= 62)

50 IU/kg (n= 31)

Inclusion Criteria

 Age 18 years or older, received 4PCC (KCentra®), presenting with spontaneous or traumatic ICH needing FXaI reversal

Exclusion Criteria

Did not have a documented computerized tomography (CT) or magnetic resonance imaging (MRI) scan, repeat CT or MRI was completed greater than 48 hours after the initial scan, received massive transfusion protocol (received 10 or more units of blood in a 24-hour period)

Methods

Patient data was collected from a multi-center set of academic and community medical centers within a central Texas healthcare system. Then patients were classified into either low- or standard-dose groups of 4PCC (25 IU/kg or 50 IU kg, respectively).

Duration

 November 2013 to November 2019

Outcome Measures

Primary outcome: Hemostatic efficacy (hematoma volume showing no change, less than or equal to 35% change, improvement on repeat CT or MRI scan vs initial scan)

Secondary: In-hospital mortality, length of stay, thrombotic events, surgery needed, blood product needed

Baseline Characteristics

  

25 IU/kg (n= 62)

50 IU/kg (n= 31)

  

Age, years

 79.5 78  

Male

 34 11  

Height, cm

 168.9 167.3  

Weight, kg

 80.4 67.2  

Facility type

Academic medical center

Community hospital

 

51.6%

48.4%

 

61.3%

38.7%

  

Thrombotic event history

History of antiplatelet use

Systolic blood pressure > 180 mmHg at presentation

27.9%

37.1%

22.6%

29.0%

12.9%

29.0%

  

FXaI history

Apixaban

Rivaroxaban

Edoxaban

 

40.3%

59.7%

0

 

58.1%

41.9%

0

  

Type of ICH

Spontaneous

Traumatic

 

29.0%

71.0%

 

58.1%

41.9%

  

Timing of follow-up scan

< 12 h

12-24 h

24-48 h

 

72.6%

19.4%

8.1%

 

71.0%

25.8%

3.2%

  

Results

Endpoint

25 IU/kg (n= 62)

50 IU/kg (n= 31)

p-Value

Hemostatic efficiency

82.3%

83.9%

0.846

In-hospital mortality

12 (19.4%)

9 (29.0%)

0.293

Length of stay, days (interquartile range [IQR])

6 (3.0 to 9.5)

5 (2.5 to 8.5)

0.987

Thrombotic event

 3 (4.8%) 0 0.548

Surgery needed

 15 (24.2%) 6 (19.4%) 0.599

Blood products needed

 27 (43.5%) 10 (32.3%) 0.294

Adverse Events

Thrombotic events that occurred in the three 25 IU/kg patients may have been precipitated by patient-specific factors such as those with a history of atrial fibrillation and upper extremity deep-vein thrombosis, myocardial infarction, and arteriovenous malformation

Study Author Conclusions

For the reversal of FXaI in ICH, a 25 IU/kg dose may be an effective alternative to 50 IU/kg 4PCC dosing.

InpharmD Researcher Critique

 Small sample size, lack of standardized testing, and missing data introduce limitations that weaken the conclusions regarding 4PCC's effects.



References:

Cascone AE, Daley MJ, Pan N, Padilla-Tolentino E, Milling TJ. Low-dose versus standard-dose four-factor prothrombin complex concentrate for factor-Xa inhibitor reversal in spontaneous and traumatic intracranial hemorrhage. Pharmacotherapy. 2021;41(6):501-507. doi:10.1002/phar.2525

 

A low-dose 4F-PCC protocol for DOAC-assoicated intracranial hemorrhage

Design

Retrospective study

N= 22

Objective

To evaluate the effectiveness and safety of a low-dose four-factor prothrombin complex concentrate (4F-PCC) protocol in direct oral anti-coagulant (DOAC) associated intracranial hemorrhage (ICH), through assessment of hemostatic effectiveness and thromboembolic events

Study Groups

All patients (n= 22)

Inclusion Criteria

Age ≥ 18 years, received at least one dose of 4F-PCC for DOAC-associated ICH

Exclusion Criteria

Patients who received 4F-PCC at an outside hospital

Methods

At the 3 centers, all eligible patients received a dose of 25 units/kg 4F-PCC per the hospital reversal guideline, rounded to the nearest 500-unit vial. Additional hemostatic agents administered within 4 hours of 4F-PCC administration and blood products administered within 6 hours prior and 24 hours after 4F-PCC administration were also recorded.

Neuroimaging results were collected 24 hours after 4F-PCC administration. Physician progress notes in the 14 days following 4F-PCC administration were assessed and thromboembolic events were confirmed with radiological imaging techniques and laboratory markers as appropriate.

Duration

March 2014 to December 2015

Outcome Measures

Primary outcome: Hemostatic effectiveness within 24 hours of 4F-PCC administration, measured by the first neuroimaging result within 24 hours of 4F-PCC administration that showed no change or an improvement in hematoma volume.

Secondary outcome: Cumulative incidence of thromboembolic events (upper and lower extremity deep vein thrombosis (DVT), pulmonary embolism (PE), ischemic stroke, myocardial infarction (MI), line-associated thrombosis, or any other documented thromboses) occurring in the 14 days following 4F-PCC administration and hospital mortality. 

Baseline Characteristics

  

All patients (n= 22)

 

Age, years (IQR)

79.5 (74.3–83.5)

  

Male

11 (50%)

  

Weight, kg (IQR)

74.3 (69.1–85.2)

  

4F-PCC dose, units/kg (IQR)

25.9 (24.5–27.3)

  

DOAC reversal

Rivaroxaban

Apixaban

Dabigatran

 

15 (68.2%)

5 (22.7%)

2 (9.1%) 

  

Reason for anticoagulation

Atrial fibrillation

VTE prophylaxis or treatment

 

17 (77.3%)

3 (13.6%)

  

Thromboembolic history

Cerebrovascular accident

Upper or lower extremity DVT

 

6 (27.3%)

5 (22.7%)

  

Additional agents within 4 hr of 4F-PCC

Desmopressin*

Vitamin K*

Platelets†

 

5 (22.7%)

2 (9.1%)

10 (45.5%)

  

*Given within 4 hr of 4F-PCC

†Given 6 hours before through 24 hours after 4F-PCC

Results

 

Evaluable patients* (n= 19)

All patients (n= 22)

Hemostatic effectiveness

Rivaroxaban

Apixaban

Dabigatran

18 (94.7%)

13 (92.9%)

4 (100%)

1 (100%)

 --

Hemostatic effectiveness by type of ICH

Intraparenchymal hemorrhage

Subdural hematoma

Subarachnoid hemorrhage

Suprasellar hematoma

18 (94.7%)

5 (83.3%)

5 (100%)

7 (100%)

1 (100%)

 --

Patients with thromboembolic events

Rivaroxaban

Apixaban

Dabigatran

 

--

 

2 (9.1%)

1 (6.7%)

1 (20%)

0 (0%)

Thromboembolic events

Ischemic stroke

Lower extremity (LE) DVT

 --

1 (4.5%)

1 (4.5%)

Hospital mortality

 --

4 (18.2%)

*There were 3 patients without follow-up neuroimaging

Adverse Events

N/A

Study Author Conclusions

The use of a lower dose protocol of 25 units/kg of 4F-PCC resulted in high rates of hemostasis in patients with DOAC-associated ICH. Two patients developed thrombotic events within 14 days of 4F-PCC administration.

InpharmD Researcher Critique

The study lacked a comparator group making it difficult to independently correlate hemostatic effectiveness and thromboembolic rates with 4F-PCC administration. The participating insitutions also did not have valid tests to measure DOAC exposure prior to 4F-PCC administration, meaning pateints could have had significant DOAC elimination before treatment was given. 



References:

Berger K, Santibañez M, Lin L, Lesch CA. A Low-Dose 4F-PCC Protocol for DOAC-Associated Intracranial Hemorrhage. J Intensive Care Med. 2020;35(11):1203-1208. doi:10.1177/0885066619840992