What is the 28-day in-hospital mortality rate associated with Andexxa in confirmed intracranial hemorrhage patients on anticoagulation?

Comment by InpharmD Researcher

One retrospective cohort study (Table 1) specifically reported 28-day mortality of 39.1% in andexanet alfa- vs. 40.4% in four-factor thrombin complex concentrate (4F-PCC)-recipients for reversal of apixaban- or rivaroxaban-associated intracranial hemorrhage. Recent similar studies reporting 30-day all-cause mortality yielded a larger magnitude of difference (7.9-30.0% andexanet alfa vs.19.6-48.9% 4F-PCC), but without a significant difference. Additionally, none were adequately powered to assess 28/30-day mortality, as it was only examined as one of many secondary endpoints.
Background

Recent studies have examined andexanet alfa versus four-factor thrombin complex concentrate (4F-PCC) for reversal of apixaban- or rivaroxaban-associated intracranial hemorrhage. All reported lower rates of 30-day all-cause mortality in andexanet alfa-recipients compared to 4F-PCC-recipients; the reported 30-day all-cause mortality ranged approximately from 7.9 to 30.0% in andexanet alfa as opposed to 19.6 to 48.9% in 4F-PCC groups in this cohort of patients. [1], [2], [3]

References:

[1] 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. J Thromb Thrombolysis. 2022;53(1):167-175. doi:10.1007/s11239-021-02495-3
[2] Cohen AT, Lewis M, Connor A, et al. Thirty-day mortality with andexanet alfa compared with prothrombin complex concentrate therapy for life-threatening direct oral anticoagulant-related bleeding. J Am Coll Emerg Physicians Open. 2022;3(2):e12655. Published 2022 Mar 5. doi:10.1002/emp2.12655
[3] Costa OS, Connolly SJ, Sharma M, et al. Andexanet alfa versus four-factor prothrombin complex concentrate for the reversal of apixaban- or rivaroxaban-associated intracranial hemorrhage: a propensity score-overlap weighted analysis. Crit Care. 2022;26(1):180. Published 2022 Jun 16. doi:10.1186/s13054-022-04043-8
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What is the 28-day in-hospital mortality rate associated with Andexxa in confirmed intracranial hemorrhage patients on anticoagulation?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Table 1 for your response.

 

Comparison of 4-factor prothrombin complex concentrate and andexanet alfa for reversal of apixaban and rivaroxaban in the setting of intracranial hemorrhage

Design

Single-center, retrospective, descriptive cohort study

N= 70

Objective

To evaluate and compare clinical outcomes in patients who experienced intracranial hemorrhage (ICH) while taking apixaban or rivaroxaban and were reversed with four-factor prothrombin complex concentrates (4F-PCC) or andexanet alfa (AA)

Study Groups

4F-PCC (n= 47)

AA (n= 23)

Inclusion Criteria

Adult patients (≥ 18 years old) who received 4F-PCC or AA for apixaban- or rivaroxaban-associated ICH diagnosed via computed tomography (CT) scan

Exclusion Criteria

ICH associated with edoxaban or betrixaban, DOAC reversal indication for non-ICH major bleeding, hemostatic agents or clotting factors administered prior to reversal, surgical intervention prior to receiving either study drug

Methods

4F-PCC was administered as a fixed dose of 50 units/kg (up to 5,000 units per dose) and AA was dosed according to product labeling for life-threatening bleeding associated with factor Xa-inhibitors.

Duration

January 1, 2015 to February 28, 2021

Outcome Measures

Primary: excellent or good hemostatic efficacy at 12 h post-reversal, defined as less than 20% increase or greater than 20% but less than 35% increase in hematoma volume, respectively, compared to baseline CT

Secondary: change in hematoma volume size at 12 h, functional status at discharge, need for surgical intervention or additional hemostatic agents post-reversal, new thrombotic event within 28 days, 28-day all-cause mortality, hospital and intensive care unit lengths of stay

Baseline Characteristics

  

4F-PCC (n= 47)

AA (n= 23)

 p-Value

Age, median years [IQR]

81 [74–87]

80 [73–85]

 0.46

Male

30 (63.8%)

10 (43.5%)

 0.11 

Body Mass Index (BMI), kg/m2 (± SD)

27.7 ± 6.5

29.7 ± 6.5

 0.17 

Anticoagulant

Apixaban

Rivaroxaban

 

24 (51.1%)

23 (48.9%)

 

20 (87.0%)

3 (13.0)%

 

0.004

0.004

Anticoagulant dose

Apixaban 

2.5 mg PO twice daily

5 mg PO twice daily

10 mg PO twice daily

Unknown

Rivaroxaban

15 mg PO daily

20 mg PO daily

Unknown

 

(n= 24)

5 (20.8%)

11 (45.8%)

1 (4.2%)

7 (29.2%)

(n= 23)

6 (26.1%)

11 (47.8%)

6 (26.1%)

 

(n= 20)

3 (15.0%)

17 (85.0%)

0 

0

(n= 3)

2 (66.7%)

1 (33.3%)

0

 

 

0.71

0.01

1.00

0.01

 

0.22

1.00

0.56

Indication for anticoagulation

Atrial fibrillation

Venous thromboembolism

Unknown

 

32 (68.1%)

12 (25.5%)

3 (6.4%)

 

15 (65.2%)

6 (26.1%)

2 (8.7%)

 

0.81

0.96

0.66

Concurrent antiplatelet therapy

Aspirin

P2Y12 inhibitor

Other

 

21 (44.7%)

2 (4.3%)

1 (2.1%)

 

11 (47.8%)

1 (4.3%)

0

 

1.00

1.00

1.00

GCS on admission, median [IQR]

13 [6–15]

12 [5–14]

 0.43

Mechanism of injury

Traumatic

Spontaneous

 

32 (68.1%)

15 (31.9%)

 

16 (69.6%)

7 (30.4%)

 

0.90

0.90

Multicompartment hemorrhage

22 (46.8%)

12 (52.2%)

 0.67

Initial hematoma volume, mL [IQR]

(n= 27)

15.7 [6.1–33.0]

(n= 20)

18.3 [7.7–64.0]

 

0.25 

Baseline ICH median score, median score [IQR]

(n= 27)

2 [1–3]

(n= 20) 

3 [2, 3]

 

0.03 

Reversal agent dosing

Andexanet alfaa

Low-dose

High-dose

4F-PCC: 50 units/kg infusion

 

 

-

-

47 (100%)

 

 

17 (73.9%)

6 (26.1%)

-

 

 

 

 

 

Values are presented either mean +/- standard deviation, median [interquartile range], or quantity (%)

aLow dose—400 mg bolus followed by 4 mg/min infusion for up to 120 min; high dose—800 mg bolus followed by 8 mg/min infusion for up to 120 min

Results

Endpoint

4F-PCC (n= 47)

AA (n= 23)

p-Value

Primary

Excellent or good hemostatic efficacy at 12 h

(n= 21)

14 (66.7%)

(n= 12)

9 (75%)

 

0.62

Secondary

Change in hematoma volume at 12 h, mL (± SD)

Receipt of other hemostatic agents

Need for surgical intervention after reversal

Modified Rankin Scale, median [IQR]

Glasgow Outcome Scale, median [IQR]

Cerebral Performance Category, median [IQR]

28-day mortality

ICU length of stay, median days [IQR]

Hospital length of stay, median days [IQR]

(n= 21) 

1.0 ± 11.8

2 (4.3%)

8 (17.0%)

5 [3–6]

3 [1–4]

3 [3–5]

19 (40.4%)

3 [1–8]

7 [3–11]

(n= 12) 

−0.5 ± 5.5

1 (4.3%)

7 (30.4%)

5 [4–6]

3 [1–3]

3 [3–5]

9 (39.1%)

3.5 [1–10]

7 [4–12]

 

0.44

1.00

0.20

0.24

0.37

0.29

0.92

0.75

0.61 

Safety outcome

New thrombotic event within 28 days

Cardiovascular death

Venous thromboembolism 

 

8 (17.0%)

0

8 (100%)

 

5 (21.7%)

1 (20%)

4 (80%)

 

0.63

0.38

0.38

Adverse Events

See Results

Study Author Conclusions

In patients who experienced an ICH while taking apixaban or rivaroxaban, 4F-PCC and AA were found to have similar rates of excellent or good hemostatic efficacy

InpharmD Researcher Critique

28-day mortality was merely one of the many secondary endpoints which lacks proper power for analysis. Based on the assigned p-value for 28-day mortality, the difference was insignificant. 



References:

Lipski M, Pasciolla S, Wojcik K, Jankowitz B, A Igneri L. Comparison of 4-factor prothrombin complex concentrate and andexanet alfa for reversal of apixaban and rivaroxaban in the setting of intracranial hemorrhage [published online ahead of print, 2022 Dec 25]. J Thromb Thrombolysis. 2022;10.1007/s11239-022-02752-z. doi:10.1007/s11239-022-02752-z