How soon after traumatic brain injury/intracerebral hemorrhage can DOACs be resumed or started?

Comment by InpharmD Researcher

Evidence regarding the optimal timing to resume DOACs after traumatic brain injury/intracerebral hemorrhage (ICH) remains inconclusive and highly dependent on individual patient risk profile. Guidelines and consensus statements suggest resumption of oral anticoagulants 4 to 8 weeks after the index event in patients with low to moderate thrombotic risks. An early start, 10 to 14 days after traumatic brain injury, may be considered in patients with a stable injury and a high risk of cerebral ischemia (i.e., those with mechanical valve prosthesis or non-valvular atrial fibrillation and a CHA2DS2-VASc score ≥ 4). It should be noted that most recommendations apply to oral anticoagulants as a whole class and are not exclusive to DOACs.

Background

Guideline statements in 2015 from the American Heart Association (AHA) and 2017 from the American College of Cardiology (ACC) both express concern regarding the lack of evidence for the timing to restart oral anticoagulation in patients who suffer intracerebral hemorrhage. In both guidelines, avoidance of oral anticoagulation for at least 4 weeks is recommended in patients without high thrombotic risk with the caveat that optimal timing remains uncertain. [1], [2]

A 2020 systematic review observed the literature for guidance on the timing to restart oral anticoagulation after traumatic intracranial hemorrhage (ICH). While restarting oral anticoagulation is generally supported, the timing remains uncertain. The authors highlight issues regarding the available evidence with focus on the intermingling observation of traumatic versus sudden ICH. Sudden ICH differs in that the risk of rebleeding may be higher and rate of thromboembolism may be lower, yet most data focuses on sudden ICH patients which is then applied to traumatic ICH. [3]

While the strategy remains unclear, a number of ongoing and registered clinical trials are currently underway to address the timing of anticoagulation restart in sudden and traumatic ICH. These include the SoSTART (NCT03153150) trial comparing oral anticoagulations (DOAC or warfarin) versus no treatment, ASPIRE (NCT03907046) comparing apixaban versus aspirin, STATICH (NCT03186729) comparing anticoagulants versus no treatment, A3ICH (NCT03243175) comparing apixaban versus left atrial appendage closure or no treatment, and ENRICH-AF (NCT03950076) comparing edoxaban versus no treatment. The APACHE-AF (NCT02565693) has recently been completed and published which found that re-initiating apixaban in patients who survived intracerebral hemorrhage 7 to 90 days after the event had similar events to those who did not restart anticoagulation (see Table 1). However, only 101 patients were recruited and larger studies are needed to confirm the lack of benefit. [3], [4]

A 2019 review discusses when spontaneous intracerebral hemorrhage (ICH) patients should resume oral anticoagulation (OAC). Generally, studies have documented a median starting point between 4 to 6 weeks after ICH. However, studies specifically evaluating timing of resumption have identified a broad range of potentially optimal time points ranging from 72 hours to 10-30 weeks. While it remains unclear when to optimally resume OAC after ICH, ongoing randomized trials may help provide more clarity. Expert opinion currently suggests a timeframe between 4 to 8 weeks after index ICH in patients with atrial fibrillation depending on patients’ individual risk profile. A shorter resumption time period may be preferred in life-threatening situations, such as symptomatic intracardiac thrombus formation or acute pulmonary embolism, but only after confirmation of hematoma stability and strict blood pressure control. It should be noted that data are not specific to DOACs and include other anticoagulants, including vitamin K antagonists. [5], [6]

An Austrian interdisciplinary consensus statement recommends that therapeutic anticoagulation may be continued 10–14 days after traumatic brain injury in patients with a stable injury and a high risk of cerebral ischemia (i.e., those with mechanical valve prosthesis or non-valvular atrial fibrillation and a CHA2DS2VASc score ≥ 4). In patients with moderate or low risk of thromboembolic events, it may be more appropriate to resume anticoagulation after 4–8 weeks. This is in agreement with European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage. [7], [8]

References: [1] Hemphill JC 3rd, Greenberg SM, Anderson CS, et al. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2015;46(7):2032-2060. doi:10.1161/STR.0000000000000069
[2] Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(24):3042-3067. doi:10.1016/j.jacc.2017.09.1085
[3] King B, Milling T, Gajewski B, et al. Restarting and timing of oral anticoagulation after traumatic intracranial hemorrhage: a review and summary of ongoing and planned prospective randomized clinical trials. Trauma Surg Acute Care Open. 2020;5(1):e000605. Published 2020 Dec 3. doi:10.1136/tsaco-2020-000605
[4] Schreuder FHBM, van Nieuwenhuizen KM, Hofmeijer J, et al. Apixaban versus no anticoagulation after anticoagulation-associated intracerebral haemorrhage in patients with atrial fibrillation in the Netherlands (APACHE-AF): a randomised, open-label, phase 2 trial. Lancet Neurol. 2021;20(11):907-916. doi:10.1016/S1474-4422(21)00298-2
[5] Sembill JA, Kuramatsu JB, Schwab S, Huttner HB. Resumption of oral anticoagulation after spontaneous intracerebral hemorrhage. Neurol Res Pract. 2019;1:12. Published 2019 May 10. doi:10.1186/s42466-019-0018-0
[6] Kuramatsu JB, Huttner HB. Management of oral anticoagulation after intracerebral hemorrhage. Int J Stroke. 2019;14(3):238-246. doi:10.1177/1747493019828555
[7] Wiegele M, Schöchl H, Haushofer A, et al. Diagnostic and therapeutic approach in adult patients with traumatic brain injury receiving oral anticoagulant therapy: an Austrian interdisciplinary consensus statement. Crit Care. 2019;23(1):62. Published 2019 Feb 22. doi:10.1186/s13054-019-2352-6
[8] Steiner T, Al-Shahi Salman R, Beer R, et al. European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage. Int J Stroke. 2014;9(7):840-855. doi:10.1111/ijs.12309
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

How soon after traumatic brain injury/intracerebral hemorrhage can DOACs be resumed or started?

Level of evidence

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


Please see Tables 1-3 for your response.

 

Apixaban versus no anticoagulation after anticoagulation- associated intracerebral haemorrhage in patients with atrial fibrillation in the Netherlands (APACHE-AF): a randomised, open-label, phase 2 trial

Design

Prospective, randomized, open-label, phase 2 trial

N= 101

Objective

To provide reliable estimates of the rates of non­fatal stroke or vascular death in patients with atrial fibrillation and a recent anticoagulation-­associated intracerebral hem­orrhage (ICH) who were treated with apixaban versus those in whom anticoagulation was avoided

Study Groups

Apixaban (n= 50)

Avoid anticoagulation (n= 51)

Inclusion Criteria

Adults with a spontaneous ICH (including isolated intraventricular hem­orrhage) in the previous 7–90 days during treatment with anticoagulation (vitamin K antagonist, direct oral anticoagulant [DOAC], or heparin or low-­molecular-­weight heparin at therapeutic dose) for paroxysmal or non­-paroxysmal non­valvular atrial fibrillation; CHA2DS2­-VASc score of at least 2 and a score on the modified Rankin scale (mRS) of 4 or less

Exclusion Criteria

Had conditions other than atrial fibrillation requiring long­term anticoagulation (e.g., mechanical prosthetic heart valve); had other serious bleeding events besides ICH in the previous 6 months; had a high risk of bleeding; had an ischaemic stroke in the previous 7 days; had active alcohol or drug misuse; had a life expectancy of less than 1 year; had severe renal insufficiency; had liver test abnormalities; women with childbearing potential or who were pregnant or breastfeeding

Methods

Eligible patients were randomized (1:1) to receive apixaban 5 mg BID (2.5 mg BID in qualified individuals) or to avoid anticoagulation. Patients in the avoid anticoagulation could receive an oral antiplatelet at the discretion of the treating physician. Without definitive evidence on the optimal timing of resumption of antithrombotic therapy after ICH, patients could start treatment 7 to 90 days post-ICH based on clinical judgment of the treating physician. 

Participants were scheduled for follow­up at 1 month (±7 days), 6 months (±14 days), and 12 months (±28 days), and subsequently every 12 months (±28 days) until the end of the study.

Duration

Between Jan 15, 2015, and July 6, 2020 

Median duration of follow-up: 1.9 years

Outcome Measures

Primary: non­fatal stroke (ischaemic stroke, ICH, or subarachnoid hemorrhage) or vascular death, whichever came first, during follow­up 

Secondary: ICH, subarachnoid hem­orrhage, traumatic intracranial hemorrhage, major extracranial hemorrhage, clinically relevant non­major bleeding, ischaemic stroke, unclassified stroke, any stroke, myocardial infarction, pulmonary embolism, systemic embolism, vascular death, and all­cause death

Baseline Characteristics

  

Apixaban (n= 50)

Avoid anticoagulation (n= 51)

  

Median age, years (interquartile range [IQR])

 77 (74–83) 79 (72–83)  

Female

23 (46%) 23 (45%)  

White

 49 (98%) 51 (100%)  

Median CHA2DS2­-VASc score (IQR)

 4 (3–5)

4 (3–5)

  

Cardiovascular risk factors 

Previous ischaemic stroke

Previous intracerebral hemorrhage

Previous myocardial infarction

Hypertension

Diabetes

 

10 (20%)

4 (8%)

8 (16%)

45 (90%)

9 (18%)

 

14 (27%)

3 (6%)

4 (8%)

50 (98%)

7 (14%)

  

Oral anticoagulant at time of ICH

Vitamin K antagonist

Non-vitamin K oral antagonist

 

33 (66%)

17 (34%)

 

37 (73%)

14 (27%)

  

Intracerebral hemorrhage characteristics

Volume, mL (IQR)

Location

Lobar 

Deep 

 

5.7 (1.8 to 11.9)

 

14 (28%)

27 (54%)

 

6.6 (2.3 to 14.3)

 

14 (27%)

25 (49%)

  

Time from intracerebral hemorrhage to randomization, days (IQR)

45 (22 to 70)

 46 (20 to 76)  

Modified Rankin scale at randomization (IQR)

2 (1 to 3)

 3 (1 to 4)  

Results

Endpoint

Apixaban (n= 50)

Avoid anticoagulation (n= 51)

Adjusted HR (95% CI);
p-value

Non-fatal stroke or vascular death

 13 (26%)  12 (24%) 1.05 (0.48 to 2.31); 0.9

Secondary outcomes

Intracerebral hemorrhage

All major hemorrhagic events

Ischemic stroke

All major occlusive events

All major vascular events according to the protocol†

All major vascular events (myocardial infarction, stroke, or vascular death)¶

 

4 (8%)

6 (12%)

6 (12%)

6 (12%)

14 (28%)

13 (26%)

 

1 (2%)

3 (6%)

6 (12%)

11 (22%)

16 (31%)

13 (25%)

 

4.08 (0.45 to 36.91); 0.21

2.11 (0.52 to 8.51); 0.29

0.96 (0.31 to 2.97); 0.94

0.46 (0.17 to 1.25); 0.13

0.80 (0.39 to 1.64); 0.54

0.93 (0.43 to 2.00); 0.85 

CI = confidence interval; HR = hazard ratio 

†All major hemorrhagic events, all major occlusive events, or vascular death, whichever occurred first.

¶As defined by the Antithrombotic Trialists’ Collaboration.

Adverse Events

Common Adverse Events: N/A

Serious Adverse Events (not outcome events): apixaban vs avoid anticoagulation (58% vs 57%)

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

Patients with atrial fibrillation who had an intracerebral hemorrhage while taking anticoagulants have a high subsequent annual risk of non-fatal stroke or vascular death, whether allocated to apixaban or to avoid anticoagulation. Our data underline the need for randomized controlled trials large enough to allow the identification of subgroups in whom restarting anticoagulation might be either beneficial or hazardous.

InpharmD Researcher Critique

Given the small sample size and low incidence rate of primary outcomes, results from this phase II trial are considered hypothesis-generating for future studies to detect clinically significant differences in outcomes of interest. Additionally, the open-label design may introduce biases, leading to overestimation or underestimation of apixaban effects. The applicability of the results is primarily limited to patients receiving warfarin as the majority of patients in this trial were noted to have received vitamin K antagonists.



References:
[1] Schreuder FHBM, van Nieuwenhuizen KM, Hofmeijer J, et al. Apixaban versus no anticoagulation after anticoagulation-associated intracerebral haemorrhage in patients with atrial fibrillation in the Netherlands (APACHE-AF): a randomised, open-label, phase 2 trial. Lancet Neurol. 2021;20(11):907-916. doi:10.1016/S1474-4422(21)00298-2

 

Optimal Timing of Anticoagulant Treatment After Intracerebral Hemorrhage in Patients With Atrial Fibrillation

Design

Retrospective analysis

N= 2,619

Objective

To provide observational data on the relationship between the timing of antithrombotic treatment and the competing risks of severe thrombotic and hemorrhagic events in a cohort of Swedish patients with atrial fibrillation and intracerebral hemorrhage (ICH)

Study Groups

All patients (N= 2,619)

Inclusion Criteria

First-ever ICH recorded in the Swedish Stroke Register (Riksstroke), concomitant diagnosis of atrial fibrillation, surviving hospital discharge

Exclusion Criteria

Traumatic ICH, subdural hematomas, subarachnoid hemorrhage

Methods

Data from Riksstroke were linked with other national registers to find information on treatment, comorbidity, and outcome. The starting point for follow-up of antithrombotic treatment was time of first dispensed prescription of antithrombotic treatment after discharge, given that the patient was not on treatment at discharge. 

Duration

First-ever ICH recorded between July 1, 2005 and December 31, 2012

Median follow-up: 1.7 years

Outcome Measures

Thrombotic events and hemorrhagic events

Baseline Characteristics

  

All patients (N= 2,619)

Age, years

 78 ± 9.1

Female

1,065 (40.7%)

Medical history

Diabetes mellitus

Previous ischemic stroke

Venous thromboembolism

Ischemic heart disease

Hypertension

Heart failure

Valvular disease

Peripheral arterial disease

Dementia


605 (23.1%)

640 (24.4%)

140 (5.3%)

713 (27.2%)

2,180 (83.2%)

672 (25.7%)

213 (8.1%)

156 (6%)

153 (5.8%)

Treatment at ICH onset

Anticoagulant

Antiplatelet

Both anticoagulant and antiplatelet

Statins


1,239 (47.3%)

1,175 (44.9%)

205 (7.8%)

723 (27.6%)

Median CHA2DS2-VASc

Score 0-4

Score 5-9

4 

1,595 (60.9%)

1,024 (39.1%)

Results

Endpoint

All patients (N= 2,619)

Thrombotic events

Ischemic stroke

379

302 (79.7%)

Hemorrhagic events

Recurrent ICH events

115

96 (83.5%)

The risk reduction of thrombotic events in patients treated with anticoagulants compared with no treatment was statistically significant in the 4- to 16-week interval for both the low- and high-risk patients.

Initiation of anticoagulants was not associated with any significantly increased risk of a hemorrhagic event. However, initiation of anticoagulation very early may increase the risk of bleeding, compared with no treatment. 

The lowest estimated cumulative incidence functions (CIFs) of vascular death or nonfatal stroke were found when anticoagulant treatment was started in the 7- to 8-week interval. For high-risk women, the total risk of vascular death or stroke recurrence within 3 years was 17.0% when anticoagulant treatment was initiated 8 weeks after ICH, when compared with 28.6% without any antithrombotic treatment (95% confidence interval [CI] for difference 1.4% to 21.8%). The corresponding risks were 14.3% versus 23.6% (95% CI for difference 0.4% to 18.2%) for high-risk men, 8.2% versus 12.6% (95% CI for difference −2.1% to 10.8%) for low-risk women, and 7.3% versus 10.7% (95% CI for difference −2.7% to 9.4%) for low-risk men.

Patients who initiated anticoagulant treatment within 8 weeks after ICH had a reduced rate of thrombotic events (95% CI for difference −13.9% to −1%) and no significantly increased rate of hemorrhagic events (95% CI for difference −3.7% to 8.7%) as compared with patients without any antithrombotic treatment within 8 weeks.

Adverse Events

N/A

Study Author Conclusions

The optimal timing of starting anticoagulant treatment in patients with AF who have survived an ICH seems to be around 7 to 8 weeks after the hemorrhage. In high-risk patients, anticoagulant treatment started in this interval reduces not only the risk of thrombotic events but also the combined risk of vascular death and nonfatal stroke. If treatment is started in this interval, there seems to be no excess risk of major bleeding.

InpharmD Researcher Critique

This study was observational in nature. Additionally, patients were not specifically required to have received a direct oral anticoagulant following ICH; patients could have received antiplatelets or other anticoagulants, which limits its applicability.



References:
[1] Pennlert J, Overholser R, Asplund K, et al. Optimal Timing of Anticoagulant Treatment After Intracerebral Hemorrhage in Patients With Atrial Fibrillation. Stroke. 2017;48(2):314-320. doi:10.1161/STROKEAHA.116.014643

 

Resumption of Direct Oral Anticoagulants in Patients with Acute Spontaneous Intracerebral Hemorrhage

Design

Retrospective, single-center chart review

N= 43

Objective

To demonstrate the timing of direct oral anticoagulants (DOAC) resumption and factors that influence decision-making in DOAC resumption

Study Groups

DOAC Resumption (n= 19)

No DOAC resumption (n= 24)

Inclusion Criteria

Nonvalvular atrial fibrillation (AF) patients who were treated with DOAC before the onset of intracerebral hemorrhage (ICH)

Exclusion Criteria

Not explicitly specified

Methods

Eligible patients were divided into those who resumed DOAC and those who did not resume DOAC during hospitalization. The indication for and timing of DOAC resumption were determined at the attending physicians’ discretion.

Duration

Admission period: March 2014 to February 2018

Outcome Measures

Hematoma expansion, presence of microbleeds, days from ICH onset to resumption of DOAC therapy, clinical outcome according to the modified Rankin Scale (mRS) score at discharge, duration of hospital stay

Baseline Characteristics*

  

DOAC Resumption (n= 19)

No DOAC resumption (n= 24)

p-value

Age, years

 74.1 72.4 0.412

Female

9 (47%)

7 (29%)

 0.220

Body mass index, kg/m2

24.0

 22.8 0.413

Preadmission mRS score

 0 0  0.542

Risk factors

Hypertension

Diabetes mellitus

Dyslipidemia

Current smoking

Alcohol intake

Ischemic stroke

Hemorrhagic stroke

Coronary artery disease 

Heart failure

 

18 (95%)

5 (26%)

8 (42%)

1 (5%)

5 (26%)

6 (32%)

1 (5%)

1 (5%)

6 (32%)

 

19 (79%)

8 (33%)

7 (29%)

2 (8%)

5 (9%)

11 (46%)

3 (13%)

2 (8%)

4 (17%)

 

0.143

0.619

0.377

0.695

0.673

0.342

0.417

0.695

0.250

CHADS2 score (interquartile range [IQR])

CHA2DS2-VASc score (IQR)

Glasgow Coma Scale score on admission (IQR)

NIHSS score (IQR)

2 (2 to 3)

4 (3 to 5)

14 (11.5 to 15)

6 (3.5 to 14)

3 (2 to 3.25)

4 (3 to 5)

10.5 (4 to 14.25)

17 (4.75 to 30.5)

0.298

0.754

0.041

0.119

Antiplatelet drugs

1 (5%)

 1 (4%) 0.865

The National Institutes of Health Stroke Scale score (NIHSS) at admission tended to be higher in the no resumption group than in the resumption group (p= 0.119).

Results

Endpoint

DOAC Resumption (n= 19)

Non DOAC resumption (n= 24)

 p-value

Hematoma status

Initial volume, mL

Expantion

 

23.3

1 (5%)

 

28.9

0

 

0.723

0.255

Presence of microbleeds

6 (55%)

11 (79%)

0.389

mRS score at discharge (IQR)

3 (2 to 4)

4 (3 to 5)

 0.070

Mortality

 0 4 (17%) 0.062

Duration of hospital stay, days

31 ± 23

 32 ± 31 0.625

Based on the mRS, DOAC was not resumed in most patients with poor functional outcomes (p= 0.070).

In the resumption group, DOAC was resumed at a median of 11 days (IQR, 5-21 days) after ICH onset.

A worse mRS score at discharge was associated with later DOAC resumption (p= 0.013).

Adverse Events

During the hospital stay, one patient developed hematoma expansion immediately after DOAC resumption, and one patient developed cerebral embolism during the DOAC discontinuation period.

Study Author Conclusions

In half of patients, DOAC was resumed relatively early after ICH onset. Early resumption of DOAC for ICH in patients with nonvalvular atrial fibrillation is considered to be safe. The functional outcome was associated with not only resumption of DOAC but also the timing of resumption.

InpharmD Researcher Critique

The study was performed in Japan, limiting the external validity of the results to other patient populations. In addition to limitations based on single-center, retrospective nature, only a small number of patients followed up during the hospital stay. Moreover, functional recovery after discharge may have resulted in resumption of DOAC in some patients. 



References:
[1] Kato Y, Hayashi T, Suzuki K, et al. Resumption of Direct Oral Anticoagulants in Patients with Acute Spontaneous Intracerebral Hemorrhage. J Stroke Cerebrovasc Dis. 2019;28(10):104292. doi:10.1016/j.jstrokecerebrovasdis.2019.07.008