Efficacy and Safety of Novel Oral Anticoagulants in Patients with Cervical Artery Dissections

Design

Retrospective and controlled trial 

N= 149

Objective

To describe the utility of direct oral anticoagulants (DOACs), traditional anticoagulants, and antiplatelet agents as treatment for cervical artery dissection (CAD) 

Study Groups

DOAC (n= 39)

Traditional anticoagulants (n= 70)

Antiplatelets (n= 40)

Inclusion Criteria

Patients with carotid or vertebral artery dissection; one confirmatory angiographic examination using magnetic resonance angiography (MRA), computerized tomographic angiography (CTA), or digital subtraction angiography (DSA)

Exclusion Criteria

Patients with intracranial dissection 

Methods

This was a retrospective study of a single health system in Illinois. Patients with cervical carotid or vertebral artery dissection were retrospectively identified by International Classification of Diseases (ICD-9) codes. Patients were typically treated with antithrombotic agents, but off-label DOACs could be considered with informed consent. Traditional anticoagulation was warfarin or treatment dose low molecular weight heparin. Antiplatelets choices were aspirin, clopidogrel, or aspirin/dipyridamole). Recurrent cerebral ischemic events were assessed through patient reports or radiographic findings at follow-up appointments.

Duration

January 2010 to August 2013

Median duration of anticoagulants: 4 months

Median duration of DOACs: 3 months

Outcome Measures

Primary: recurrent cerebral ischemic events; worsening stenosis

Safety: gastrointestinal upset/ peptic ulcer disease and hemorrhagic complications

Baseline Characteristics

DOAC (n= 39)

Traditional anticoagulants (n= 70)

Age, years

Female

Past medical history

Hypertension

Prior stroke

Atrial fibrillation

Coronary artery disease

10 (25.6%)

0

0

0

13 (18.6%)

3 (4.3%)

2 (2.9%)

1 (1.4%)

8 (20.0%)

0

1 (2.0%)

3 (7.5%)

0.677

0.178

0.576

0.080

Presentation

Headache

Neck pain

Ischemic symptoms

Explicit trauma

26 (66.7%)

21 (34.4 %)

25 (64.1%)

18 (46.2%)

35 (50.0%)

26 (37.1%)

38 (54.3%)

33 (47.1%) 

17 (42.5%)

14 (35.0%)

18 (45.0%)

18 (45.0%)

0.086

0.158

0.234

0.977

Patients with severe stenosis or occlusion were more likely to be treated with a DOAC, whereas those with no or mild luminal stenosis were more likely to be treated with antiplatelet agents (p= 0.002).

Results

Traditional anticoagulants (n= 70)

Antiplatelets (n= 40)

Recurrent stroke

Worsened stenosis

Any hemorrhagic complication

Major hemorrhagic complications

2 (5.1%)

0

11 (15.7%)

8 (11.4%)

2 (5.0%)

1 (2.5%)

0.369

0.034 

Heartburn or Peptic Ulcer disease 

Of the three DOAC-treated patients who had a worsened degree of stenosis on follow-up imaging, two were treated with dabigatran and one took rivaroxaban. Of the two cases of recurrent stroke with DOAC use, one was on dabigatran and one was on apixaban.

Adverse Events

N/A

Study Author Conclusions

Compared to traditional anticoagulants for cervical artery dissection, treatment with direct oral anticoagulation is associated with similar rates of recurrent stroke, fewer hemorrhagic complications, but greater rates of radiographic worsening. These data suggest that DOACs may be a reasonable alternative in the management of CAD. Prospective validation of these findings is needed.

InpharmD Researcher Critique

This was a retrospective study, which relies on accurate health record documentation; however, since diagnoses were based on ICD-9 codes, there is a possibility of misclassification and lack of ascertainment of all CAD patients. Additionally, the choice of antithrombotic therapy was not standardized and physicians may have been biased to treat patients based on clinical and radiographic findings.

Cervical artery dissection causing severe luminal stenosis or occlusion was more likely to be treated with an anticoagulant, and patients with no or mild stenoses are treated with antiplatelets. Since severe stenosis may be more likely to have to worsen, there may be a bias against the anticoagulation groups. Stroke severity upon presentation was not prospectively recorded, but there was no association observed between antithrombotic choice and the ischemic symptoms at presentation or the presence of infarction on brain imaging.

Helsinki Experience on Nonvitamin K Oral Anticoagulants for Treating Cervical Artery Dissection

Design

Retrospective, single-center study

N= 68

Objective

To gather data on the use of nonvitamin K oral anticoagulants/direct-acting oral anticoagulants (NOACs/DOACs) for the treatment of cervical artery dissection as compared to vitamin K antagonists (VKAs) in patients with stroke due to vertebral (VAD) or internal carotid artery dissection (ICAD)

Study Groups

DOAC (n=6)

VKA (n=62) 

Inclusion Criteria

Patients with a stroke due to VAD or ICAD using oral anticoagulation

Exclusion Criteria

Patients who underwent endovascular stenting followed by antiplatelet therapy; patients treated with only heparin or LMWH; patients with multiple traumatic injuries not using oral anticoagulation

Methods

This was a retrospective study from a single institution in Finland. The institutional protocol recommends six months of anticoagulation for patients with cervical artery dissection, but the selection of anticoagulant was at the discretion of the neurologist.

Data was recorded between November 2011 and January 2014 from consecutive patients with a stroke due to VAD or ICAD and who were using oral anticoagulants. The patients were divided into two groups: patients using NOACs, and patients using VKAs.

Duration

November 2011 to January 2014 

Outcome Measures

Recurrent ischemic stroke, intracranial hemorrhage, recanalization rate, and functional outcome on the modified Rankin Scale (mRS) within six months (score ≤1)

Baseline Characteristics

DOAC (n=6)

VKA (N=62)

Median age, years (interquartile range)

Male

NIHSS at baseline (interquartile range)

Vertebral artery dissection

Occlusion

Stenosis 

33%

33%

67%

61%

40%

60%

Internal carotid artery dissection

Occlusion

Stenosis 

67%

33%

67%

44%

52%

48%

Prior trauma 

Results

DOAC (n=6)

Recanalization

Intracerebral hemorrhage 

Death

Adverse Events

Study Author Conclusions

In this small, consecutive single-center patient sample treating ischemic stroke patients with cervical artery dissection with DOACs did not bring up safety concerns and resulted in similar, good outcomes compared to patients using VKAs.

InpharmD Researcher Critique

This study adds new information with respect to safety issues on secondary prevention with NOACs in stroke patients with CeAD. The study limitations are the small sample size on the DOAC subgroup and it was a retrospective study. Additionally, the choice of DOACs were not reported.

The impact of direct oral anticoagulants in traumatic brain injury patients greater than 60-years-old

Design

Retrospective, single-center, observational study

N=186

Objective

To compare the use of direct oral anticoagulants (DOACs), vitamin K antagonists (VKAs), and antiplatelets in patients with traumatic brain injury (TBI)

Study Groups

No antithrombotic therapy (n=80)

Antiplatelets (n=41)

VKA (n=32)

DOAC (n=33)

Inclusion Criteria

≥60 years old; proven intracranial hemorrhage (ICH) by initial cranial computed tomography (CT); considered to be at risk of delayed development of an intracranial bleeding

Exclusion Criteria

<60 years old; transferred from the emergency room to the normal ward; abbreviated injury scale score (other than head) >2

Methods

This was a retrospective single-center study of a level 1 trauma center in Austria. The traumatic brain injury patients were stratified into four groups based on their medication usage: patients without antithrombotic therapy, antiplatelets (e.g., aspirin or adenosine diphosphate antagonists), VKA (e.g., phenprocoumon or acenocoumarol), and DOACs (e.g., dabigatran, rivaroxaban, edoxaban, or apixaban).

After the initial cranial CT scan, intracranial hemorrhage was reassessed 12–24 h after hospital admission, depending on the patients’ condition and neurologic status. Potential hematoma progression was identified and documented by a radiologist.

Duration

January 2014 to May 2017

Outcome Measures

Primary outcomes: mortality, progression of ICH

Secondary outcomes: ICU and hospital length of stay

Baseline Characteristics

No antithrombotic therapy (n=80)

Antiplatelets (n=41)

Median age, years (IQR)

Male

Median abbreviated injury scale head score (IQR)

Results

No antithrombotic therapy (n=80)

Antiplatelets (n=41)

ICH progression

There were no significant differences in ICU and hospital length of stay between the groups.

There was significantly higher in-hospital mortality in the VKA group compared with DOACs, antiplatelets, and no antithrombotic therapy (p= 0.047). Hematoma progression was also significantly higher in patients on VKA therapy compared to the other groups (p= 0.023).

Adverse Events

N/A

Study Author Conclusions

Although TBI patients anticoagulated with DOACs share demographic and clinical similarities with those on VKAs, their mortality was significantly lower. This is of particular interest as significantly more patients on VKAs received reversal agents compared to DOAC patients. These findings are in line with previous results that also showed superior overall outcomes in trauma patients on DOACs compared to patients on VKAs.

InpharmD Researcher Critique

This study is limited by the retrospective, single-center design. Specific values were not reported (e.g., mortality incidence of each group). Additionally, the specific DOACs used were not reported.

Design

N= 314

Objective

To address the paucity of data regarding delayed intracranial hemorrhage in patients on direct oral anticoagulants (DOACs)

To determine the incidence of delayed intracranial hemorrhage (d-ICH), defined as intracranial hemorrhage which developed following negative initial head computed tomography (CT) scan of patients on DOACs who sustained blunt head trauma

Study Groups

Rivaroxaban (n= 129)

Apixaban (n= 182)

Inclusion Criteria

Patients aged 18 and older, evaluated at a single institution in Michigan, were currently taking one of the DOACs (apixaban, rivaroxaban, or dabigatran) at the time of injury, had a negative initial head CT scan

Exclusion Criteria

Patients who did not have a repeat head CT scan within 72 h of the first one

Methods

Duration

January 2017 - August 2018

Outcome Measures

Primary outcome: the incidence of delayed intracranial hemorrhage amongst the included patient population

Baseline Characteristics

All patients (N= 314)

Age, years (range)

79 (21-96)

Female

175 (55%)

3 (1-26)

143 (45.5%)

Glasgow Coma scale <14

Indication for anticoagulation

Atrial Fibrillation

Venous thromboembolism

Other

232 (67.5%)

71 (23.5%)

11 (6%)

DOAC

Apixaban

Rivaroxaban

Dabigatran

181 (57.6%)

129 (41.1%)

4 (1.27%)

Antiplatelet use

Dual antiplatelet therapy

105 (33.4%)

8 (2.5%)

Results

Three patients (0.95%) were found to have delayed intracranial hemorrhage on the repeat CT scan. Two of the three were on concomitant antiplatelet medication. None of these cases required neurosurgical intervention.

Age (years)

Length of stay (days)

81

2

88

92

3

7

Adverse Events

N/A 

Study Author Conclusions

InpharmD^TM Researcher

Critique

The study was an observational retrospective study, thus has the potential to be biased. The study also only focused on one institution, thus having a small sample size. In addition, patients were all identified via the trauma registry, thus showing inherent selection bias, and excluded patients who had blunt head trauma and were on a DOAC.