INTRODUCTION
Stroke represents one of the most important causes of death in many countries and
the second in Brazil. In 2019, 101.074 Brazilians died of a stroke[1].
The incidence of stroke in our country is around 105 to 137 cases per 100,000 individuals
per annum[12].
Stroke is a major cause of disability. Around 15-30% of survivors have severe disabilities[3].
Stroke represents a significant public health problem globally.
According to Benjamin et al., more than 795,000 individuals in the United States have
a stroke every year; about 610,000 are first or new strokes. Nearly one in four patients
have had a previous stroke[4].
Acute ischemic stroke treatment is crucial to minimize the burden of stroke, while
secondary prevention therapy is also needed to avoid stroke recurrence.
The treatment of hyperacute ischemic stroke focuses on reperfusion therapy of ischemic
cerebral tissue with thrombolytic drugs and, more recently, mechanical thrombectomy.
Unfortunately, stroke registries have found that only 15% to 32% of patients presenting
with ischemic stroke arrive at the hospital within three hours of symptom onset and
only 40% to 50% of these are eligible for tPA (Alteplase). Even for mechanical thrombectomy
within six hours, a single-center study estimated that only 1.7-2.5% of patients would
be eligible for this treatment[5].
General supportive care with the management of physiological factors such as blood
pressure, oxygenation, control of glycemia, avoiding dehydration and hyperthermia
are essential in all patients[6].
Anticoagulation therapy in acute ischemic stroke may be a therapeutic option in selected
patients. This article will discuss some controversies on this topic but also emphasize
the benefit of anticoagulation for secondary prevention in cardioembolic stroke and
other situations.
ANTICOAGULATION IN ACUTE ISCHEMIC STROKE
Emergent anticoagulants have been used in acute ischemic stroke, but there are controversies
about their efficacy, the type of anticoagulant, route of administration, and treatment
duration.
In the TOAST trial, anticoagulation with intravenously low molecular weight heparinoid,
ORG 10172 (danaparoid sodium) was evaluated in acute ischemic stroke patients. It
was a randomized, double-blind, placebo-controlled, multicenter trial and enrolled
1281 individuals in the United States. The treatment included a seven-day course of
danaparoid sodium or placebo with an initial bolus. Doses of heparinoids were adjusted
according to anti-factor Xa activity. After seven days more patients treated with
anticoagulation presented favorable outcomes but this benefit was not observed after
three months. In the group receiving anticoagulation treatment, more patients presented
intracranial bleeding complications. The authors' conclusions were that, despite the
initial positive response to treatment at seven days, emergent treatment with anticoagulation
was not associated with clinical improvement at three months[7].
In another study, the FISS-tris-trial patients with acute stroke with large artery
occlusion were treated with anticoagulation with LMWH (fraxiparine) or aspirin. When
analyzing subgroups of stroke, patients with symptomatic stenosis in the posterior
circulation could benefit from treatment with LMWH anticoagulation[8].
The IST trial compared patients with acute ischemic stroke treated with aspirin or
anticoagulation with subcutaneous heparin. Treatment with aspirin produced a small
reduction of deaths and recurrence of stroke without a significant increase in cerebral
hemorrhage. Patients treated with subcutaneous heparin used a two-dose regimen: 12.500UI
or 5.000UI twice daily. No benefit was observed in either subcutaneous heparin treatment.
Fewer recurrent strokes were observed after 14 days but there was also an increase
in hemorrhagic stroke and extracranial bleeding[9].
A meta-analysis of IST, TOAST and FISS-tris describes a 0.8% risk of cerebral hemorrhage
complications with the use of heparinoids without the benefit of anticoagulation in
the stroke's acute phase[10].
American Heart Association guidelines do not recommend urgent anticoagulation in acute
ischemic stroke in avoiding its recurrence or halting progression, since meta-analysis
studies have shown a lack of benefit for anticoagulation treatment in these patients[6].
In patients with ischemic stroke associated with severe stenosis of an internal carotid
artery, urgent anticoagulation is not recommended (AHA Guidelines 2019)[6]. However, some small studies have shown that for patients with extracranial artery
intraluminal thrombus associated strokes, intravenous heparin or LMWH could be of
benefit[11],[12].
We recommend anticoagulation with intravenous unfractionated heparin for some patients
with embolization from carotid artery intraluminal thrombus or from basilar artery.
Cerebral venous thrombosis
Patients with acute cerebral venous thrombosis are treated with anticoagulation but
this topic will be discussed in another chapter.
Cervical artery dissection
Cervical artery dissection is a common cause of stroke in young patients. Intramural
hematoma can cause arterial stenosis or vessel occlusion. Cerebral infarction caused
by cervical artery dissection may be a consequence of a hemodynamic mechanism or artery-to-artery
embolization. Patients with moderate or severe arterial narrowing (intramural hematoma)
associated with cerebral embolization could benefit from emergent anticoagulation
with unfractionated heparin or LMW heparin.
The CADISS (Cervical Artery Dissection in Stroke Study) group performed a randomized
trial with 250 patients with extracranial carotid or vertebral artery dissection.
When comparing anticoagulation and antiplatelet treatment there is no significant
difference in outcome in Cervical Dissection patients[13].
The presence of HITS (High-intensity transient signal) that represents embolic events
occurrence in transcranial doppler monitoring may be another indication of anticoagulation
in cervical artery dissection patients[13]. Large stroke cerebral infarcts could present hemorrhagic transformation therefore
we avoid emergent anticoagulation in these situations.
According to AHA guidelines (2019) patients with acute ischemic stroke and extracranial
carotid or vertebral arterial dissection may be treated with antiplatelet or anticoagulation
for a period of three to six months[6].
Thrombophilia and stroke
Patients with thrombotic states, such as in SARS-Cov-2 patients, antiphospholipid
antibodies syndrome and other causes of thrombophilia could present thrombotic cerebral
infarctions[14],[15]. Except for patients with large strokes, anticoagulation could be started in the
acute period.
Case 1
In August 2020, a 60-year-old female, was admitted to our institution presenting flu-like
symptoms (fever, cough, odynophagia) and dyspnea. She had a positive SARS-Cov-2 PCR
test. Two days later, she suddenly presented subtle right hemiparesis and aphasia.
Head Computer tomography (CT) showed no evidence of cerebral hemorrhage, and the patient
was treated with intravenous thrombolysis (alteplase). CT-angiography evidenced a
thrombus in the left common carotid artery ([Figure 1] and [2]). After 24 hours she had a further head CT ([Figure 3]) and intravenous unfractionated heparin was started. She received warfarin for three
months. Follow-up CT-angiography ([Figure 4]) showed recanalization and anticoagulation was discontinued.
Figure 1 Sagittal reformatted CTA image shows the thrombus floating in the lumen of the left
common carotid artery (arrow).
Figure 2 Axial reformatted CTA image also shows the luminal thrombus in the left common carotid
artery.
Figure 3 Follow-up head CT depicts the ischemic area in the left hemisphere more clearly as
a hypoattenuation involving the left insula and frontal lobe.
Figure 4 Follow-up sagittal reformatted CTA image shows the complete reabsorption of the thrombus.
SECONDARY STROKE PREVENTION TREATMENT
Around 20%of ischemic strokes are cardioembolic. Nonvalvular atrial fibrillation is
one of the main causes of these strokes. Atrial fibrillation (AF) increases stroke
risk three to five fold. Other cardioembolic mechanisms include: left atrial or ventricular
thrombus, acute anterior ST-segment elevation myocardial infarction with anterior/apical
akinesis or dyskinesis, mechanical left ventricular assist device, left ventricular
ejection fraction less than 35%, and valvular heart disease including rheumatic mitral
valve disease or mechanical prosthetic heart valves in the aortic or mitral position.
In all of these cases, treatment with anticoagulants is recommended[16].
Anticoagulation in atrial fibrillation (AF) and stroke
AF predisposes the formation of thrombi-related left atrial appendage stasis and represents
an important cause of cardiac embolism. Treatment with anticoagulation reduces the
stroke risk associated with AF. A meta-analysis study including eight trials with
9598 patients with chronic AF, vitamin K antagonist (VKA) anticoagulants (warfarin)
significantly reduced the risk of ischemic stroke (odds ratio (OR) 0.68, 95% confidence
interval (CI) 0.54 to 0.85), by about one third, compared with aspirin (reduction
of 60% with anticoagulation and 20% with aspirin) [17].
However, anticoagulation increased the number of hemorrhagic complications. The International
normalized ratio (INR) for VKA anticoagulation in patients with nonvalvular AF and
prior ischemic stroke or transient ischemic attack (TIA) is recommended at a range
between 2.0 and 3.0[16].
More recent studies have evidenced the efficacy of Direct Oral Anticoagulants (DOAC):
direct thrombin inhibitors (dabigatran) and inhibitors of factor Xa (rivaroxaban,
apixaban, and edoxaban) anticoagulants. In trials with patients with AF, DOACs were
compared with warfarin and they performed similar benefits, reducing ischemic stroke
risk with a lower incidence of hemorrhagic cerebral complications. These studies compared
DOAC and warfarin: ARISTOTLE (apixaban vs. warfarin in atrial fibrillation), RE-LY
(dabigatran vs. warfarin in atrial fibrillation), ROCKET-AF (rivaroxaban vs. warfarin
in atrial fibrillation), and ENGAGE AF-TIMI (edoxaban vs. warfarin in atrial fibrillation)
[18]-[21].
The risk of strokes related to AF can be estimated using CHA2DS2-VASc Score[22].
CHA2DS2VASc Score includes eight items ([Table 1]):
-
congestive heart failure or left ventricular systolic dysfunction with ejection fraction
<40% (one point);
-
hypertension (one point);
-
age ≥75 (doubled = two points);
-
diabetes (one point);
-
stroke (doubled = two points);
-
vascular disease (one point);
-
age 65 to 74 (one point) and;
-
sex category (female = one point).
Table 1
CHA2DS2VASc score.
|
Condition
|
Points
|
|
Congestive heart failure
|
1
|
|
Hypertension
|
1
|
|
Age ≥ 75
|
2
|
|
Diabetes
|
1
|
|
prior Stroke or TIA
|
2
|
|
Vascular disease
|
1
|
|
Age 65-75
|
1
|
|
Sex
|
1
|
|
MAXIMUM SCORE
|
9
|
This score varies from 1 to 9. A patient with CHA2DS2-VASc Score 9 has an annual risk of 15.2% of presenting a stroke.
European Society of Cardiology guidelines for Atrial Fibrillation recommend stratifying
patients with AF into three groups according to CHA2DS2-VASc score: score 0 - low risk, score 1 - medium risk, score ≥2 - high risk of presenting
a stroke[23].
In [Table 2] we could observe that the stroke risk increased if a patient with AF presented other
risk factors. According to European Society of Cardiology guidelines, patients with
AF and CHA2DS2VASc Score ≥ 2 should be anticoagulated. The decision to initiate anticoagulation
for a determined stroke patient must consider not only the stroke risk recurrence
but also the risk of hemorrhagic complications[23]-[25].
Table 2
CHA2DS2VASC score and stroke risk.
|
CHA2DS2VASC score
|
Stroke risk %/year
|
|
0
|
0
|
|
1
|
1.3
|
|
2
|
2.2
|
|
3
|
3.2
|
|
4
|
4.0
|
|
5
|
6,7
|
|
6
|
9.8
|
|
7
|
9.6
|
|
8
|
12.5
|
|
9
|
15.2
|
Risks and prevention of bleeding with oral anticoagulants
There is no anticoagulant therapy without an increased risk of bleeding.
The studies showed that the pathogenesis of anticoagulant-associated bleeding included
loss of vascular wall integrity and microbleeds related to microscopic pseudoaneurysm
formation. When analyzing the risk of bleeding in anticoagulant therapy, the established
risk factors are: type of anticoagulant, dose level, age, non-white race, prior bleeding,
prior stroke, hypertension, cerebral amyloid angiopathy, liver disease, kidney disease,
diabetes, oncologic diseases and disturbances of hemostasis[26].
If someone considers these risk factors before choosing an anticoagulant therapy,
the risk of serious bleeding could be reduced.
A number of bleeding risk scores have been validated, identifying potentially modifiable
risk factors; however, the association is not causation and too many factors act as
a cause and also a risk factor for anticoagulation.
The HAS-BLED ([Table 3]) score was derived from a Euro Heart Study, only with patients with atrial fibrillation
and its use has been recommended in European and Canadian guidelines[26].
Table 3
HAS-BLED score.
|
Letter
|
Clinical characteristic
|
Points
|
|
H
|
Hypertension (ie, uncontrolled blood pressure)
|
1
|
|
A
|
Abnormal renal and liver function (1 point each)
|
1 or 2
|
|
S
|
Stroke
|
1
|
|
B
|
Bleeding tendency or predisposition
|
1
|
|
L
|
Labile INRs (for patients taking warfarin)
|
1
|
|
E
|
Elderly (age greater than 65 years)
|
1
|
|
D
|
Drugs (concomitant aspirin or NSAIDs) or excess alcohol use (1 point each)
|
1 or 2
|
|
|
|
Maximum 9 points
|
Other scores: ATRIA score, VTE-BLEED, HEMORR2HAGES score.
When to initiate anticoagulation after a stroke
According to Hart et al., within two weeks of a stroke associated with nonvalvular
atrial fibrillation (AF), the risk of developing an early recurrent cerebral embolism
is calculated at around 0.1% and 1.3% per day[25].
However, the time for introducing anticoagulation therapy remains unclear.
The RAF study evaluated 1029 patients in five groups: Low Molecular Weight Heparin
(LMWH) alone, vitamin K antagonists (VKA) anticoagulants, direct oral anticoagulants,
LMWH followed by VKA anticoagulants, and 449 were treated with antiplatelets[27].
The study concluded that the recurrence of ischemic events (ischemic stroke or TIA)
was 7.6% and symptomatic cerebral bleeding was 3.6% with 1.4% of major bleeding.
In patients with CHA2DS2-VASc score 4 to 8, the annual risk of stroke recurrence was higher and varied between
9.88% and 20.3%.
When analyzing the composite clinical events (risk of ischemic stroke recurrence and
major bleeding), high CHA2DS2-VASc score, high NIHSS (National Institute of Health Stroke Scale), large lesion
size, and type of anticoagulant were predictive factors[27].
RAF study recommends initiating anticoagulant therapy to avoid ischemic stroke recurrence
between four and 14 days, except for patients with large ischemic lesion size associated
with cerebral hemorrhage (hemorrhagic transformation - HT). In these patients, anticoagulation
should be delayed. When anticoagulation was started within 30 days in patients with
large lesion sizes, it was associated with a higher risk of complications. This is
the main risk factor for HT[27].
Even in moderate size ischemic stroke lesions, cardioembolic stroke is prone to present
HT. Hornig et al. in a Magnetic Resonance Image study (MRI) showed that HT was present
in 68.6% (24) of the 35 patients with Cardioembolic stroke. The risk of HT was associated
with ischemic stroke volume (≥ 10ml). Hemorrhages are common in medium-size and large
cardioembolic infarcts[28].
Mac Grory et al. suggest the resumption of oral anticoagulation in Cardioembolic stroke
patients with AF should be done preferably after 48 hours, taking into consideration
the cardioembolic stroke risk recurrence versus HT risk. The treatment included DOAC
or VKA anticoagulation (warfarin). They suggest restarting anticoagulation after two
days in patients with small strokes, 7-10 days in those with moderate-sized strokes,
and 10-14 days in those with large strokes. In the case of multiple infarcts, they
recommend considering the size of the largest. In the presence of hemorrhagic transformation,
anticoagulation is usually delayed, mainly in large infarcts, for 30 days[29].
Resumption of OAC after anticoagulation-related intracerebral hemorrhage
When considering resuming anticoagulation in a patient with hemorrhagic transformation
due to OAC we need to analyze the risk of thromboembolism and the risk of enlargement
of cerebral hematoma.
Fiorelli et al. classified the Hemorrhagic Transformation according to the volume
of hematoma: HI1, HI2, PH1 and PH2:
-
HI 1 Hemorrhage infarction type 1 - Small hyperdense petechiae;
-
HI2 - Hemorrhage infarction type 2- More confluent hyperdensity throughout the infarct
zone; without mass effect;
-
PH 1- Parenchymal hematoma type 1 - Homogeneous hyperdensity occupying <30% of the
infarct zone; some mass effect;
-
PH 2 - Parenchymal hematoma type 2 - Homogeneous hyperdensity occupying >30% of the
infarct zone; significant mass effect.
Kuramatsu et al. performed a retrospective cohort study in Germany and included 1176
patients with anticoagulation-related intracerebral hemorrhage and patients with AF
and other cardiomyopathies[30].
In 853 patients they analyzed hemorrhage enlargement and in 719 oral anticoagulation
resumption. Intracerebral hemorrhage enlargement was observed in 307 of 853 patients
(36%). Factors that contributed to reducing the risk of hemorrhage enlargement were:
rapid reversal of anticoagulation for INR levels <1,3 (within four hours) and rigorous
blood pressure control with systolic BP levels <160mmHg within four hours.
Oral anticoagulation resumption was done in only 172 of 719 patients and was associated
with a lower risk of ischemic stroke. OAC resumption occurred on average 31 days after
the HT[30].
Patients with previous cerebral microbleeds or previous lobar hemorrhage suggestive
of amyloid angiopathy or without blood pressure control or large ischemic stroke present
a major risk of HT or recurrence of cerebral bleeding after the resumption of anticoagulation[31]. In these patients, anticoagulants must be used with caution.
Mac Grory suggests that patients with mechanical heart valves have a higher potential
for cardiac embolization. They suggest, except in cases of large-size cerebral infarction,
that these patients should receive early anticoagulation within four to seven days,
and the occurrence of cerebral hemorrhage enlargement should be monitored[29]. Another indication was thrombus in the left atrium or left ventricle and malignancy
and stroke.
Mac Grory observed that it is safe to reintroduce anticoagulation in patients with
small infarcts and HT after two days. However, in patients with moderate-size cerebral
infarction, they recommend delaying anticoagulation for seven to 28 days. In these
cases, HT type PH2 was observed even 28 days after the stroke. In cases of large cerebral
infarction, they suggest delaying anticoagulation for 10 to 42 days for the same reason.
According to Lansberg et al., annual hemorrhagic transformation in patients using
oral anticoagulation varies between 0.6% to 1%[32].
In a Danish study, 1725 patients with acute ischemic stroke anticoagulation resumption
was done between two to 10 weeks later.
Researchers recommend delaying ACO resumption after an ICH for at least two weeks,
usually restarting after around four weeks. However, in patients with cerebellar ICH
it would be better to wait eight to 10 weeks and in patients with mechanical prosthetic
valves and small ICH ACO should be reintroduced after two weeks[33],[34].
Embolic stroke of undetermined source (ESUS)
For embolic stroke of undetermined source (ESUS) patients, two trials, NAVIGATE -
ESUS (rivaroxaban and aspirin) and RES-PECT ESUS, compared the effect of anticoagulation
and aspirin[36]-[38].
In the NAVIGATE- ESUS trial, rivaroxaban was no better than aspirin with regard to
the prevention of recurrent stroke in ESUS patients and was associated with a higher
risk of bleeding[37].
Comparison of LMWH/Heparin Bridging Versus No Bridging Therapy to oral anticoagulation
According to Yaghi et al patients treated with LMWH/heparin bridging presented a significantly
higher rate of symptomatic cerebral hemorrhage (4.4% versus 1.0%)[35].
Bridging could be considered in patients with small infarcts and intracardiac thrombus.
Stroke and malignancy
Stroke and malignancy can occur simultaneously, while thrombosis is a well-known complication
in cancer.
Although the number of publications on cancer-related stroke has recently increased,
there are no evidence-based guidelines for treatment of cancer-related stroke. The
effects of DOACs were reported in only a few cases, most of all retrospective studies,
but the efficacy and safety of DOACs in cancer-related stroke have not yet been settled
by comprehensive studies.
A large retrospective study demonstrated the efficacy and safety of DOACs as compared
with warfarin in patients with atrial fibrillation and active cancer. DOACs were more
effective in preventing venous thromboembolism (VTE) than warfarin. They were similar
or superior to warfarin in stroke prevention and less major bleeding, though lacked
statistical significance[39].
A clinical trial, ENGAGE AF-TIMI 48, studied 1153 atrial fibrillation patients with
new or recurrent cancer treated with warfarin or edoxaban. The results show that high-dose
and low-dose edoxaban decreased stroke and systemic embolic events as compared with
warfarin, but there was no statistical significance and a low tendency to major bleeding[40].
A recent meta-analysis comparing available data regarding the efficacy and safety
of DOACs versus warfarin in cancer patients with nonvalvular AF. In comparison to
VKA, DOACs were associated with a significant reduction in the rates of thromboembolic
events and major bleeding complications in patients with AF and cancer[41].
The occurrence of venous thromboembolism (VTE) as a stroke complication is extremely
frequent in both. Anticoagulant therapy is the cornerstone of treatment. Acute treatment
for patients with no severe renal insufficiency or contraindication to anticoagulation
is the use of low molecular weight heparin; to avoid using injections, apixaban is
an alternative, based upon a single randomized trial with similar efficacy and safety
compared with LMW heparin[42].
Antiphospholipid antibodies syndrome
Antiphospholipid syndrome is an autoimmune disease that is associated with a high
rate of recurrent thrombosis such as stroke, pulmonary thromboembolism, peripheral
venous thrombosis and sometimes miscarriages.
According Sapporo criteria to fulfill the diagnosis of APS a patient must present
one clinical criterion and one laboratorial criterion (the presence of at least one
of antiphospholipid antibodies: lupus anticoagulant, anticardiolipin antibodies and
anti beta2 glycoprotein I antibodies). A challenging situation is a life-threatening
multiorgan thrombosis, Catastrophic APS.
EULAR recommends anticoagulation after a first arterial thrombosis with VKA drugs
(warfarin) with a target INR between 2 and 3. DOACs are not recommended mainly in
patients with triple APL positive (three APL antibodies positive) and arterial events.
Patients with catastrophic APS are treated with anticoagulation with heparin associated
with glucocorticoids and plasma exchange or intravenous immunoglobulin[43].
In conclusion, anticoagulation in stroke treatment remains a challenge. It is important
always to keep in mind anticoagulation and analyze the patient’s risk of stroke recurrence
and HT. However, even in patients with a high risk of HT it is important not to exclude
this option, but to consider delaying it, mainly in patients with high CHA2DS2VASc.
