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Anticoagulation and Stroke

Abstract In 2019, the American Heart Association did not recommend the emergent use of anticoagulation to prevent recurrence or progression of acute ischemic stroke. However, its indication in patients with extracranial artery intraluminal thrombus with artery-to-artery cerebral embolization must be analyzed. In this article, we will also discuss other indications of anticoagulation. This treatment could be indicated in patients with ischemic stroke caused by embolization from cervical artery dissection, catastrophic antiphospholipid antibodies syndrome (APS) and some cases of Covid 19. For secondary prevention, anticoagulation is recommended for Cardioembolic stroke such as nonvalvular atrial fibrillation and other cardiopathies, some patients with cervical artery dissection, stroke associated with cancer, and thrombophilia such as APS. The timing to restart anticoagulation after a large ischemic stroke or after a cerebral hemorrhagic transformation always represent a challenge. Even in patients with high risk of thromboembolism it should be delayed at least two weeks, ideal after four weeks.


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 2 .
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 CEREBROVASCULAR DISEASE 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.

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 .
The risk of strokes related to AF can be estimated using CHA 2 DS 2 -VASc Score 22 . CHA 2 DS 2 VASc Score includes eight items (Table 1): y congestive heart failure or left ventricular systolic dysfunction with ejection fraction <40% (one point); y hypertension (one point); y age ≥75 (doubled = two points); y diabetes (one point);     y stroke (doubled = two points); y vascular disease (one point); y age 65 to 74 (one point) and; y sex category ( female = one point).
This score varies from 1 to 9. A patient with CHA 2 DS 2 -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 CHA 2 DS 2 -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 CHA 2 DS 2 VASc 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][24][25] .

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 anticoagulantassociated 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 .

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 CHA 2 DS 2 -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 CHA 2 DS 2 -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.
Kuramatsu et al. performed a retrospective cohort study in Germany and included 1176 patients with anticoagulationrelated 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 .

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.

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 .

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 lowdose 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 CHA 2 DS 2 VASc.