Continuing Education Activity

Anticoagulation is a class of medications used in the management and prevention of stroke. This activity outlines the role, indications, action, and contraindications for the use of anticoagulation in acute ischemic stroke. This activity will highlight the mechanism of action, indications, contraindications, and role of the interprofessional team in managing patients with acute ischemic stroke.

Objectives:

• Identify the indications, and contraindication of anticoagulation in acute ischemic stroke.
• Describe the anatomy of acute ischemic stroke.
• Review appropriate evaluation of the potential complications and clinical significance of stroke anticoagulation.
• Summarize interprofessional team strategies for improving care coordination and communication to advance stroke anticoagulation and improve outcomes.

Introduction

Stroke is one of the leading causes of death and long-term disability worldwide.[1][2] As medical management advances, the incidence and mortality rate of stroke declines, with the majority of strokes presenting as ischemic strokes vs. hemorrhagic strokes. As such, the focus of this article will be on ischemic strokes.

Various etiologies lead to ischemic stroke, including both modifiable and non-modifiable risk factors. Non-modifiable risks include age, sex, and race/ethnicity.[3] Whereas, modifiable risk factors encompass: physical inactivity, waist-to-hip ratio, alcohol consumption, smoking, nutrition, hypertension, hyperlipidemia, diabetes mellitus, cardiac causes, such as atrial fibrillation (AF), and metabolic syndromes.[3][4][5] Moreover, short term triggers may also pose a risk for stroke, including acute infectious process, and stress, etc. Assessing a patient’s risk for stroke based on risk factors is an important component of primary care for strokes. There are several validated risk stratification calculators used to assist in identifying patients needing preventative therapies. For instance, a recognized, continuously updated tool to predict clinical stroke is the Framingham Stroke Risk Profile, which combines both modifiable and non-modifiable risks.[3][6] Ultimately, targeted interventions can decrease the burden of stroke.

Stroke rule out should be completed in patients presenting with altered consciousness or sudden, focal, or global neurological deficits. Time is of the essence in completing a thorough history and physical in patients presenting with stroke-like symptoms. Upon presentation, one of the most crucial steps is to identify the time of ischemic stroke symptoms onset, as that helps to determine eligibility for antithrombotic treatment or endovascular intervention. The goals of physical examination are to determine stroke location, distinguish stroke mimics, complete neurological deficit assessment, and identify comorbidities and conditions that can affect treatment. A clinician should complete a neurological assessment, and baseline function calculated via the National Institutes of Health Stroke Scale (NIHSS). The history and physical examination should be used to rule out other mimics of stroke, including hyperglycemia, hypoglycemia, seizures, syncope, migraines, or drug toxicity, etc. A focused history should identify ischemic stroke risk factors discussed earlier in this article and should also identify any recent trauma, coagulopathies, use of oral contraceptives, illicit drug use, such as cocaine, and migraines.

The following merit consideration when starting therapy: non-contrast brain CT or MRI, blood glucose, and oxygen saturation. In addition, all patients should also have baseline labs that include: complete blood count with platelet count, serum electrolytes/renal function, cardiac panel, activated partial thromboplastin time (APTT), prothrombin time/international normalized ratio (INR), and electrocardiogram (ECG); although it is desirable to know the results of the preceding labs, therapy should not be delayed while results are pending, the exception being if there is suspicion for thrombocytopenia or bleeding abnormalities, and use of heparin or warfarin or other anticoagulants. In patients with suspected stroke, an emergent non-contrast computed tomography (CT) is generally the first step in the diagnostic study to rule out any bleeding. The results of the CT will also help determine if the patient is a candidate for antithrombotic therapy. Magnetic resonance imaging (MRI) testing may also be used to identify intracerebral hemorrhaging and is more sensitive than CT for early detection of brain infarction. The essential lab before initiation of therapy is blood glucose, as hypoglycemia or hyperglycemia can mimic stroke.[7][8][9][10]

A vitals assessment with a focus on respiration, temperature, and blood pressure should also be obtained upon presentation. Elevation in blood pressure could be indicative of the body’s response to maintain brain perfusion to occluded section. Patients with hypoventilation can result in an increase in carbon dioxide partial pressure, which can further cause cerebral vasodilation and elevation in intracranial pressure (ICP), at which point there should be an assessment of the need for intubation. Finally, normothermia is important for the first few days post-acute stroke, as fever can worsen ischemia. [7], [10]

There are significant updates to literature that have come to surface for effective and appropriate management of patients with ischemic stroke. Also, the American Heart Association/American Stroke Association (AHA/ASA) has published guidelines, most recent being in 2018, outlining optimal treatment for the early management of patients with ischemic stroke. Ischemic stroke intervention includes the use of thrombolytic, anticoagulants, antiplatelet, statins, antihypertensive, and blood glucose management.[11] Previously, anticoagulation played a significant role in the acute treatment of ischemic stroke. Recent studies have helped refine their use and have restricted the start time of anticoagulation post-ischemic stroke to only certain patient populations. Anticoagulants now play a major role in primary and secondary prevention of ischemic strokes.

Anatomy and Physiology

Acute ischemic stroke (AIS) is the result of the sudden loss of cerebral blood flow. Usually, there is cerebral artery thrombotic or embolic occlusion that corresponds with a loss of neurologic function. In general, ischemia leads to hypoxia and a decrease in cellular adenosine triphosphate (ATP), which results in a lack of energy to maintain ionic concentration gradient across the cellular membrane. Inhibition of ion pump leads to cellular depolarization and influx of sodium and calcium ions, along with H2O into cells, leading to cytotoxic edema. The exact pathophysiology of ischemic stroke depends on the etiologic process. The differing etiologic subtypes that can lead to stroke include lacunar, cardioembolic, atherosclerotic, dissections, vasculitis, specific genetic disorders, idiopathic, etc.[12][13][14]

The histopathological consequences of ischemic stroke can lead to deficits in cognitive and motor function. Severe focal ischemia results in structural changes in both gray and white brain matter. Furthermore, changes develop in inflammatory, neuronal, vascular endothelial, and astrocytic cells. In white matter regions, axonal damage occurs with oligodendrocyte injury and subsequent demyelination. If the ischemic attack is less severe, there may be a selective neuronal injury to weak neuronal populations without damage to neighboring cells.[15][16][17][18][19] Understanding the histopathology associated with ischemic stroke serves to identify effective stroke prevention and treatment.

Indications

Restoring blood flow in a timely fashion is the most effective intervention to salvage ischemic brain tissue. The use of intravenous (IV) thrombolytic to restore blood flow using recombinant tissue-type plasminogen activator or rt-PA, also known as alteplase, is well established in the literature through major clinical trials and has remained unchanged in recent years. Patients treated with IV alteplase within 3 to 4.5-hours from stroke onset, generally see significant improvement. The decision to administer alteplase is based on certain inclusion and exclusion criteria. Trials have recommended the expansion of treatment with IV alteplase to patients with mild but disabling stroke.[20] Moreover, recent meta-analysis analyzed the efficacy and safety of tPA from 4.5 to 9-hours from time of stroke symptom onset or wake-up stroke with evidence of salvageable brain tissue, as evident on perfusion imaging. The analysis included three trials: EXTEND, ECASS4-EXTEND, and EPITHET and a total patient population of N=414. The authors concluded that the patients who received alteplase had favorable outcomes, achieving better functional outcomes in comparison to patients who received placebo (36% vs 29%; adjusted odds ratio [OR] 1·86, 95% CI 1·15-2·99, p=0·011). However, the rate of intracranial hemorrhage was higher in the alteplase group vs the placebo group (5% vs less than 1%; adjusted OR 9·7, 95% CI 1·23-76·55, p=0·031) but not significant enough to negate the overall benefit of thrombolysis.[21] It is important to note that the majority of patients included in the analysis had large-vessel occlusion and small ischemic core. Applying the results to current practice would be a risk vs benefits assessment and the use of tPA outside of the 3 to 4.5-hour window would be more beneficial in centers that do not have access to endovascular treatment.[11]

The current AHA/ASA 2018 guidelines provide a grade-A recommendation against the use of anticoagulation in AIS, regardless of the extent of stenosis.[11] The recommendation is based on meta-analyses that confirmed the lack of evidence supporting urgent anticoagulation. Of note, the meta-analyses did not include a randomized control trial that compared the efficacy of low molecular weight heparin (LMWH) vs aspirin in preventing early neurological deterioration and venous thromboembolism (VTE), and 6-months outcomes follow-up. The study included N=1368 patients and found statistically significant results in averting early neurologic deterioration (END) and VTE in patients receiving LMWH (3.95%, 1.46%, respectively) vs aspirin (11.82%, 4.23%) during the first 10 days of admission (P<0.001). However, there was a lack of significance in the 6-months modified Rankin Scale score, which is the most important outcome measure in stroke trials (LMWH, 64.2% vs aspirin, 62.5%; P=0.33). In terms of safety endpoints, the results were comparable. The authors concluded, that initiating LMWH within 48 hours of stroke until 10 days may reduce the risk of VTE and END, the benefit is greater in the elderly and in patients with basilar artery stenosis and posterior circulation. The AHA/ASA 2018 guidelines, however, still do not give a well-established recommendation for urgent anticoagulation in stroke patients with severe stenosis of an internal carotid artery.[11]

The guidelines also recommend further clinical trials and suggest a lack of well-established data for use of direct thrombin inhibitors and factor Xa inhibitors, including argatroban, dabigatran, etc., as monotherapy or adjunctive therapy to alteplase in AIS. [11] The studies demonstrating the safety and efficacy of using thrombin inhibitors or factor Xa inhibitors, have small populations, as such limiting applicability of the results. The safety and feasibility of dabigatran within 24 hours of minor strokes or transient ischemic attacks (TIA), defined as NIHSS score less than or equal to 3, was studied in N=53 patients. The study found that initiating dabigatran was feasible as no patients experienced symptomatic hemorrhagic stroke, however, a larger randomized controlled trial is needed to confirm safety.[22] Another study looked at the safety of direct thrombin inhibitor, argatroban, in conjunction with tPA. The open-label, pilot study, known as ARTSS-2 (Argatroban with Recombinant Tissue Plasminogen Activator for Acute Stroke), included N=90 patients and found that rates of intracerebral hemorrhage were comparable among control and study arm groups; however, a larger trial is needed to determine efficacy.[23] Additionally, a post hoc analysis from a multicenter prospective study, CROMIS-2 (Clinical Relevance of Microbleeds in Stroke-2), reviewed initiation of anticoagulation timing post-ischemic strokes and looked at 90-day clinical outcomes. The results included N=1355 patients and found that initiation of oral anticoagulation (OAC) early-on (0 to 4 days) vs later (greater than or equal to 5 days or never started) post-stroke associated with atrial fibrillation, had similar odds for the composite endpoint of ischemic stroke, intracerebral hemorrhage, and death at 90 days.[23] However, the data is still not sufficient to change practice as adequately powered controlled randomized trials are still needed.[11][24]

Furthermore, the use of prophylaxis anticoagulation, such as unfractionated heparin (UFH) or LMWH, in immobile patients with AIS is also controversial. Meta-analysis data suggests that prophylactic doses of anticoagulation did not have a significant effect on functional status nor mortality. Although there were statistically significant reductions in symptomatic pulmonary embolisms (OR, 0.69; 95% CI, 0.49–0.98) and deep vein thrombosis (DVTs) (OR, 0.21; 95% CI, 0.15–0.29), there was a significant increase in symptomatic intracranial (OR, 1.68; 95% CI, 1.11–2.55) and extracranial (OR, 1.65; 95% CI, 1.0–2.75) hemorrhage. There was a suggestion that if patients are at increased risk of VTE, it may be more beneficial to treat prophylactically, specifically with LMWH once daily vs. UFH. However, there has yet to be the identification of such subgroups.[25][26][27][28]

Although the use of anticoagulation is controversial in AIS, the use of oral anticoagulation (OAC) is currently strongly recommended as first-line therapy for the prevention of primary and secondary strokes in patients with atrial fibrillation. Patients with atrial fibrillation with moderate to high risk of thromboembolic events may benefit from long term anticoagulation. Most studies have shown that using direct thrombin and factor Xa inhibitors, such as apixaban and rivaroxaban, may have less risk of intracranial hemorrhage than patients on warfarin. The risk versus benefit for assessment of initiating anticoagulation for patients with atrial fibrillation can be calculated by using validated calculations, such as CHA2DS2-VASc for stroke risk, and HAS-BLED for bleeding risk. Although these tools do not have high predictive ability, they can still be used to help with establishing an individualized clinical plan considering risks versus benefits. The recommendation is to initiate OAC if the CHA2DS2-VASc stratification score is greater than or equal to 2.[29]

The appropriate time to initiate or reinitiate anticoagulation in a patient that received IV alteplase for AIS is individualized based on risk factors. The guidelines agree that this area remains controversial, and the risk of conversion to intracranial hemorrhage within 24-hours post tPA therapy remains unclear.[11] Some data suggest initiating OAC at 4 to 5 days status-post AIS or TIA in patients with no risk of hemorrhagic transformation and with mild-to-moderate stroke (NIHSS score 3 to 8).[29] A study conducted in South Korea, referenced in guidelines, did not find a significant increase in hemorrhagic risk with early introduction of anticoagulation therapy (less than 24 hours) in comparison with later administration (over 24 hours).[29][30]

Contraindications

The use of anticoagulation for the prevention of stroke is a risk-vs-benefit assessment. Patients initiated on anticoagulation should not be bridged with unfractionated heparin or LMWH, as there is an increased risk of hemorrhagic transformation and ischemic recurrence. Furthermore, patients with severe stroke (NIHSS score over 8), a longer delay in initiation of anticoagulation may be reasonable.[31]

Patients at increased risk of bleed, where risk is greater than benefit, should most likely avoid anticoagulation. There are unresolved questions, yet anticoagulation is unsuitable in patients who have severely impaired renal function, severely impaired liver function, severe, and symptomatic hemorrhagic transformation, such as parenchymal hematoma.[29]

Complications

The most obvious complication associated with ischemic stroke is conversion to hemorrhagic stroke, especially with the use of anticoagulation.

Clinical Significance

Anticoagulation decreases the risk of ischemic stroke or other embolic events by over two-thirds, regardless of baseline.[32] Clinical trials are ongoing assessing the safety and efficacy of anticoagulants in conjunction, or in lieu of tPA in AIS. As such, more data is needed prior to making a definitive recommendation. Anticoagulants, however, do play a major role in the prevention of primary and secondary stroke.

Enhancing Healthcare Team Outcomes

Managing AIS with an interprofessional healthcare team is essential to provide safe and optimal care to patients. These patients should have a careful ongoing clinical assessment, including frequent neurological examinations. The AHA/ASA 2018 guidelines recommend designating an acute stroke team consisting of physicians, nurses, laboratory/radiology personnel, and others such as a pharmacist. (Class I, Level B-non-randomized) The pharmacist will play a significant role in helping the clinicians select the appropriate agent, verifying dosing and the absence of drug interactions, and counseling patients about anticoagulation. They can also assist in developing proper pharmacotherapeutic regimens, monitoring medications, ordering appropriate labs, and dose adjustments, including thrombolytic, antiplatelets, and anticoagulants. Cardiovascular specialized nursing will administer these agents, and they should have open and active communication with both pharmacy staff as well as the clinicians/specialists managing the case. Finally, discussion with other healthcare providers, including neurology specialists, will optimize both acute and chronic management.[11] This interprofessional approach will maximize the therapeutic effects of anticoagulation therapy while minimizing the not insignificant potential risks, thereby optimizing patient care. [Level 5]

Nursing, Allied Health, and Interprofessional Team Interventions

Nurses play a role in educating patients and their family about stroke burden and secondary-prevention including lifestyle changes and medications. The nurses aid in early intervention emergency department triage including ensuring medical stability for airway, breathing, and circulation. Nurses are needed at the bedside while antithrombotic therapy is infusing for close monitoring of therapy. Furthermore, nurses can intervene in interrupting therapy should the patient develop signs/symptoms of bleeding or changes in mental status. Nurses can encourage and recommend treatment for blood pressure, fever, and blood glucose.

Nursing, Allied Health, and Interprofessional Team Monitoring

Protocols are available for the initiation of antithrombotic and anticoagulation. If antithrombotic therapy is initiated, nurses will monitor vitals at least every 15 minutes and provide neurological assessments hourly. Nurses may also play a role in short-term and long-term monitoring, especially in closely identifying signs/symptoms of bleeding. Nurses can also follow-up with patients post-hospital discharge. All patients should have baseline labs collected prior to the initiation of anticoagulation. For warfarin monitoring, baseline INR is measured, as well as liver function tests and renal function. For other OAC monitoring, baseline complete blood count, liver function tests, prothrombin time, aPTT, renal function is appropriate to measure and follow-up annually and when clinically indicated.