Management of Acute Ischemic Stroke: a Review of Pertinent Guideline Updates

US Pharm. 2019;44(2):HS-2-HS-5.

ABSTRACT: In January 2018 the American Heart Association/American Stroke Association published a guideline outlining evidenced-based literature updates and optimal treatment for early management of patients with acute ischemic stroke (AIS). Among the recommendations, the guidelines expand and clarify thrombolytic treatment with IV alteplase and discuss timing of administration. Aspirin is reaffirmed as the drug of choice for antiplatelet treatment of AIS, and recommendations regarding dual antiplatelet therapy for secondary prophylaxis are updated. The new guidelines continue to reference no benefit in using anticoagulation for the treatment of AIS. Statin use, blood pressure, and blood glucose are discussed. Screening for depression in AIS patients is newly recommended.

There have been significant evidence-based literature updates regarding the management of acute ischemic stroke (AIS) in adult patients since the publication of the 2013 American Heart Association/American Stroke Association (AHA/ASA) guidelines.¹ In January 2018 the AHA/ASA published a guideline outlining these changes and optimal treatment for early management of patients with ischemic stroke.² This article reviews updates to thrombolytic, antiplatelet, and anticoagulation therapies, statin use, blood pressure and blood glucose targets, and a new recommendation for depression screening.

Thrombolytic Therapy

Recommendations regarding thrombolytic therapy with IV alteplase have largely remained unchanged in recent years.³ Recommendations based on three randomized, controlled trials have expanded treatment with IV alteplase to otherwise eligible patients with “mild but disabling stroke.” This was defined using the National Institutes of Health Stroke Scale, and most patients in these trials had a score between 0 and 5. Furthermore, guideline recommendations now state that it is at the discretion of the physician to use IV alteplase regardless of stroke score if the clinical benefit is believed to be higher than the risk.^4-6

The new guidelines have also clarified that IV alteplase should not be administered to patients who have received treatment doses of low-molecular-weight heparin products within the previous 24 hours, whereas it has been previously implied that both prophylactic and treatment doses were contraindicated.⁷ The new guidelines specify that IV alteplase should be administered to patients receiving antiplatelet monotherapy and dual antiplatelet therapy (DAPT), although administration with DAPT has a lower quality of evidence. The guidelines explain that mechanical thrombectomy should not be delayed in order to assess a patient’s response to IV alteplase.²

There is significant expansion in the guidelines in highlighting the importance of establishing quality, time-effective hospital policies and procedures in stroke management. These recommendations emphasize the importance of allowing brain-imaging studies to be conducted promptly (within 20 minutes of arrival in the emergency department) and prompt administration of IV alteplase, if indicated (newly recommended metric of door-to-needle time of 60 minutes in 50% of stroke patients).² While the guidelines do not call upon pharmacists explicitly to aid in achieving these, they do suggest creating a “multidisciplinary quality improvement committee” to assess quality assurance measurements and metrics.² Some institutions have taken this a step further and proven that when made part of the interdisciplinary team, pharmacists were able to decrease door-to-needle time by 23.5 minutes.⁸

Antiplatelet Therapy

Aspirin continues to be the drug of choice for the antiplatelet treatment of AIS, with administration required within 24 to 48 hours after onset of stroke symptoms. However, the guidelines emphasize that aspirin alone is not a substitute for mechanical thrombectomy or IV alteplase if indicated. If IV alteplase is given, however, aspirin may be withheld for 24 hours after IV alteplase administration unless the patient has a compelling condition in which withholding aspirin would cause greater harm than benefit. Guidelines state that in patients with a contraindication to aspirin, an alternate agent may be considered, provided that glycoprotein IIb/IIIa-receptor antagonists are not used.² Compared with other antiplatelet agents, glycoprotein IIb/IIIa-receptor antagonists have been associated with a higher risk of intracranial hemorrhage without improvement in clinical outcomes of death and poststroke disability.⁹

The guidelines state that there is not enough clinical data to provide a well-balanced recommendation regarding patients who have a subsequent (noncardioembolic) AIS while already on aspirin therapy. It is not well established whether this type of patient will receive any additional benefit in stroke prevention with increasing doses of aspirin upon a subsequent AIS, but he or she certainly will have a higher risk of bleeding. The guidelines also do not provide any recommendation on the appropriateness of switching to an alternative antiplatelet agent after experiencing an AIS while on aspirin therapy. However, it is stated clearly that these patients will not receive any benefit in switching from aspirin to warfarin for secondary stroke prevention.²

Aspirin has also continued to be the guideline-recommended, first-line antiplatelet option for the secondary prophylaxis of AIS.² Perhaps the most controversial updates in the guidelines are the recommendations regarding DAPT for secondary prophylaxis of AIS. Historically, trials such as CHARISMA, MATCH, and SPS3 all suggested that DAPT increased bleeding risk without reducing the risk of stroke.^10-12 However, the CHANCE trial, which included 5,170 Chinese patients with minor AIS (NIHSS score 3), found a reduction in 90-day stroke incidence with DAPT for 21 days followed by aspirin monotherapy compared with aspirin monotherapy for the entire treatment course.¹³ The guidelines now permit considering (with a low quality of evidence) treatment for 21 days with DAPT followed by antiplatelet monotherapy for up to 90 days poststroke in patients classified with a minor stroke.² However, the POINT trial (recently published and therefore not yet included in these guidelines) which included 4,881 patients from multiple countries with minor AIS or high-risk transient ischemic attack, failed to find reduction in a composite outcome of ischemic stroke, myocardial infarction, or death from ischemic/vascular causes in the DAPT arm compared with the aspirin monotherapy arm. In fact, this trial was stopped early due to more major bleeding in the DAPT arm.¹⁴ Ongoing clinical trials will be forthcoming and may shed more light on recommendations regarding the appropriateness of DAPT for secondary prophylaxis.

Anticoagulation

The new guidelines still find no benefit in using anticoagulation for the treatment of AIS, regardless of the extent of stenosis or the duration of anticoagulant therapy. There is limited observational evidence on the usefulness of direct thrombin inhibitors and factor Xa inhibitors in the treatment of AIS. The guidelines highlight the need for further clinical trials, which are ongoing.²

Deep vein thrombosis prophylaxis in immobile AIS patients also remains controversial, with the guidelines noting no benefit with subcutaneous heparin or low-molecular-weight heparin, but rather recommending continued treatment with aspirin as well as intermittent pneumatic compression stockings.¹⁵

The proper time to resume a patient’s therapeutic anticoagulant therapy following IV alteplase administration is currently an area of controversy in clinical practice, and the guidelines agree that the risk of conversion to intracranial hemorrhage upon resuming antithrombotic therapy up to 24 hours after IV alteplase remains uncertain.² The guidelines reference one study conducted in South Korea that did not find a difference in risk of hemorrhage with early initiation (<24 hours) of anticoagulant therapy compared with later initiation of anticoagulant therapy (>24 hours).¹⁶ Guidelines suggest individualizing this decision for each patient, especially for those with a compelling indication for anticoagulation therapy in which withholding treatment would cause substantial risk to the patient.²

Statins

Recommendations regarding statin therapy in AIS patients have largely remained unchanged since the prior published guidelines. The updated guidelines still recommend treatment with a high-intensity statin in men and women aged 75 years or younger. The guidelines recommend against routine measurement of blood cholesterol levels in patients not previously taking a statin; however, measurement might be helpful in patients already taking optimized statin therapy to aid in further preventing a subsequent AIS. The only update to the guidelines with regard to statin therapy is that the authors believe initiating a statin while the patient is hospitalized is appropriate.²

Blood Pressure

Blood pressure is elevated in over 75% of acute stroke patients and is associated with poor outcomes.¹⁷ Hypertension is the single most modifiable risk factor for stroke prevention.¹⁸ Management of hypertension is the most common and impactful way to limit the reccurrence of stroke.¹⁹ While evidence continues to increase our understanding of the role of blood pressure management in AIS, how to best modify the blood pressure in a patient experiencing an AIS continues to be debated.

Patients experiencing AIS who are hypertensive but otherwise candidates for IV alteplase do have a specific target blood pressure to limit the risk of hemorrhage in elevated and variable blood pressure. The goal is less than 185 mm Hg systolic blood pressure (SBP) and less than 110 mm Hg diastolic blood pressure before the initiation of IV fibrinolytic therapy.² This is not a new recommendation; however, it is a clarification from the previous guideline recommendations.¹ This goal aims to decrease the risk of hemorrhage when using IV alteplase in patients with elevated or variable blood pressures.²

Not withholding an antihypertensive medication in patients with comorbidities that warrant such therapy after initial presentation is currently recommended. These blood pressure goals should be individualized; however, a decrease in SBP of approximately 15% within the first 24 hours is generally accepted. In patients with extreme hypertension (220/120 mm Hg) or those not receiving an IV fibrinolytic, a 15% decrease in SBP after initial AIS treatment may be reasonable. This allows for some blood-pressure lowering, but not enough to worsen cerebral ischemia; this is termed permissive hypertension. It is also recommended to initiate antihypertensive therapy in patients with elevated blood pressure (>140/90 mm Hg) who are neurologically stable.²

Patients with AIS are often hypertensive upon admission with decreasing blood pressures throughout the natural disease progression. However, patients may present with hypotension, and this is associated with poor outcomes as well.²⁰ There is little guidance on specific goals to manage hypotension in AIS patients. The most recent guidelines do not suggest an exact blood pressure goal but rather a broad goal of maintaining perfusion to promote vital organ function.² 

Blood Glucose

Similar to blood pressure, when it comes to blood glucose, a U-shaped curve can be observed indicating negative clinical outcomes associated with both hypoglycemia and hyperglycemia.²¹ Hyperglycemia frequently presents concomitantly with AIS and is associated with increased healthcare expenditures, worsening morbidity and mortality, and a negative effect on brain recovery.²² Normoglycemia is preferred, and the goal blood glucose level for an AIS patient is between 140 and 180 mg/dL. Blood glucose levels less than 60 mg/dL should be avoided and immediately treated to prevent hypoglycemia.²

Pharmacist’s Role

Every 4 minutes in the United States, someone dies of a stroke; 87% of these strokes are ischemic in nature.²³ Therefore, keeping abreast of current management guidelines for patients with AIS is paramount for pharmacists to provide optimal care to this growing patient population. Pharmacists can provide a unique perspective and role to the multidisciplinary team in caring for these patients by focusing on proper pharmacotherapeutic regimens.

REFERENCES

1. Jauch EC, Saver JL, Adams HP, et al. Guidelines for the early management of patients with acute ischemic stroke. Stroke. 2013;44:870-894.
2. Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2018;49:e46-e99.
3. Nguyen VHV, Wong BM, Shen DD, et al. Early management of acute ischemic stroke: focus on IV tPA and timely reperfusion. US Pharm. 2016;41(1):HS-9-HS-12.
4. Bluhmki E, Chamorro A, Dávalos A, et al. Stroke treatment with alteplase given 3.0-4.5 h after onset of acute ischaemic stroke (ECASS III): additional outcomes and subgroup analysis of a randomised controlled trial. Lancet Neurol. 2009;8:1095-1102.
5. Ahmed N, Wahlgren N, Grond M, et al. Implementation and outcome of thrombolysis with alteplase 3-4.5 h after an acute stroke: an updated analysis from SITS-ISTR. Lancet Neurol. 2010;9:866-874.
6. Romano JG, Smith EE, Liang L, et al. Outcomes in mild acute ischemic stroke treated with intravenous thrombolysis: a retrospective analysis of the Get With the Guidelines-Stroke registry. JAMA Neurol. 2015;72:423-431.
7. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scientific rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2016;47:581-641.
8. Rech MA, Bennett S, Donahey E. Pharmacist participation in acute ischemic stroke decreases door-to-needle time to recombinant tissue plasminogen activator. Ann Pharmacother. 2017;51(12):1084-1089.
9. Ciccone A, Motto C, Abraha I, et al. Glycoprotein IIb-IIIa inhibitors for acute ischaemic stroke. Cochrane Database Syst Rev. 2014:CD005208.
10. Bhatt DL, Fox KAA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354:1706-1717.
11. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364(9431):331-337.
12. SPS3 Investigators. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012;367:817-825.
13. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369:11-19.
14. Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med. 2018;379:215-225.
15. Dennis M, Sandercock P, Reid J, et al. CLOTS (Clots in Legs Or sTockings after Stroke) Trials Collaboration. Effectiveness of intermittent pneumatic compression in reduction of risk of deep vein thrombosis in patients who have had a stroke (CLOTS 3): a multicentre randomised controlled trial. Lancet. 2013;382:516-524.
16. Jeong HG, Kim BJ, Yang MH, et al. Stroke outcomes with use of antithrombotics within 24 hours after recanalization treatment. Neurology. 2016;87:996-1002.
17. Appleton JP, Sprigg N, Bath PM. Blood pressure management in acute stroke. Stroke Vasc Neurol. 2016;2:72-82.
18. MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease. Part 1, Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335:765-774.
19. Arima H, Chalmers J, Woodward M, et al. Lower target blood pressures are safe and effective for the prevention of recurrent stroke: the PROGRESS trial. J Hypertens. 2006;24(6):1201-1208.
20. McManus M, Liebeskind DS. Blood pressure in acute ischemic stroke. J Clin Neurol. 2016;2:137-146.
21. Willams LS, Rotich J, Qi N, et al. Effects of admission hyperglycemia on mortality and costs in acute ischemic stroke. Neurology. 2002;59:67-71.
22. Baker L, Juneja R, Bruno A. Management of hyperglycemia in acute ischemic stroke. Curr Treat Options Neurol. 2011;13:616-628.
23. Benjamin EJ, Blaha MJ, Chiuve SE, et al. Heart disease and stroke statistics—2017 update: a report from the American Heart Association. Circulation. 2017;135:e229-e445.
24. Chollet F, Tardy J, Albucher JF, et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomized placebo-controlled trial. Lancet Neurol. 2011;10:123-130.
25. Meader N, Moe-Byrne T, Llewellyn A, et al. Screening for poststroke major depression: a meta-analysis of diagnostic validity studies. J Neurol Neurosurg Psychiatry. 2014;85:198-206.

 To comment on this article contact rdavidson@uspharmacist.com.