The American Heart Association (AHA) in 2018 issued new recommendations for the use of aspirin and clopidogrel (dual antiplatelet therapy) for acute minor ischemic stroke that began in the first 24 hours after the event up to 21 days and continued with clopidogrel only until the 90th day. This therapy can help avoid the incidence of ischemic stroke within 90 days after the first incident.

Risk and Benefit of Aspirin and Clopidogrel in Minor Ischemic Stroke Treatment
Source picture: https://twitter.com/nejm/status/1020405593302093824

Aspirin and clopidogrel are antiplatelet drugs. Aspirin has an antithrombotic effect through its mechanism of PGH-synthase / COX inhibition by irreversibly making acetylation in specific serine groups (serine present in COX-1 and COX-2). It will reduce the production of prostaglandins and TXA2 (thromboxane A2), which can reduce platelet aggregation. The active metabolite of clopidogrel binds irreversibly to the P2Y12 receptor on platelets, thereby decreasing platelet function, and is called a platelet inhibitor.

The latest recommendations from the AHA for the use of aspirin and clopidogrel are aimed at minor ischemic strokes and also high-risk TIA (transient-ischemic stroke). The definition of Minor ischemic strokes is a stroke with an NIHSS (National Institute of health stroke score) ≤3, and high-risk TIAs are described as ABCD2 scores ≥ 4. The NIHSS assesses the severity of strokes from various aspects, namely: awareness, eyeball movement, vision, paralysis, high risk. Motoric strength, ataxia, sensory, the presence or absence of aphasia, dysarthria, and inattentive. The ABCD2 score for TIA is assessed by age, blood pressure, clinical features, duration, and diabetes mellitus.

Recurrent stroke after Minor Ischemic Stroke or TIA

Cardiovascular events (deaths from cardiovascular causes, nonfatal strokes, acute coronary syndromes) in studies involving more than 3000 patients with TIA or minor strokes in 5 years are 12.9%, and half of these occur in the second to fifth years. There were 341 fatal and nonfatal stroke events from 3847 patients (8.9%).

The risk of recurrent stroke increases with time after the occurrence of TIA or minor ischemic stroke. The risk of recurrent stroke after TIA at the end of the first month is 11.5%, and the third month is 17.3%, whereas minor ischemic stroke is 15% and 18.5%.


Benefits of the combination of aspirin and clopidogrel

Aspirin antiplatelet has been found in several studies to reduce recurrent stroke risk by up to 20%. In the 2013 Clopidogrel in High-Risk Patients with Acute Non-enabling Cerebrovascular Events (CHANCE) by Wang et al., The incidence of stroke decreased by 32% in groups given a combination of aspirin and clopidogrel compared to aspirin alone for minor or ischemic stroke events. TIA. This finding is in line with a 2018 study by Johnston et al., Which found that a combination of aspirin and clopidogrel can reduce the recurrence rate of ischemic events (ischemic stroke, myocardial infarction, or death due to ischemic events) by up to 25%.

In 2018, A study by Johnston et al. found that a combination of aspirin and clopidogrel increased the risk of bleeding compared to aspirin alone. Within 90 days, out of 1000 patients given a combination of aspirin and clopidogrel, they were able to avoid approximately 15 ischemic events but caused five major bleeding events.

Major bleeding events are defined as symptomatic intracranial hemorrhage, intraocular hemorrhage that causes visual impairment, conditions that cause transfusion of more than two units of PRC / packed red cells, and the need for treatment prolongation of hospital stay or death due to bleeding). This finding was different from the previous study by Wang et al. (2013); that was no significant difference in the incidence of bleeding between the aspirin group and the aspirin-clopidogrel combination group.


The Risk of the aspirin and clopidogrel combination 

In the literature study and meta-analysis comparing the combination of clopidogrel and aspirin, there was a significant increase in the risk of bleeding compared to aspirin alone or clopidogrel alone. The increased risk is all bleeding, especially the gastrointestinal tract. The use of aspirin alone increases bleeding risk, especially in the gastrointestinal tract, compared to placebo. At this increased risk, there is no fatal bleeding, such as intracranial hemorrhage or noncardiovascular death. However, the risk of this bleeding must still be considered in consideration of the benefits and risks.

Both of these studies used different doses and administration of clopidogrel and aspirin. Johnston, et al. (2018) used clopidogrel loading dose 600 mg the first day, followed by 75 mg per day until the 90th day and aspirin doses in the range of 50 - 325 mg. Wang, et al. (2013) used a 300 mg loading dose of clopidogrel followed by 75 mg per day until the 90th day and a loading dose of aspirin 75 - 300 mg the first day, followed by 75 mg day only until the 21st day.

Advanced Study
Advanced Studies are needed to determine the effectiveness of a combination of aspirin and clopidogrel, especially dosage, to reduce the risk of recurrent stroke events and also its side effects on bleeding events. The dosage used should be tailored to the patient's ethnicity, one of which is because clopidogrel metabolism is influenced by genetic differences between ethnic Caucasians, Hispanics, and Asians.



Conclusions and Clinical Implications
The combination of dual antiplatelet, i.e., aspirin and clopidogrel in the event of a minor ischemic stroke (NIHSS score ≤ 3) and high-risk TIA (ABCD score ≥ 4) is recommended by the American Heart Association to be given within the first 24 hours from the event until the 21st day and continued with clopidogrel alone until the 90th day was found to provide benefits for the prevention of recurrent strokes. Doses that have been found clinically advantageous and used in studies with the ethnic majority in Asia are loading a dose of clopidogrel 300 mg followed by 75 mg per day for 90 days and a loading dose of aspirin 75 - 300 mg followed by 75 mg per day for 21 days.

One of the side effects that need attention is the onset of bleeding. There were no significant side effects of bleeding on using the aspirin and clopidogrel combination in several studies. Aspirin itself was found to increase bleeding risk, especially the digestive tract, compared to placebo. Thus, considering risk and benefit, screening for risk factors for bleeding, and education regarding signs and symptoms of bleeding must be done before implementing a dual antiplatelet protocol for minor ischemic stroke and high-risk TIA.


References
1. 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; DOI: 10.1161/STR.0000000000000158
2. Amarenco P, Lavallee PC, Tavares LM, et al. Five-year risk of stroke after TIA or minor ischemic stroke. N Engl J Med, 2018; DOI: 10.1056/NEJMoa1802712
3. Awtry EH, Loscalzo J. Aspirin. Circulation, 2000;101:1206-1218
4. Chong K. Clopidogrel dosing and CYP2C19. Updated: Oct 2015. Available from: https://emedicine.medscape.com/article/1733280-overview
5. Coull AJ, Lovett JK, Rothwell PM. A population-based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and services organization. BMJ, 2004;328(7435):326
6. Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. New England J Med, 2018; DOI: 10.1056/NEJMoa1800410
7. McQuaid KR, Laine L. Systemic review and meta-analysis of low-dose aspirin and clopidogrel's adverse-events in randomized controlled trials. The Am J of Med, 2006;119:624-638
NIH Stroke Scale. Updated: 2003. Available from: https://stroke.nih.gov/documents/NIH_Stroke_Scale.pdf
8. Wallentin L. P2Y12 inhibitors: differences in properties and mechanisms of action and potential clinical use consequences. Eur H J, 2009;30(16):1964-1977
9. 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