Antiplatelets options for recurrent ischemic stroke

ANTIPLATELETS MEDICATIONS ㅡ The preferred options of antiplatelets for recurrent ischemic stroke are aspirin, clopidogrel (Plavix) or combination of aspirin and clopidogrel for short term then followed by EITHER aspirin or clopidogrel alone. Dipyridamole ER/aspirin (Aggrenox) can be used. Non-preferred options include aspirin plus ticagrelor (Brilique), Ticlopidine, Cilostazol alone or with clopidogrel.

ASPIRIN

Aspirin is the most common antiplatelet used for ischemic stroke. The loading dose of aspirin is usually 160 to 300 mg daily and should be started within 24 to 48 hours of an acute ischemic stroke. Maintenance dose is usually 81 mg once daily.

• Guidelines recommend 80 to 325 mg (Canada), 75 to 100 mg (American College of Chest Physicians - ACCP), and 50 to 325 mg (American Heart Association - AHA/American Stroke Association - ASA) once daily as maintenance dose for aspirin. Benefit is similar for doses from 50 to 1,500 mg daily. There are very limited data for doses < 75 mg. The bleeding complications increase at doses > 100 mg daily.

CLOPIDOGREL (PLAVIX)

There are very limited data with loading doses of clopidogrel after an acute ischemic stroke (mostly limited to minor strokes or high-risk TIAs). However, loading doses of 300 to 600 mg rapidly inhibit platelets compared to platelet inhibition taking about five days with daily doses of 75 mg. Maintenance dose is usually 75 mg once daily. Maintenance dosing efficacy of clopidogrel is similar to dipyridamole ER/aspirin (Aggrenox). Lower GI bleed risk and stomach upset compared to aspirin.

     SHORT-TERM aspirin plus clopidogrel, followed by EITHER aspirin or clopidogrel alone ― Maintenance dose: low-dose aspirin (usually 81 mg) plus clopidogrel 75 mg once daily for ten to 21 days, then continue EITHER aspirin or clopidogrel. Aspirin loading doses (e.g., 162 to 325 mg/day for one to five days) were not consistently used in studies and were more common in aspirin-naive patients. Clopidogrel loading doses, on day one, were not consistently used in studies, but ranged from 300 to 600 mg (300 mg was used more often than 600 mg).

     SHORT-TERM aspirin plus clopidogrel ideally start within 24 hours (limited data starting after 24 hours) of: (1) High-risk TIA (e.g., ABCD² score ≥ 4), (2) Minor ischemic stroke (e.g., NIHSS score ≤ 3), see  https://www.stroke.nih.gov/documents/NIH_Stroke_Scale_508C.pdf. There are no safety data for short-term aspirin plus clopidogrel in patients who received alteplase.

Limit the combination of aspirin plus clopidogrel to no more than 21 days to maximize benefits and minimize risks. Can consider using ten days instead of 21 days for patients at higher bleeding risk (e.g., taking an NSAID or anticoagulant). After 21 days of combination therapy, continue EITHER aspirin or clopidogrel as monotherapy (aspirin 81 mg/day generally preferred). The combination prevents one stroke in the next three months compared to aspirin alone. However, there is no significant impact on mortality or recurrent TIAs. The combination therapy may cause one episode of major bleeding (e.g., bleeding requiring or prolonging hospital stay, death due to bleeding) compared to aspirin alone. The risk of intracranial hemorrhage was not increased. Reserve long-term (> 21 days) aspirin plus clopidogrel therapy for patients with another indication (e.g., coronary stent). Avoid combining aspirin and clopidogrel in patients who have a major stroke, due to increased risk for intracranial bleeding.

DIPYRIDAMOLE ER/ASPIRIN (AGGRENOX)

May prevent one more event (vascular death, stroke, MI, major bleed) for every 100 patients treated/year vs aspirin. Bleeding risk from Aggrenox similar to aspirin. Maintenance dosing is Dipyridamole ER 200 mg/aspirin 25 mg twice daily. Aggrenox is expensive and one in four patients discontinue it due to headache. Do not substitute immediate-release dipyridamole plus aspirin for the combo ER product; no proof it’s as effective. 

NON-PREFERRED OPTIONS

SHORT-TERM aspirin plus ticagrelor ― Aspirin plus ticagrelor for 30 days prevents one stroke or death within 30 days compared to aspirin alone. However, there is no significant impact on mortality alone or disability scores. In addition, use for 30 days may cause one episode of severe bleeding (e.g., fatal bleeding, intracranial hemorrhage [most common], or other bleeding that caused hemodynamic compromise requiring intervention) compared to aspirin alone.

     Note that ticagrelor ALONE (180 mg LD, followed by MD of 90 mg BID) for 90 days is NOT superior to aspirin (300 mg LD, followed by 100 mg daily) in preventing the combined endpoint of stroke, myocardial infarction (MI), or death within 90 days in minor stroke (NIHSS score ≤ 5) or high-risk TIA (ABCD² score ≥ 4). There are no safety data for short-term aspirin plus ticagrelor in patients who received alteplase. If using aspirin plus ticagrelor, don’t exceed 30 days and ideally start within 24 hours of: (1) High-risk TIA (e.g., ABCD² score ≥ 6), (2) Minor ischemic stroke (e.g., NIHSS score ≤ 5). Disadvantages; may cause dyspnea, twice-daily dosing and expensive.

Ticlopidine ― there is NO loading dose, the maintenance dose is 250 mg BID. Rarely used due to side effects/availability of safer alternatives. Black box warning regarding life threatening hematological reactions. Ticlopidine is at least as effective as aspirin.

Cilostazol (Pletal) ― there is NO loading dose, the maintenance dose is 100 mg BID. Better than no antiplatelet at all if patient cannot take aspirin or clopidogrel. FDA-approved Pletal for intermittent claudication. 

     Cilostazol plus aspirin or clopidogrel: preliminary open-label data (conducted only in Japan) indicate cilostazol plus either aspirin or clopidogrel may reduce the risk of recurrent stroke compared to either aspirin (81 to 100 mg) or clopidogrel (50 to 75 mg) alone, without increasing bleeding risk. More robust studies are needed to confirm these results.

PRACTICAL NOTES

TIPS AND CLINICAL PEARLS ABOUT ANTIPLATELETS REGIMENS

• Individualize regimens based on cost, patient risk factors, tolerability, and efficacy.
• About 5% of patients who have a minor ischemic stroke or transient ischemic attack will have another stroke within a year.
• The risk of a stroke can be more than 30% within a week after a TIA.
• If a patient has had a stroke or TIA despite aspirin therapy, switching to another antiplatelet agent can be considered.
• The risk of a recurrent stroke may be lower if these patients are switched to a different long-term antiplatelet, especially in the first few days after a stroke or TIA. However, there is no proof that any agent is more effective than aspirin in these patients.
• There is no evidence that increasing the aspirin dose improves efficacy.
• For most patients who receive intravenous thrombolysis for stroke (e.g., alteplase), generally delay aspirin therapy for at least 24 hours, but consider comorbidities.
• Prasugrel and vorapaxar are contraindicated in patients with a history of stroke or TIA due to increased risk of intracranial bleeding.
• If a patient has a gastrointestinal (GI) bleed on aspirin, stop the aspirin, add a proton pump inhibitor (PPI), and restart aspirin within 7 days, and ideally one to 3 days post-bleed.
• Do not use anticoagulants unless the patient has another indication for one (e.g., atrial fibrillation).
• Address stroke risk factors and medication adherence.

REFERENCES

• Kernan, W.N., Ovbiagele, B., and American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease (2014). Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke, [online] 45(7), pp.2160–236. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24788967

  Lansberg, M.G., and others (2012). Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, [online] 141(2 Suppl), pp.e601S–e636S. Available at: https://pubmed.ncbi.nlm.nih.gov/22315273
  

  Wang, Y., Wang, Y., Zhao, and others (2013). Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack. New England Journal of Medicine, 369(1), pp.11–19. Available at: https://www.nejm.org/doi/full/10.1056/nejmoa1215340

  Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. (2006). The Lancet, 367(9523), pp.1665–1673. Available at: https://pubmed.ncbi.nlm.nih.gov/16714187

  Diener, H.-C., Bogousslavsky, J., Brass, L.M., Cimminiello, C., Csiba, L., Kaste, M., Leys, D., Matias-Guiu, J. and Rupprecht, H.-J. (2004). 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. The Lancet, 364(9431), pp.331–337. Available at: https://pubmed.ncbi.nlm.nih.gov/15276392

  Powers, W.J., Rabinstein, and others (2019). Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke, 50(12). Available at: https://pubmed.ncbi.nlm.nih.gov/31662037

  American Heart Association. Cilostazol-combo antiplatelet therapy reduced risk for recurrent stroke. [online] Available at: https://newsroom.heart.org/news/cilostazol-combo-antiplatelet-therapy-reduced-risk-for-recurrent-stroke?preview=c1b1

  Clinicaltrials.gov. Cilostazol Stroke Prevention Study for Antiplatelet Combination - Full Text View - ClinicalTrials.gov. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT01995370