Antiplatelets for Recurrent Ischemic Stroke

(modified February 2024)

The chart below provides dosing, cost, and other information to help you choose among options for recurrent ischemic stroke. The information in the chart pertains to secondary stroke prevention in general and is not specific to patients who have a stroke while on aspirin. Below the chart, find tips and clinical pearls about antiplatelet regimens.

Drug

Dose

Comments

Cost/30 daysa

Preferred options1,3,10

Aspirin

LD: see comments

MD: usually 81 mg once daily (see comments)

Loading dose, usually 160 to 300 mg daily, should be started within 24 to 48 hours of an acute ischemic stroke.11

Maintenance dose:

  • Guidelines recommend 80 to 325 mg (Canada), 75 to 100 mg (ACCP), and 50 to 325 mg (AHA/ASA) once daily.1,3,10
  • Limited data for doses <75 mg.3
  • Bleeding complications increase at doses >100 mg daily.3

<$3

Clopidogrel (Plavix, generics)

LD: see comments

MD: 75 mg once daily1,10

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.23

Maintenance dosing efficacy similar to dipyridamole ER/aspirin (Aggrenox).6

May have lower GI bleed risk and stomach upset compared to aspirin.7

U.S.: <$10

Canada: <$10

SHORT-TERM aspirin plus clopidogrel, followed by EITHER aspirin or clopidogrel alone

LD: see comments

MD: Low-dose aspirin (usually
81 mg) plus clopidogrel 75 mg once daily usually for 21 days (see comments), then continue EITHER aspirin or clopidogrel.10,19,20

Loading dose:  of the three major RCTs, POINT used clopidogrel 600 mg x 1 with aspirin 162 mg x 5 days, CHANCE used clopidogrel 300 mg x 1 with aspirin
75 to 300 mg x 1, and INSPIRES used clopidogrel 300 mg x 1 with aspirin
100 to 300 mg x 1.2,8,22  Canadian guidelines recommend an aspirin LD of 160 to 300 mg.10

Start as soon as possible, ideally within 72 hours, or at least within seven days, of:1,2,8,10,18,22

  • High-risk TIA (e.g., ABCD2 scoreb ≥4).
  • Minor ischemic stroke (e.g., NIHSS scorec ≤3; INSPIRES used NIHSS scorec ≤5).

Prevents stroke within three months better than aspirin alone (NNT ~50) [Evidence level A-1].8,20  Significant impact on mortality or recurrent TIAs has not been shown.19,20,22

May cause more major bleeding (e.g., bleeding requiring or prolonging hospital stay, death due to bleeding) or moderate-to-severe GUSTO bleeding compared to aspirin alone (NNH ~ 200) [Evidence Level A-1].8,22,d  The risk of intracranial hemorrhage was increased (NNH ~ 333) in INSPIRES wherein the window for initiation was 72 hours.8

Generally, limit the combination of aspirin plus clopidogrel to not more than 21 days to maximize benefits and minimize risks.10,19,20 

  • Can consider using ten days instead of 21 days for patients at higher bleeding risk (e.g., taking an NSAID or anticoagulant).19,20
  • Can consider combination therapy for up to 90 days after stroke or TIA attributable to severe stenosis (70% to 99% ) of a major intracranial artery if bleeding risk is low (based on SAMMPRIS study).1,10

After 21 days of combination therapy, continue EITHER aspirin or clopidogrel as monotherapy (aspirin 81 mg/day generally preferred).8,19,20

Avoid combining aspirin and clopidogrel in patients who have a major stroke, due to increased risk for intracranial bleeding.19  Also, there are no safety data for short-term aspirin plus clopidogrel in patients who received alteplase.2,22

U.S.: <$10

Canada: ~$12

Dipyridamole ER/aspirin (Aggrenox, generic [U.S.])

LD: none1

MD: Dipyridamole ER 200 mg/aspirin 25 mg BID1

May prevent one more event (vascular death, stroke, MI, major bleed) for every 100 patients treated/year vs aspirin.4

Bleeding risk similar to aspirin.4

Twice-daily dosing. Expensive. One in four patients discontinue due to headache.4

Do not substitute immediate-release dipyridamole plus aspirin for the combo ER product; no proof it’s as effective.

U.S.: ~$90

Canada: ~$45

Non-preferred options1,3,10

SHORT-TERM aspirin plus ticagrelor (Brilinta)

LD: Aspirin: 300 to 325 mg; Ticagrelor: 180 mg

MD: Aspirin: 75 to 100 mg/day Ticagrelor: 90 mg BID for 30 days

Aspirin plus ticagrelor for 30 days prevents one stroke or death within 30 days compared to aspirin alone, NNT = 91 [Evidence Level A-1].17 However, there is no significant impact on mortality alone or disability scores.17 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 (NNH = 263) [Evidence Level A-1].17

  • Based on subgroup analysis of this study, ticagrelor could be added to aspirin for up to 30 days for patients with minor stroke or high-risk TIA with ≥30% stenosis of a major intracranial artery on the same side as the event.1,10
  • 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 scorec ≤5) or high-risk TIA (ABCD2 scoreb ≥4) [Evidence Level A-1].16

There are no safety data for short-term aspirin plus ticagrelor in patients who received alteplase.17

If using aspirin plus ticagrelor, don’t exceed 30 days and ideally start within 24 hours of:17

  • High-risk TIA (e.g., ABCD2 scoreb ≥6).
  • Minor ischemic stroke (e.g., NIHSS scorec ≤5).

May cause dyspnea.17

Twice-daily dosing. Expensive.

U.S.: ~$400

Canada: ~$100

Ticlopidine (U.S. only; generic only)

LD: none9

MD: 250 mg BID9

Rarely used due to side effects/availability of safer alternatives.3

“Black box” warning regarding life-threatening hematological reactions.9

At least as effective as aspirin.3

~$80

Cilostazol (U.S. only)

LD: none3

MD: 100 mg BID3

Better than no antiplatelet at all if patient cannot take aspirin or clopidogrel.3

~$20

Cilostazol plus aspirin or clopidogrel

LD: none

MD: cilostazol 100 mg BID added to aspirin or clopidogrel (see comments)1

Can consider adding cilostazol to aspirin or clopidogrel for patients with stroke or TIA due to 50% to 99% stenosis of a major intracranial artery.1

  • This recommendation is based on Level B-1 evidence in mostly Asian populations (TOSS-1, TOSS-2, CATHARSIS, CSPS).1

The role of cilostazol for secondary prevention after stroke due to small vessel disease needs more study.1

~$40
  1. Pricing based on wholesale acquisition cost (WAC). U.S. medication pricing by Elsevier, accessed December 2021.
  2. See https://www.mdcalc.com/abcd2-score-tia.
  3. See https://www.stroke.nih.gov/documents/NIH_Stroke_Scale_508C.pdf.
  4. NNH of 200 represents 90 days of aspirin plus clopidogrel. Risk may be lower with only ten to 21 days of dual-antiplatelet therapy.

Abbreviations: ACCP = American College of Chest Physicians; AHA = American Heart Association; ASA = American Stroke Association; BID = twice daily; ER = extended-release; GUSTO = Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; LD = loading dose; MD = maintenance dose; NIHSS = National Institutes of Health Stroke Scale; TIA = transient ischemic attack.

Tips and Clinical Pearls about Antiplatelet Regimens

  • About 5% of patients who have a minor ischemic stroke or transient ischemic attack will have another stroke within a year.21 The risk is especially high in the first week.10
  • The choice among aspirin, clopidogrel, or dipyridamole/aspirin should be individualized.10
  • Dual antiplatelet therapy can be considered for certain patients, but only short-term.1
  • If a patient has had a stroke or TIA despite aspirin therapy, switching to another antiplatelet agent can be considered.10
    • 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 [Evidence Level B-2].12 However, there is no proof that any agent is more effective than aspirin in these patients.1,10
    • There is no evidence that increasing the aspirin dose improves efficacy.1
  • For most patients who receive intravenous thrombolysis for stroke (e.g., alteplase), generally delay aspirin therapy for at least 24 hours, but consider comorbidities.11
  • Prasugrel (Effient) and vorapaxar (Zontivity [U.S.]) are contraindicated in patients with a history of stroke or TIA due to increased risk of intracranial bleeding.13-15
  • If a patient has a gastrointestinal (GI) bleed on aspirin, stop the aspirin, add a proton pump inhibitor (PPI), and restart aspirin within seven days, and ideally one to three days post-bleed.5
  • Do not use anticoagulants unless the patient has another indication for one (e.g., atrial fibrillation).10 
  • Address stroke risk factors and medication adherence.10

References

  1. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 guideline for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline from the American Heart Association/American Stroke Association. Stroke 2021;52:e364-467.
  2. 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;11-9.
  3. Lansberg MG, O’Donnell MJ, Khatri P, et al. 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 2012;141(2 Suppl):e601S-36S.
  4. The ESPRIT Study Group, Halkes PH, van Gijn J, et al. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006;367:1665-73. (Erratum in Lancet 2007;369:274).
  5. Laine L, Jensen DM. Management of patients with ulcer bleeding. Am J Gastroenterol 2012;107:345-60.
  6. Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008;359:1238-51.
  7. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996;348:1329-39.
  8. Gao Y, Chen W, Pan Y, et al. Dual Antiplatelet Treatment up to 72 Hours after Ischemic Stroke. N Engl J Med. 2023 Dec 28;389(26):2413-2424.
  9. Product information for ticlopidine. Teva Pharmaceuticals. Sellersville, PA 18960. February 2012.
  10. Gladstone DJ, Lindsay MP, Douketis J, et al. Canadian stroke best practice recommendations: secondary prevention of stroke update 2020. Can J Neurol Sci 2021 Jun 18: 1-69. doi: 10.1017/cjn.2021.127.
  11. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute 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 2019;50:e344-418.
  12. Lee M, Saver JL, Hong KS, et al. Antiplatelet regimen for patients with breakthrough strokes while on aspirin: a systematic review and meta-analysis. Stroke 2017;48:2610-3.
  13. Product information for Zontivity. Aralez Pharmaceuticals US. Parsippany, NJ 08540. November 2019.
  14. Product information for Effient. Eli Lilly and Company. Indianapolis, IN 46285. December 2020.
  15. Product monograph for JAMP-prasugrel. JAMP Pharma. Boucherville, QC J4B 5H3 July 2020.
  16. Johnston SC, Amarenco P, Albers GW, et al. Ticagrelor versus aspirin in acute stroke or transient ischemic attack. N Engl J Med 2016;375:35-43.
  17. Johnston SC, Amarenco P, Denison H, et al. Ticagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA. N Engl J Med 2020;383:207-17.
  18. Kim JT, Park MS, Choi KH, et al. Comparative effectiveness of aspirin and clopidogrel versus aspirin in acute minor stroke or transient ischemic attack. Stroke 2019;50:101-9.
  19. Prasad K, Siemieniuk R, Hao Q, et al. Dual antiplatelet therapy with aspirin and clopidogrel for acute high risk transient ischaemic attack and minor ischaemic stroke: a clinical practice guideline. BMJ 2018;363:k5130. (Erratum in BMJ 2019;364:I103).
  20. Hao Q, Tampi M, O’Donnell M, et al. Clopidogrel plus aspirin versus aspirin alone for acute minor ischaemic stroke or high risk transient ischaemic attack: systematic review and meta-analysis. BMJ 2018;363:k5108.
  21. Amarenco P, Lavallee PC, Labreuche J, et al. One-year risk of stroke after transient ischemic attack or minor stroke. N Engl J Med 2016;374:1533-42.
  22. Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med 2018;379:215-25.
  23. Jauch EC, Saver JL, Adams HP Jr, et al. 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 2013;44:870-947.

Cite this document as follows: Clinical Resource, Antiplatelets for Recurrent Ischemic Stroke. Pharmacist’s Letter/Prescriber’s Letter. January 2022. [380105]