US Pharm. 2020;45(1):HS8-HS-12.
ABSTRACT: Antiplatelet therapy has been shown to reduce the risk of recurrent stroke in patients who have already experienced a noncardioembolic ischemic stroke or transient ischemic attack. The American Heart Association/American Stroke Association and the American College of Chest Physicians have published guidelines that provide recommendations on antiplatelet therapy for secondary prevention of ischemic stroke. Aspirin, clopidogrel, and aspirin/extended-release dipyridamole are the most commonly used agents. Although single antiplatelet therapy is the standard for stroke prevention, some data suggest that short courses of dual antiplatelet therapy in selected patients may provide additional protection against recurrent stroke.
Stroke is a leading cause of death and disability.1 Each year, more than 795,000 people in the United States experience a stroke, 87% of which are ischemic.1 Antiplatelet therapy reduces the risk of recurrent ischemic stroke, particularly those that are of noncardioembolic origin, and is the treatment of choice.2 Guidelines for secondary prevention of ischemic stroke recommend a variety of antiplatelet medications. Aspirin, clopidogrel, and aspirin/extended-release dipyridamole (ER-DP) are the most commonly used agents. Antiplatelets are preferred over anticoagulants for this indication because of their association with lower rates of intracranial hemorrhage and slightly lower overall mortality rates.2-5 Single antiplatelet therapy is generally preferred over dual antiplatelet therapy (DAPT) because DAPT results in increased bleeding, which outweighs any benefit.6,7 However, evidence exists that a short course of DAPT immediately following a minor ischemic stroke or high-risk transient ischemic attack (TIA) can provide benefit that outweighs risk in patients with acute minor ischemic stroke or high-risk TIA.8 This article will briefly review the guidelines and antiplatelet medications related to reducing the risk of noncardioembolic ischemic stroke.
The 2019 American Heart Association/American Stroke Association (AHA/ASA) guidelines, which focus on early management of ischemic stroke, strongly recommend the administration of aspirin within 24 to 48 hours of acute ischemic stroke (AIS).9 Cited trials investigated doses of 160 mg to 300 mg. If oral administration is not possible, rectal or nasogastric administration is appropriate. Aspirin is not advised as a substitute for thrombolytics or mechanical thrombectomy in patients who are eligible for these therapies. For patients with minor stroke or high-risk TIA, the guidelines also strongly recommend the use of 21 days of DAPT with aspirin and clopidogrel started within 24 hours of presentation. Ticagrelor showed no additional benefit and is not preferred over aspirin for acute treatment of stroke, although it may be a reasonable alternative in patients who are unable to use aspirin.9
The 2014 AHA/ASA guidelines for prevention of recurrent stroke provide comprehensive recommendations for reducing the risk of recurrent stroke that are beyond the scope of this article.4 Regarding antiplatelet therapy, the guidelines recommend the use of aspirin 50 mg to 325 mg daily (class I recommendation), aspirin/ER-DP 25 mg/200 mg twice daily (class I), or clopidogrel 75 mg daily (class IIb). The combination of clopidogrel and aspirin may be considered for 21 days in patients with minor ischemic stroke or TIA (class IIb).4
The 2012 American College of Chest Physicians guidelines for antithrombotic therapy for ischemic stroke advise long-term antiplatelet therapy in patients who have had a noncardioembolic stroke.5 Specific agents recommended include clopidogrel 75 mg daily, aspirin/ER-DP 25 mg/200 mg twice daily, aspirin 75 mg to 100 mg daily, and cilostazol 100 mg twice daily. These agents are recommended over no antiplatelet therapy, oral anticoagulants, or the combination of clopidogrel and aspirin. Additionally, clopidogrel and aspirin/ER-DP are recommended over aspirin or cilostazol.5
Aspirin: This nonsteroidal anti-inflammatory drug exerts its effect through inhibition of cyclooxygenase (COX)-1 and COX-2.10 At the lower doses used in stroke or TIA, typically 325 mg or less daily, aspirin demonstrates primarily antithrombotic effects.11 Higher doses, particularly total daily doses greater than 1,000 mg, exhibit strong anti-inflammatory effects.11 Aspirin also increases the risk of bleeding events, including hemorrhagic stroke and gastrointestinal (GI) bleeding, in a dose-dependent fashion.10 Previous guidelines recommended dosages of 325 mg daily; however, recent clinical trials have led to a dosing range of 75 mg to 300 mg for monotherapy.12
Aspirin therapy in AIS or TIA has been the subject of many large clinical trials and meta-analyses. In the International Stroke Trial (IST), 19,435 patients with AIS presenting within 48 hours of symptom onset were randomized to aspirin 300 mg daily versus no aspirin.13 For every 1,000 patients receiving aspirin, 11 fewer deaths had occurred by 6 months.13 In the Chinese Acute Stroke Trial (CAST), which randomized 21,106 patients with AIS to aspirin 160 mg daily versus placebo, 6.8 fewer deaths or nonfatal strokes were reported for every 1,000 patients treated at 4 weeks.14 In 2002, the Antithrombotic Trialists’ Collaboration (ATC) meta-analysis found a 22% reduction of risk of secondary stroke, myocardial infarction (MI), or vascular death in patients with prior cerebrovascular disease.12 A 2009 ATC meta-analysis of 16 placebo-controlled trials revealed a 19% reduction in serious vascular events and a 22% reduction in ischemic stroke risk.15
Clopidogrel: This agent, a P2Y12 inhibitor, is FDA approved for reducing cardiovascular events in patients with recent acute coronary syndrome (ACS), MI, or stroke.16 Approval of clopidogrel was based on results of the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial, which compared outcomes between patients with atherosclerotic vascular disease on aspirin or clopidogrel.17 The composite primary outcome—reduction in risk of ischemic stroke, MI, or vascular death—was statistically significantly lower with clopidogrel. Although aspirin had a higher risk of GI bleeding, overall safety was comparable between groups.17 The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial assessed the effectiveness of clopidogrel and aspirin versus aspirin alone following ACS (without ST elevation) in preventing death from cardiovascular causes, nonfatal MI, or stroke.18 The trial determined that DAPT was associated with a significant reduction in the composite of cardiovascular mortality, nonfatal MI, and stroke (driven by a reduction in MI) and with an increased risk of major bleeding.18
Aspirin/ER-DP: The combination of aspirin 25 mg and ER-DP 200 mg is approved to reduce the risk of stroke in patients with a history of ischemic stroke or TIA.19 The European Stroke Prevention Study 2 (ESPS 2) evaluated the safety and efficacy of this combination versus placebo, aspirin alone, and ER-DP alone.20 The combination of aspirin and ER-DP was more effective than aspirin 50 mg alone, dipyridamole 400 mg alone, or placebo for the secondary prevention of stroke and TIA. However, there was no difference in the composite endpoint of stroke or death. Headache occurred more frequently in the combination group; however, no other significant between-group differences were noted regarding safety and side effects.20
Cilostazol: Cilostazol, a phosphodiesterase III inhibitor, is approved for the treatment of intermittent claudication.21,22 Approval of cilostazol was based on eight clinical trials.21,22 The primary endpoints of these trials were related to the patients’ maximal walking distance.22-25 The Cilostazol for Prevention of Secondary Stroke (CSPS 2) trial compared cilostazol 100 mg twice daily with aspirin 81 mg daily for prevention of stroke in patients with history of noncardioembolic stroke.26 Following the start of therapy, the number of cerebral infarctions, cerebral hemorrhages, or subarachnoid hemorrhages was found to be noninferior in the cilostazol group versus the aspirin group. A higher rate of hemorrhagic events occurred in patients who took aspirin, but other adverse events were more common with cilostazol (e.g., headache, diarrhea, palpitations, and tachycardia).26
Another trial reviewed long-term combination therapy consisting of cilostazol 100 mg twice daily and either aspirin 81 mg to 100 mg daily or clopidogrel 50 mg to 75 mg versus monotherapy with the same doses of aspirin or clopidogrel.27 Ischemic stroke occurred in 3% of patients with DAPT and 7% of those receiving monotherapy. General and life-threatening GI or intracranial bleeding events were similar in both treatment groups, but more patients in the cilostazol group discontinued treatment because of diarrhea or palpitations.27 Both trials were conducted in Japan, which limits the generalizability of the data.26,27
Ticagrelor: This oral reversible P2Y12 inhibitor is FDA approved for use in ACS, but it is also used off-label for ischemic stroke.28 The Study of Platelet Inhibition and Patient Outcomes (PLATO) found that ticagrelor 90 mg twice daily was superior to clopidogrel 75 mg daily for the primary composite endpoint of vascular death, MI, or stroke at 12 months. The composite outcome was driven by vascular death and MI, with no observed difference in stroke.29
The Acute Stroke or Transient Ischaemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes Trial (SOCRATES) compared ticagrelor 90 mg twice daily with aspirin 100 mg daily for prevention of major ischemic events in 13,199 patients with mild stroke or TIA.30 Investigators found no difference in the primary composite endpoint of stroke, MI, or death; they did, however, find a significant decrease in ischemic stroke in the ticagrelor group. This ischemic stroke benefit was accompanied by a numerical, but not statistically significant, increase in major or minor bleeding.30
Prasugrel: Prasugrel, a P2Y12 inhibitor, is FDA approved for reducing cardiovascular events in patients with ACS who are receiving percutaneous coronary intervention (PCI).31 Prasugrel was approved based on results of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 trial.32 This trial compared a 60-mg loading dose of prasugrel followed by 10 mg daily with a 300-mg loading dose of clopidogrel followed by 75 mg daily in ACS patients scheduled to receive PCI. The primary composite endpoint of MI, stroke, or cardiovascular death was significantly lower for prasugrel; however, significantly more major, life-threatening, and fatal bleeding occurred with prasugrel. A subgroup analysis of patients with a history of stroke or TIA revealed a numerical, nonsignificantly increased incidence of the primary endpoint and significantly greater risk of major bleeding in the prasugrel group.32 Prasugrel is contraindicated in patients with a history of TIA or stroke as a result of TRITON-TIMI 38 findings.31
CHANCE Trial: Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) was a randomized, placebo-controlled, double-blind trial conducted in China that included 5,170 patients with acute minor ischemic stroke or high-risk TIA.8 Patients were randomized to either monotherapy with aspirin 75 mg daily with a loading dose of 75 mg to 300 mg or combined aspirin at the same doses plus clopidogrel 75 mg daily with a 300-mg loading dose for 21 days followed by clopidogrel monotherapy. The primary outcome of new ischemic or hemorrhagic stroke at 90 days was reduced in the combined group. The occurrence of moderate or severe hemorrhage was similar between groups; however, there was a nonsignificant trend toward increased overall bleeding in the combined group. It was concluded that combined therapy for 21 days followed by clopidogrel monotherapy, started within 24 hours of presentation, reduced the risk of another event at 90 days compared with aspirin alone, without an increase in hemorrhage.8
POINT Trial: Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) was a randomized, placebo-controlled, double-blind trial of 4,881 patients with acute minor ischemic stroke or high-risk TIA.33 Patients were randomized within 12 hours of the event into two groups: clopidogrel 75 mg daily with a 600-mg loading dose plus aspirin 50 mg to 325 mg daily for 90 days and aspirin alone at the same doses for 90 days. The primary outcome was a composite of ischemic stroke, MI, or death from ischemic vascular causes, and the primary safety outcome was the risk of major hemorrhage. Although the combined group demonstrated a lower risk of the primary outcome, the trial was stopped early because of an increased risk of major hemorrhage in this group. This increase was due primarily to nonfatal, nonintracranial hemorrhage. The only differences observed in secondary outcomes were a reduction in ischemic stroke and ischemic or hemorrhagic stroke in the clopidogrel-plus-aspirin group. When specific time periods were analyzed, the benefit of clopidogrel plus aspirin was greater in the first 7 days and the first 30 days, compared with 90 days. Also, the risk of hemorrhage was greater on days 8 to 90 compared with the first 7 days of therapy. It was concluded that patients receiving clopidogrel plus aspirin had a lower risk of the composite outcome but a higher risk of major hemorrhage at 90 days.33
Antiplatelets are the antithrombotic agents of choice for secondary prevention in patients with noncardioembolic ischemic stroke. Monotherapy with aspirin, clopidogrel, or aspirin/ER-DP is typically recommended, although DAPT may be used in the initial 3-week poststroke period in patients with acute minor stroke or high-risk TIA.
1. 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(10):e146-e603.
2. Berge E, Sandercock PA. Anticoagulants versus antiplatelet agents for acute ischaemic stroke. Cochrane Database Syst Rev. 2002;(4):CD003242.
3. De Schryver EL, Algra A, Kappelle LJ, et al. Vitamin K antagonists versus antiplatelet therapy after transient ischaemic attack or minor ischaemic stroke of presumed arterial origin. Cochrane Database Syst Rev. 2012;(9):CD001342.
4. Kernan WN, Ovbiagele B, Black HR, et al. 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. 2014;45(7):2160-2236.
5. 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(suppl 2):e601S-e636S.
6. 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.
7. Bath PM, Woodhouse LJ, Appleton JP, et al. Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial. Lancet. 2018;391(10123):850-859.
8. 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(1):11-19.
9. Powers WJ, Rabinstein AA, Ackerson T, et al. 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. 2019;50(12):e344-e418.
10. Vane JR, Botting RM. The mechanism of action of aspirin. Thromb Res. 2003;110(5-6):255-258.
11. Morris T, Stables M, Hobbs A, et al. Effects of low-dose aspirin on acute inflammatory responses in humans. J Immunol. 2009;183(3):2089-2096.
12. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324(7329):71-86.
13. International Stroke Trial Collaborative Group. International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet. 1997;349(9065):1569-1581.
14. Chen Z-M. CAST: randomised placebo-controlled trial of early aspirin use in 20 000 patients with acute ischaemic stroke. Lancet. 1997;349(9066):1641-1649.
15. Berger JS, Krantz MJ, Kittelson JM, Hiatt WR. Aspirin for the prevention of cardiovascular events in patients with peripheral artery disease: a meta-analysis of randomized trials. JAMA. 2009;301(18):1909-1919.
16. Plavix (clopidogrel) package insert. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; May 2019.
17. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348(9038):1329-1339.
18. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;357(7):494-502.
19. Aggrenox (aspirin/extended-release dipyridamole) package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc; November 2018.
20. Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143(1-2):1-13.
21. Pletal (cilostazol) package insert. Rockville, MD: Otsuka America Pharmaceutical, Inc; May 2017.
22. Beebe HG, Dawson DL, Cutler BS, et al. A new pharmacological treatment for intermittent claudication: results of a randomized, multicenter trial. Arch Intern Med. 1999;159(17):2041-2050.
23. Dawson DL, Cutler BS, Meissner MH, Strandness DE Jr. Cilostazol has beneficial effects in treatment of intermittent claudication: results from a multicenter, randomized, prospective, double-blind trial. Circulation. 1998;98(7):678-686.
24. Money SR, Herd JA, Isaacsohn JL, et al. Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease. J Vasc Surg. 1998;27(2):267-274.
25. Elam MB, Heckman J, Crouse JR, et al. Effect of the novel antiplatelet agent cilostazol on plasma lipoproteins in patients with intermittent claudication. Arterioscler Thromb Vasc Biol. 1998;18(12):1942-1947.
26. Shinohara Y, Katayama Y, Uchiyama S, et al. Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial. Lancet Neurol. 2010;9(10):959-968.
27. Toyoda K, Uchiyama S, Yamaguchi T, et al. Dual antiplatelet therapy using cilostazol for secondary prevention in patients with high-risk ischaemic stroke in Japan: a multicentre, open-label, randomised controlled trial. Lancet Neurol. 2019;18(6):539-548.
28. Brilinta (ticagrelor) package insert. Wilmington, DE: AstraZeneca Pharmaceuticals LP; October 2019.
29. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057.
30. Johnston SC, Amarenco P, Albers GW, et. Ticagrelor versus aspirin in acute stroke or transient ischemic attack. N Engl J Med. 2016;375(1):35-43.
31. Effient (prasugrel) package insert. Indianapolis, IN: Eli Lilly and Co; March 2019.
32. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001-2015.
33. 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(3):215-225.
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