[Skip to Content]
[Skip to Content Landing]

Dual Antiplatelet Therapy in Transient Ischemic Attack and Minor Stroke With Different Infarction PatternsSubgroup Analysis of the CHANCE Randomized Clinical Trial

Educational Objective
To determine whether the efficacy and safety of clopidogrel plus aspirin vs aspirin alone was consistent across different infarction patterns after transient ischemic attack (TIA) or minor stroke.
1 Credit CME
Key Points

Question  Are the efficacy and safety of clopidogrel plus aspirin vs aspirin alone consistent in different infarction patterns after transient ischemic attack or minor stroke?

Findings  In the imaging substudy of the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events randomized clinical trial that included 1089 transient ischemic attacks and minor strokes, a significant risk reduction of 50% in stroke recurrence was observed in patients with multiple acute infarctions administered clopidogrel plus aspirin compared with aspirin alone, and this finding was not observed in patients with a single acute infarction or no acute infarction. The bleeding risk was similar among treatment groups.

Meaning  Patients with multiple acute infarctions received the most pronounced clinical benefit from dual antiplatelet therapy.

Abstract

Importance  Infarction patterns may serve as important imaging markers to assess the probability of stroke recurrence in transient ischemic attack (TIA) and minor stroke. However, it is unclear whether patients with different infarction patterns benefit differently from dual antiplatelet therapy.

Objectives  To investigate whether infarction patterns can stratify the risk of recurrent stroke and whether the efficacy and safety of clopidogrel plus aspirin vs aspirin alone are consistent in different infarction patterns after TIA or minor stroke.

Design, Setting, and Participants  In this prespecified imaging substudy of the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) randomized clinical trial, a total of 1342 patients with noncardioembolic TIA or minor stroke at 45 sites of CHANCE from October 1, 2009, to July 30, 2012, were included in this substudy. The final analysis was conducted on July 30, 2016, and included 1089 patients with required magnetic resonance imaging sequences. Infarction patterns were grouped into multiple acute infarctions (MAIs), single acute infarction (SAI), and no acute infarction (NAI) according to diffusion-weighted imaging.

Main Outcomes and Measures  Primary and secondary efficacy outcomes were stroke recurrence and new clinical vascular event after 3 months, respectively. The safety outcome was moderate to severe bleeding risk after 3 months.

Results  Among 1089 patients, the mean (SD) age was 63.1 (10.7) years and 731 patients (65%) were men. Patients with MAIs (hazard ratio [HR], 5.8; 95% CI, 2.2-15.1; P < .001) and SAI (HR, 3.9; 95% CI, 1.5-10.5; P = .007) had higher risk of recurrent stroke than those with NAI after adjustment for potential confounders at 3-month follow-up. Stroke recurrence occurred in 15 (10.1%) and 25 (18.8%) of patients with MAIs administered clopidogrel plus aspirin and placebo plus aspirin, respectively (HR, 0.5; 95% CI, 0.3-0.96; P = .04), 24 (8.9%) and 24 (8.5%) of patients with SAI administered clopidogrel plus aspirin and placebo plus aspirin, respectively (HR, 1.1; 95% CI, 0.6-2.0; P = .71), and 3 (2.6%) and 2 (1.4%) of patients with NAI administered clopidogrel plus aspirin and placebo plus aspirin, respectively (HR, 1.7; 95% CI, 0.3-11.1; P = .56), with P = .04 for treatment × infarction pattern interaction effect. Clopidogrel plus aspirin did not increase moderate to severe bleeding risk.

Conclusions and Relevance  Infarction patterns can efficiently stratify the risk of recurrent stroke within 3 months of noncardioembolic TIA or minor ischemic stroke. Patients with MAIs received the most pronounced clinical benefit from dual antiplatelet therapy without increasing the risk of moderate to severe bleeding. However, even if after dual antiplatelet treatment, patients with MAIs still had a risk of stroke recurrence as high as those with SAI.

Trial Registration  clinicaltrials.gov Identifier: NCT00979589

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

Accepted for Publication: December 21, 2017.

Corresponding Author: Yilong Wang, MD, PhD, No. 6 Tiantanxili, Dongcheng District, Beijing, China, 100050 (yilong528@gmail.com).

Published Online: March 26, 2018. doi:10.1001/jamaneurol.2018.0247

Author Contributions: Dr Yilong Wang had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Jing, Zhao, Liu, Li, Johnston, Yongjun Wang, Yilong Wang.

Acquisition, analysis, or interpretation of data: Jing, Meng, Zhao, A. Wang, Pan, D. Wang, Yilong Wang.

Drafting of the manuscript: Jing, Meng, Liu.

Critical revision of the manuscript for important intellectual content: Meng, Zhao, A. Wang, Pan, Li, D. Wang, Johnston, Yongjun Wang, Yilong Wang.

Statistical analysis: Jing, A. Wang, Pan, Li.

Obtained funding: Meng, Zhao, Yongjun Wang, Yilong Wang.

Administrative, technical, or material support: Jing, D. Wang, Yilong Wang.

Study supervision: Zhao, Liu, Johnston, Yongjun Wang.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by grants 2015BAI12B04, 2015BAI12B02, 2016YFC0901000, 2016YFC0901001, and 2016YFC0901002 from the Ministry of Science and Technology of the People’s Republic of China; grants D151100002015001, D151100002015002, D151100002015003, Z15110200390000, and Z151100003915117 from the Beijing Municipal Science and Technology Commission; and grants No.2016-1-2041 and SML20150502 from the Beijing Municipal Commission of Health and Family Planning.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
von Weitzel-Mudersbach  P, Andersen  G, Hundborg  HH, Johnsen  SP.  Transient ischemic attack and minor stroke are the most common manifestations of acute cerebrovascular disease: a prospective, population-based study—the Aarhus TIA study.  Neuroepidemiology. 2013;40(1):50-55.PubMedGoogle ScholarCrossref
2.
Wu  CM, McLaughlin  K, Lorenzetti  DL, Hill  MD, Manns  BJ, Ghali  WA.  Early risk of stroke after transient ischemic attack: a systematic review and meta-analysis.  Arch Intern Med. 2007;167(22):2417-2422.PubMedGoogle ScholarCrossref
3.
Coull  AJ, Lovett  JK, Rothwell  PM. Oxford Vascular Study.  Population based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and organisation of services.  BMJ. 2004;328(7435):326.PubMedGoogle ScholarCrossref
4.
Johnston  SC, Gress  DR, Browner  WS, Sidney  S.  Short-term prognosis after emergency department diagnosis of TIA.  JAMA. 2000;284(22):2901-2906.PubMedGoogle ScholarCrossref
5.
Giles  MF, Rothwell  PM.  Risk of stroke early after transient ischaemic attack: a systematic review and meta-analysis.  Lancet Neurol. 2007;6(12):1063-1072.PubMedGoogle ScholarCrossref
6.
Amarenco  P, Lavallée  PC, Labreuche  J,  et al; TIAregistry.org Investigators.  One-year risk of stroke after transient ischemic attack or minor stroke.  N Engl J Med. 2016;374(16):1533-1542.PubMedGoogle ScholarCrossref
7.
Baird  AE, Lövblad  KO, Schlaug  G, Edelman  RR, Warach  S.  Multiple acute stroke syndrome: marker of embolic disease?  Neurology. 2000;54(3):674-678.PubMedGoogle ScholarCrossref
8.
Kang  DW, Latour  LL, Chalela  JA, Dambrosia  J, Warach  S.  Early ischemic lesion recurrence within a week after acute ischemic stroke.  Ann Neurol. 2003;54(1):66-74.PubMedGoogle ScholarCrossref
9.
Wen  HM, Lam  WW, Rainer  T,  et al.  Multiple acute cerebral infarcts on diffusion-weighted imaging and risk of recurrent stroke.  Neurology. 2004;63(7):1317-1319.PubMedGoogle ScholarCrossref
10.
Hart  RG, Diener  HC, Coutts  SB,  et al; Cryptogenic Stroke/ESUS International Working Group.  Embolic strokes of undetermined source: the case for a new clinical construct.  Lancet Neurol. 2014;13(4):429-438.PubMedGoogle ScholarCrossref
11.
Kang  DW, Chalela  JA, Ezzeddine  MA, Warach  S.  Association of ischemic lesion patterns on early diffusion-weighted imaging with TOAST stroke subtypes.  Arch Neurol. 2003;60(12):1730-1734.PubMedGoogle ScholarCrossref
12.
Wessels  T, Wessels  C, Ellsiepen  A,  et al.  Contribution of diffusion-weighted imaging in determination of stroke etiology.  AJNR Am J Neuroradiol. 2006;27(1):35-39.PubMedGoogle Scholar
13.
Fisher  CM.  Lacunes: small, deep cerebral infarcts.  Neurology. 1965;15:774-784.PubMedGoogle ScholarCrossref
14.
Miller Fisher  C.  Lacunar infarcts—a review.  Cerebrovasc Dis. 1991;1(6):311-320.PubMedGoogle ScholarCrossref
15.
Wang  Y, Johnston  SC; CHANCE Investigators.  Rationale and design of a randomized, double-blind trial comparing the effects of a 3-month clopidogrel-aspirin regimen versus aspirin alone for the treatment of high-risk patients with acute nondisabling cerebrovascular event.  Am Heart J. 2010;160(3):380-386, e1.PubMedGoogle ScholarCrossref
16.
Wang  Y, Wang  Y, Zhao  X,  et al; CHANCE Investigators.  Clopidogrel with aspirin in acute minor stroke or transient ischemic attack.  N Engl J Med. 2013;369(1):11-19.PubMedGoogle ScholarCrossref
17.
Wong  KS, Chen  C, Fu  J,  et al; CLAIR Study Investigators.  Clopidogrel plus aspirin versus aspirin alone for reducing embolisation in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR study): a randomised, open-label, blinded-endpoint trial.  Lancet Neurol. 2010;9(5):489-497.PubMedGoogle ScholarCrossref
18.
Markus  HS, Droste  DW, Kaps  M,  et al.  Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using Doppler embolic signal detection: the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial.  Circulation. 2005;111(17):2233-2240.PubMedGoogle ScholarCrossref
19.
Benavente  OR, Hart  RG, McClure  LA, Szychowski  JM, Coffey  CS, Pearce  LA; SPS3 Investigators.  Effects of clopidogrel added to aspirin in patients with recent lacunar stroke.  N Engl J Med. 2012;367(9):817-825.PubMedGoogle ScholarCrossref
20.
Benavente  OR, Pearce  LA, Bazan  C,  et al; SPS3 Investigators.  Clinical-MRI correlations in a multiethnic cohort with recent lacunar stroke: the SPS3 trial.  Int J Stroke. 2014;9(8):1057-1064.PubMedGoogle ScholarCrossref
21.
Asdaghi  N, Pearce  LA, Nakajima  M,  et al; SPS3 Investigators.  Clinical correlates of infarct shape and volume in lacunar strokes: the Secondary Prevention of Small Subcortical Strokes Trial.  Stroke. 2014;45(10):2952-2958.PubMedGoogle ScholarCrossref
22.
Liu  L, Wong  KS, Leng  X,  et al; CHANCE Investigators.  Dual antiplatelet therapy in stroke and ICAS: subgroup analysis of CHANCE.  Neurology. 2015;85(13):1154-1162.PubMedGoogle ScholarCrossref
23.
Pan  Y, Meng  X, Jing  J,  et al; CHANCE Investigators.  Association of multiple infarctions and ICAS with outcomes of minor stroke and TIA.  Neurology. 2017;88(11):1081-1088.PubMedGoogle ScholarCrossref
24.
Adams  HP  Jr, Bendixen  BH, Kappelle  LJ,  et al; TOAST Investigators.  Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial.  Stroke. 1993;24(1):35-41.PubMedGoogle ScholarCrossref
25.
GUSTO Investigators.  An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction.  N Engl J Med. 1993;329(10):673-682.PubMedGoogle ScholarCrossref
26.
Yaghi  S, Rostanski  SK, Boehme  AK,  et al.  Imaging parameters and recurrent cerebrovascular events in patients with minor stroke or transient ischemic attack.  JAMA Neurol. 2016;73(5):572-578.PubMedGoogle ScholarCrossref
27.
Nasr  DM, Brown  RD  Jr.  The challenges of stroke prediction scores.  JAMA Neurol. 2016;73(5):510-511.PubMedGoogle ScholarCrossref
28.
Bonati  LH, Lyrer  PA, Wetzel  SG, Steck  AJ, Engelter  ST.  Diffusion weighted imaging, apparent diffusion coefficient maps and stroke etiology.  J Neurol. 2005;252(11):1387-1393.PubMedGoogle ScholarCrossref
29.
Takahashi  K, Kobayashi  S, Matui  R, Yamaguchi  S, Yamashita  K.  The differences of clinical parameters between small multiple ischemic lesions and single lesion detected by diffusion-weighted MRI.  Acta Neurol Scand. 2002;106(1):24-29.PubMedGoogle ScholarCrossref
30.
Ferro  JM.  Patterns of ischaemic cerebral diseases.  J Neurol. 2004;251(1):1-10.PubMedGoogle ScholarCrossref
31.
Amarenco  P, Davis  S, Jones  EF,  et al; Aortic Arch Related Cerebral Hazard Trial Investigators.  Clopidogrel plus aspirin versus warfarin in patients with stroke and aortic arch plaques.  Stroke. 2014;45(5):1248-1257.PubMedGoogle ScholarCrossref
32.
Wong  KS, Gao  S, Chan  YL,  et al.  Mechanisms of acute cerebral infarctions in patients with middle cerebral artery stenosis: a diffusion-weighted imaging and microemboli monitoring study.  Ann Neurol. 2002;52(1):74-81.PubMedGoogle ScholarCrossref
33.
Bath  PM, Robson  K, Woodhouse  LJ, Sprigg  N, Dineen  R, Pocock  S; TARDIS Trialists.  Statistical analysis plan for the ‘Triple Antiplatelets for Reducing Dependency After Ischaemic Stroke’ (TARDIS) Trial.  Int J Stroke. 2015;10(3):449-451.PubMedGoogle ScholarCrossref
34.
Krishnan  K, Beridze  M, Christensen  H,  et al; TARDIS Trial Investigators.  Safety and efficacy of intensive vs. guideline antiplatelet therapy in high-risk patients with recent ischemic stroke or transient ischemic attack: rationale and design of the Triple Antiplatelets for Reducing Dependency After Ischaemic Stroke (TARDIS) Trial (ISRCTN47823388).  Int J Stroke. 2015;10(7):1159-1165.PubMedGoogle ScholarCrossref
35.
Wang  Y, Zhao  X, Lin  J,  et al; CHANCE Investigators.  Association between CYP2C19 loss-of-function allele status and efficacy of clopidogrel for risk reduction among patients with minor stroke or transient ischemic attack.  JAMA. 2016;316(1):70-78.PubMedGoogle ScholarCrossref
36.
Wang  Y, Zhao  X, Liu  L,  et al; CICAS Study Group.  Prevalence and outcomes of symptomatic intracranial large artery stenoses and occlusions in China: the Chinese Intracranial Atherosclerosis (CICAS) Study.  Stroke. 2014;45(3):663-669.PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right

Name Your Search

Save Search
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase

Lookup An Activity

or

My Saved Searches

You currently have no searches saved.

With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Topics
State Requirements