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Practice Rapid Recommendations

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 doi: https://doi.org/10.1136/bmj.k5130 (Published 18 December 2018) Cite this as: BMJ 2018;363:k5130

Recommendation 1: Dual vs single antiplatelet therapy

or or Dual antiplatelet therapy Single agent therapy Aspirin and clopidogrel All identified trials compared with aspirin alone Patients that have experienced: High risk transient ischaemic attack (TIA) Minor ischaemic stroke Interventions compared Recommendation Population ASA CLOP + ASA A score of 3 or less on the National Institutes of Health Stroke Scale (NIHSS), and no persistent disabling neurological deficit 0 42 0 7 A score of 4 or more on the ABCD2 scale, which estimates the risk of recurrent stroke after a TIA

We recommend dual antiplatelet therapy over single agent therapy. Start as soon as possible after index event. Moredetails Strong All or nearly all informed people would likely want this option. Benefits outweigh harms for almost everyone. Weak Most people would likely want this option. Benefits outweigh harms for the majority, but not for everyone. Weak Most people would likely want this option. Benefits outweigh harms for the majority, but not for everyone. Strong All or nearly all informed people would likely want this option. Benefits outweigh harms for almost everyone.

Comparison of benefits and harms

Favours dual antiplatelets Favours single agent Evidence quality Events per 1000 people Within 90 days No important difference The panel found that this difference was not important for most patients, because the intervention effects were negligible and/or very imprecise, for example confidence intervals that include both important benefit and harm

63 19 fewer Non-fatal recurrent stroke High More 44

Risk of Bias No serious concerns Imprecision No serious concerns Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns Dual antiplatelet therapy has a small but important benefit in reducing recurrent strokes High GRADE score, because of: GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low

No important difference All cause mortality Moderate More 6 5

Risk of Bias No serious concerns Imprecision Serious Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns Dual antiplatelet therapyprobably has little or no impacton all cause mortality Moderate GRADE score, because of: GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low

Functional disability Moderate More 128 142 14 fewer

Measured by modified Rankin Scale (mRS) score of 2-5 (Non-fatal) Risk of Bias No serious concerns Imprecision Serious Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns Dual antiplatelet therapy possibly has a small but important benefit on patient function Moderate GRADE score, because of: GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low

13 fewer Poor quality of life Moderate More 55 68

Measured by EQ-5D index score of 0.5 or less Risk of Bias No serious concerns Imprecision Serious Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns Dual antiplatelet therapyprobably has a small but importantbenefit on quality of life Moderate GRADE score, because of: GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low

No important difference Recurrent TIA Moderate More 36 40

Risk of Bias No serious concerns Imprecision Serious Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns Dual antiplatelet therapyprobably has little or no impacton recurrent TIA Moderate GRADE score, because of: GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low

2 fewer Moderate or major bleeding Moderate More 5 3

Risk of Bias Serious Imprecision Serious Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns Dual antiplatelet therapy probably results in a very small, possibly important increase inmoderate or major extracranial bleeding Moderate or major extracranial bleeding defined by individual study (nonfatal) Moderate GRADE score, because of: GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low

7 fewer Minor bleeding High More 13 6

Mild or minor extracranial bleeding events Risk of Bias No serious concerns Imprecision No serious concerns Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns Dual antiplatelet therapy results in a small and possibly important increase in mild extracranial bleeding High GRADE score, because of: GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low
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Two different tablets taken once daily at same time Aspirin tablet should be swallowed whole, but clopidogrel tablet can be crushed or split A single aspirin tablet once daily Although dosing varied slightly in the included trials, for clopidogrel, most physicians and patients would probably prefer a loading dose of 300 mg rather than a higher dose. For aspirin, a daily dose between 75 mg and 81 mg represents a reasonable choice. Dosing The panel believes almost all patients place a high value on avoiding a recurrent stroke and a lower value on avoiding moderate or major bleeding. Values and preferences Key practical issues Dual antiplatelets Single agent

Recommendation 2: Duration of dual antiplatelet therapy

Interventions compared Recommendation Population or Shorter duration Longer duration Dual antiplatelet therapy for 10-21 days after TIA or minor stroke Dual antiplatelet therapy for 22-90 days after TIA or minor stroke Patients initiating dual antiplatelet therapy after TIA or minor ischaemic stroke ASA CLOP +

We recommend administering dual antiplatelet therapy for 10-21 days after the index event Moredetails Strong All or nearly all informed people would likely want this option. Benefits outweigh harms for almost everyone. Weak Most people would likely want this option. Benefits outweigh harms for the majority, but not for everyone. Weak Most people would likely want this option. Benefits outweigh harms for the majority, but not for everyone. Strong All or nearly all informed people would likely want this option. Benefits outweigh harms for almost everyone.

Comparison of benefits and harms

Favours 10-21 days Favours 22-90 days Evidence quality Events per 1000 people Within 90 days No important difference The panel found that this difference was not important for most patients, because the intervention effects were negligible and/or very imprecise, for example confidence intervals that include both important benefit and harm

No important difference 14 Ischaemic stroke Moderate More 10

Risk of Bias No serious concerns Imprecision No serious concerns Indirectness Serious Inconsistency No serious concerns Publication bias No serious concerns A longer duration of dual antiplatelet therapy probably does not result in an important reduction in risk of ischaemic stroke Moderate GRADE score, because of: GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low

3 fewer Moderate or major bleeding High More 3 6

A longer duration of dual antiplatelet therapy increases the risk of moderate or major bleeding by a small amount Downgraded due to imprecision and upgraded due to a dose-response gradient High GRADE score, because of: GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low
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Most patients should probably remain on single antiplatelet therapy indefinitely Switch to anticoagulation instead of antiplatelet therapy when stroke workup revealsan indication (such as atrial fibrillation or patent foramen ovale without plans for closure) Key practical issues All people taking dual antiplatelets

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This article has a correction. Please see:

  1. Kameshwar Prasad, chair, stroke neurologist1,
  2. Reed Siemieniuk, general internist, methodologist23,
  3. Qiukui Hao, geriatrician24,
  4. Gordon Guyatt, general internist, methodologist25,
  5. Martin O’Donnell, stroke neurologist6,
  6. Lyubov Lytvyn, patient partnership liaison2,
  7. Anja Fog Heen, general internist7,
  8. Thomas Agoritsas, general internist, methodologist28,
  9. Per Olav Vandvik, general internist, methodologist79,
  10. Sankar Prasad Gorthi, stroke neurologist10,
  11. Loraine Fisch, stroke neurologis11,
  12. Mirza Jusufovic, stroke neurologist12,
  13. Jennifer Muller, patient partner1314,
  14. Brenda Booth, patient partner13,
  15. Eleanor Horton, patient partner15,
  16. Auxiliadora Fraiz, physiotherapist, nurse,
  17. Jillian Siemieniuk, nurse16,
  18. Awah Cletus Fobuzi, patient and carer partner17,
  19. Neelima Katragunta, vascular surgeon18,
  20. Bram Rochwerg, methods co-chair, critical care clinician25
  1. 1Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
  2. 2Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Canada
  3. 3Department of Medicine, University of Toronto, Toronto, Canada
  4. 4The Centre of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, China
  5. 5Department of Medicine, McMaster University, Hamilton, Canada
  6. 6Deparment of Medicine, NUI Galway, Galway, Ireland
  7. 7Department of Medicine, Innlandet Hospital Trust-division, Gjøvik, Norway
  8. 8Division of General Internal Medicine & Division of Clinical Epidemiology, University Hospitals of Geneva, Geneva, Switzerland
  9. 9Institute of Health and Society, Faculty of Medicine, University of Oslo, Oslo, Norway
  10. 10Department of Neurology, Kasturba Medical College, Manipal, India
  11. 11Division of Neurology, Stroke Centre, University Hospitals of Geneva, Geneva, Switzerland
  12. 12Department of Neurology, Oslo University Hospital Rikshospitalet, Oslo, Norway
  13. 13Stroke Foundation of Australia
  14. 14School of Public Health and Social Work, Faculty of Health, Queensland University of Technology, Brisbane, Australia
  15. 15School of Nursing, Midwifery and Paramedicine, University of Sunshine Coast, Maroochydore, Australia
  16. 16Peter Lougheed Hospital, Calgary, Canada
  17. 17Cochrane Consumers Group
  18. 18Department of Surgery, Stanford University, Stanford, California
  1. Correspondence to: B Rochwerg rochwerg{at}mcmaster.ca

Abstract

What is the role of dual antiplatelet therapy after high risk transient ischaemic attack or minor stroke? Specifically, does dual antiplatelet therapy with a combination of aspirin and clopidogrel lead to a greater reduction in recurrent stroke and death over the use of aspirin alone when given in the first 24 hours after a high risk transient ischaemic attack or minor ischaemic stroke? An expert panel produced a strong recommendation for initiating dual antiplatelet therapy within 24 hours of the onset of symptoms, and for continuing it for 10-21 days. Current practice is typically to use a single drug

Footnotes

  • Research, doi: 10.1136/bmj.k5108

  • This BMJ Rapid Recommendation article is one of a series that provides clinicians with trustworthy recommendations for potentially practice changing evidence. BMJ Rapid Recommendations represent a collaborative effort between the MAGIC group (http://magicproject.org/) and The BMJ. A summary is offered here and the full version including decision aids is on the MAGICapp (https://app.magicapp.org), for all devices in multilayered formats. Those reading and using these recommendations should consider individual patient circumstances, and their values and preferences and may want to use consultation decision aids in MAGICapp in language patients can easily understandto facilitate shared decision making. We encourage adaptation and contextualisation of our recommendations to local or other contexts. Those considering use or adaptation of content may go to MAGICapp to link or extract its content or contact The BMJ for permission to reuse content in this article.

  • Contributors: All panel members participated in the teleconferences and email discussions and met all authorship criteria.

  • Competing interests: All authors have completed the BMJ Rapid Recommendations interests disclosure form, and a description of all disclosures is reported in appendix 1 on bmj.com. As with all BMJ Rapid Recommendations, the executive team and The BMJ judged that no panel member had any financial conflict of interest. Professional and academic interests are minimised as much as possible, while maintaining necessary expertise on the panel to make fully informed decisions.

  • Funding: This guideline was not funded.

  • Transparency: K Prasad affirms that the manuscript is an honest, accurate, and transparent account of the recommendation being reported; that no important aspects of the recommendation have been omitted; and that any discrepancies from the recommendation as planned (and, if relevant, registered) have been explained.

  • Provenance and peer review: Commissioned; externally peer reviewed

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