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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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Re: Dual antiplatelet therapy with aspirin and clopidogrel for acute high risk transient ischaemic attack and minor ischaemic stroke: a clinical practice guideline

This rapid recommendation is a welcome addition to existing guidelines, concisely written and easy to implement in clinical practice. However, while suggesting a reasonable standard loading dose of clopidogrel, it leaves the age-old matter of aspirin dosing unnecessarily open. There were two large trials (IST and CAST) using 300 mg and 160 mg respectively (1) (2); and there are at least some suggestions that up to 100 mg may not be sufficient for all, esp. overweight patients in long-term secondary prevention (3). So why should we not keep it simple and adapt a standard asprin-loading dose of 300 mg and continue with either 100 mg or 150 mg until discharge ?

Kind regards

Joerg Wiesenfeldt

(1) The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group;
Lancet. 1997 May 31;349(9065):1569-81
(2) CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group; Lancet. 1997 Jun 7;349(9066):1641-9
(3) Peter M Rothwell et. al.; Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trials; Lancet 2018; 392: 387–99

Competing interests: No competing interests

11 January 2019
Joerg Wiesenfeldt
Staff grade neurologist
Verbundkrankenhaus Bernkastel-Wittlich
Koblenzer Str. 91, D 54516 Wittlich, Germany