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Li ZX, Xiong Y, Gu HQ, et al. P2Y12 Inhibitors Plus Aspirin Versus Aspirin Alone in Patients With Minor Stroke or High-Risk Transient Ischemic Attack. Stroke. 2021 Jul;52(7):2250-2257. doi: 10.1161/STROKEAHA.120.033040. Epub 2021 May 27. (Systematic review)

BACKGROUND AND PURPOSE: We performed a systemic review and meta-analysis to elucidate the effectiveness and safety of dual antiplatelet (DAPT) therapy with P2Y12 inhibitors (clopidogrel/ticagrelor) and aspirin versus aspirin monotherapy in patients with mild ischemic stroke or high-risk transient ischemic attack.

METHODS: Following Preferred Reported Items for Systematic Review and Meta-Analysis standards for meta-analyses, Medline, Embase, Cochrane Central Register of Controlled Trials, and the Cochrane Library were searched for randomized controlled trials that included patients with a diagnosis of an acute mild ischemic stroke or high-risk transient ischemic attack, intervention of DAPT therapy with clopidogrel/ticagrelor and aspirin versus aspirin alone from January 2012 to July 2020. The outcomes included subsequent stroke, all-cause mortality, cardiovascular death, hemorrhage (mild, moderate, or severe), and myocardial infarction. A DerSimonian-Laird random-effects model was used to estimate pooled risk ratio (RR) and corresponding 95% CI in R package meta. We assessed the heterogeneity of data across studies with use of the Cochran Q statistic and I2 test.

RESULTS: Four eligible trials involving 21 493 participants were included in the meta-analysis. DAPT therapy started within 24 hours of symptom onset reduced the risk of stroke recurrence by 24% (RR, 0.76 [95% CI, 0.68-0.83], I2=0%) but was not associated with a change in all-cause mortality (RR, 1.30 [95% CI, 0.90-1.89], I2=0%), cardiovascular death (RR, 1.34 [95% CI, 0.56-3.17], I2=0%), mild bleeding (RR, 1.25 [95% CI, 0.37-4.29], I2=94%), or myocardial infarction (RR, 1.45 [95% CI, 0.62-3.39], I2=0%). However, DAPT was associated with an increased risk of severe or moderate bleeding (RR, 2.17 [95% CI, 1.16-4.08], I2=41%); further sensitivity tests found that the association was limited to trials with DAPT treatment duration over 21 days (RR, 2.86 [95% CI, 1.75-4.67], I2=0%) or ticagrelor (RR, 2.17 [95% CI, 1.16-4.08], I2=37%) but not within 21 days or clopidogrel.

CONCLUSIONS: In patients with noncardioembolic mild stroke or high-risk transient ischemic attack, DAPT with aspirin and clopidogrel/ticagrelor is more effective than aspirin alone for recurrent stroke prevention with a small absolute increase in the risk of severe or moderate bleeding.

Discipline Area Score
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Internal Medicine 5 / 7
Neurology 5 / 7
Hemostasis and Thrombosis 5 / 7
Comments from MORE raters

Family Medicine (FM)/General Practice (GP) rater

Dual therapy is more effective in preventing strokes but does not improve mortality, possibly due to the observed risk for bleeding. It seems that clopidogrel is safer than ticagrelor. This is important because it re-enforces the approach that stronger is not always better.

Family Medicine (FM)/General Practice (GP) rater

The authors did well to identify the need for DAPT other than clopidogrel due to known genetic predisposition to clopidogrel resistance. I also appreciate that the authors gave guidance on how to avoid adverse events with blood pressure control (to prevent intracerebral hemorrhage) and H. pylori detection and treatment (to prevent gastrointestinal hemorrhage) while patients are on DAPT.

General Internal Medicine-Primary Care(US) rater

It seems this is a good way to treat non-embolic TIA. The meds are cheap; the risk is low for bleeding. We just need to ensure that it is non-embolic.

Hemostasis and Thrombosis rater

Seems to be controversial and I'm not sure this really changes the landscape all that much.

Internal Medicine rater

The study was generally done well. The results were sufficiently meaningful to suggest a large prospective RCT should be done but not change general practice on its own.

Neurology rater

The results of this meta-analysis are essentially learned from the individual trials. Therefore, "most practitioners in my discipline possibly already know this." The CHANCE and POINT trials concluded that limited duration (21 days) clopidogrel plus aspirin balances reduction of ischemic stroke with bleeding risks. All P2Y12 inhibitor in combination with aspirin increase bleeding complications. The imitation of ticagrelor was bleeding, as seen in the THALES trial as well as in the meta-analysis. There is a similar yet different systematic review this year in the Stroke journal by Brown et al. The current paper is more narrowly focused in short-term (90-day outcome) and includes the ticagrelor study. While the Brown et al paper was a component of developing guidelines and may be broader "secondary prevention," the current paper is able to give the nuance of therapy duration and risks, but is strictly about what to do for 21 (or 90) days after defined "minor stroke" and defined "high-risk" TIA.

Neurology rater

A very useful meta-analysis of various dual antiplatelet regimes vs ASA in minor stroke and TIAs. Most neurologists are familiar with the CHANCE study done in China some years ago and this has driven practice. However, some of the other studies show continued benefit for stroke prevention beyond the 21 days and the risk for bleeding, although higher than with 21 days, is not prohibitive. I am not sure we should go with ticagrelor and ASA yet, as the bleeding rate is higher. If there were a way of selecting patients who cannot convert clopidogrel to its active form, it would find a definite place in management.
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