Network Meta-Analysis of Ticagrelor for Stroke Prevention in Patients at High Risk for Cardiovascular or Cerebrovascular Events

Alexandra Bálint, MD; Dániel Tornyos, MD; Oumaima El Alaoui El Abdallaoui, MS; Péter Kupó, MD; András Komócsi, MD, DSc


Stroke. 2021;52(9):2809-2816. 

In This Article

Abstract and Introduction


Background and Purpose: Preventive antiplatelet therapy is recommended for patients with cardiac or cerebrovascular atherosclerosis. Ticagrelor has an improved safety and efficacy profile in patients with acute coronary syndrome; however, data regarding stroke prevention remain controversial. We conducted a network meta-analysis to compare ticagrelor with other receptor antagonists (P2Y12) inhibitors and aspirin in monotherapy or combination in the treatment of patients with high risk for cardiovascular or cerebrovascular disease, defined as coronary artery disease, acute coronary syndrome, stroke or transient ischemic attack, or peripheral artery disease.

Methods: Systematic searches of MEDLINE, EMBASE, and the Cochrane Library were conducted until August 1, 2020. Search terms included ticagrelor, AZD 6140, and stroke. The risk of bias was assessed using the Cochrane Collaboration assessment tool. Random-effects model was used to combine risk estimates across trials and risk ratio with 95% CIs served as summary statistics. The influence of individual components was evaluated in an additive network meta-analysis model. The primary efficacy end point was the occurrence of stroke. The safety end points included bleeding and all-cause mortality.

Results: Twenty-six randomized clinical trials comprising 124 495 patients were analyzed. When compared with controls, ticagrelor plus aspirin significantly reduced the risk of ischemic stroke by 20% (risk ratio, 0.80 [95% CI, 0.71–0.89]). Treatment with ticagrelor monotherapy did not significantly affect ischemic stroke (risk ratio, 0.88 [95% CI, 0.77–1.00]; P=0.05). Compared with aspirin alone, major bleeding was in similar ranges with antiplatelet monotherapies while the relative risk was twice higher with combined antiplatelet therapies. There was no considerable difference in the risk of mortality with ticagrelor plus aspirin (risk ratio, 0.99 [95% CI, 0.91–1.07]).

Conclusions: Ticagrelor on top of aspirin may provide more favorable outcomes on secondary stroke prevention in patients with vascular risk factors; however, this benefit may come with the price of increased bleeding risk including intracranial bleeding.


Stroke is an important cause of morbidity and mortality worldwide.[1] Platelet aggregation contributes to the mechanisms of stroke; therefore, antiplatelet therapy interferes with the evolution of these events exerting important preventive capability. Antiplatelets use different mechanisms to block platelet activation and aggregation, and their use in forms of monotherapy or combination is supported by an important body of evidence.[2,3] Currently, 4 antiplatelet agents and 1 combination are approved by the US Food and Drug Administration for secondary stroke prevention: aspirin, dipyridamole, ticlopidine, clopidogrel, and aspirin combined with clopidogrel.[4] Aspirin acts as an irreversible cyclooxygenase inhibitor suppressing the production of prostaglandins and thromboxanes while dipyridamole blocks the related intracellular cAMP signaling. The latter two drugs, however, act on the interplatelet adenosine diphosphate (ADP) signaling by blocking the surface receptor antagonist (P2Y12) ADP receptor. ADP receptor antagonists show synergistic effects on platelet aggregation when used together with aspirin.[5]

The newer generation of P2Y12 receptor inhibitors achieves more efficient platelet inhibition compared with clopidogrel.[6,7] Clopidogrel and prasugrel share the same active metabolite but with more effective bioactivation of the latter while ticagrelor is a direct-acting reversible P2Y12 receptor antagonist inhibiting ADP-mediated P2Y12-dependent platelet aggregation.[8]

Some recent data suggest the potential benefits of ticagrelor with regard to stroke prevention in high-risk populations.[9] Most recently, the THALES trial (Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA) further supported the potential of ticagrelor and aspirin in stroke prevention. In this trial, combined antiplatelet therapy with ticagrelor resulted in a significant, 17% relative reduction of stroke in patients with mild-to-moderate acute noncardioembolic ischemic stroke.[10]

Importantly, evidence supports that the intensified or combined antiplatelet therapy is also associated with an increased risk of bleeding that may have an important impact on the risk-benefit relations of these therapies.[11]

Based on the previous findings, there is growing interest in comparing ticagrelor mono- and dual antiplatelet therapies for preventing ischemic stroke or transient ischemic attack (TIA). For this purpose, we performed a multiple-treatment network meta-analysis (NMA) of randomized controlled trials to compare the relative efficacy of ticagrelor in preventing stroke in high-risk populations.