Antithrombotic therapy for secondary prevention in patients with stroke or transient ischemic attack: A multiple treatment network meta-analysis of randomized controlled trials

PLoS One. 2022 Aug 17;17(8):e0273103. doi: 10.1371/journal.pone.0273103. eCollection 2022.

Abstract

Objective: As stroke represents one of the leading causes of mortality and disability worldwide, we aimed to determine the preventive effect of different antiplatelet therapies after an ischemic stroke or transient ischemic attack.

Methods: Network meta-analysis evaluating antiplatelet regimes after an ischemic stroke or transient ischemic attack. Searches were conducted in MEDLINE, EMBASE, and Cochrane Library databases until Nov. 23, 2021, for randomized controlled trials. Direct comparisons within trials were combined with indirect evidence from other trials by using a frequentist model. An additive network meta-analysis model was used to evaluate the influence of individual components. The primary efficacy endpoint was a recurrent stroke, the main safety outcomes were the risk of major bleeding and mortality at the longest available follow-up.

Results: 58 randomized controlled trials (175,730 patients) were analyzed. The analysis involved 20 antithrombotic strategies including different antiplatelet agents, combinations with aspirin, and anticoagulant therapies. Cilostazol proved to be the most efficacious in reducing stroke recurrence and the risk of bleeding (RR = 0.66, 95%CI = 0.55-0.80 and RR = 0.39, 95%CI = 0.08-2.01) compared to aspirin, respectively. Intensification with combinations of aspirin with ticagrelor or clopidogrel resulted in a lower risk of stroke recurrence (RR = 0.79, 95%CI = 0.67-0.93 and RR = 0.79, 95%CI = 0.72-0.87) but carried a higher bleeding risk (RR = 3.01, 95%CI = 1.65-5.49 and RR = 1.78 95%CI = 1.49-2.13).

Conclusion: The prognosis of patients with an ischemic stroke or transient ischemic attack is improved with antiplatelets. Cilostazol showed the best risk-benefit characteristics without trade-off with the risk of major bleeding. Improved stroke recurrence with intensified antiplatelet regimens is counterbalanced with higher bleeding risk, and consequently, mortality remains unaffected. Treatment decisions in stroke survivals should integrate the assessment of bleeding risk for better identification of patients with the highest benefit of treatment intensification.

Systematic review registration: Prospero registration number: CRD42020197143, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=197143.

Publication types

  • Meta-Analysis
  • Systematic Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aspirin / adverse effects
  • Cilostazol / adverse effects
  • Fibrinolytic Agents* / adverse effects
  • Hemorrhage / chemically induced
  • Humans
  • Ischemic Attack, Transient* / drug therapy
  • Ischemic Attack, Transient* / prevention & control
  • Ischemic Stroke* / drug therapy
  • Ischemic Stroke* / prevention & control
  • Network Meta-Analysis
  • Platelet Aggregation Inhibitors / adverse effects
  • Randomized Controlled Trials as Topic
  • Risk Factors
  • Secondary Prevention / methods

Substances

  • Fibrinolytic Agents
  • Platelet Aggregation Inhibitors
  • Cilostazol
  • Aspirin

Grants and funding

This work was supported by the GINOP-2.3.3-15-2016-00031 grant of the Hungarian Government. The financial support does not affect the submitted work, and the researchers are independent from the funder. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.