Rationale and design of a randomised double-blind 2×2 factorial trial comparing the effect of a 3-month intensive statin and antiplatelet therapy for patients with acute mild ischaemic stroke or high-risk TIA with intracranial or extracranial atherosclerosis (INSPIRES)

Abstract

BackgroundIt remains unclear if intensive antiplatelet and statin treatments begun within 24–72 hours of cerebral ischaemic events from intracranial or extracranial atherosclerosis is effective or safe.MethodsThe Intensive Statin and Antiplatelet Therapy for High-risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial is a randomised, double-blind, placebo-controlled, multicentre and 2×2 factorial trial. 6100 individuals between the ages of 35 and 80 who have experienced a mild ischaemic stroke or high-risk transient ischaemic attack (TIA) within the previous 72 hours that is attributed to ≥50% atherosclerotic stenosis of a major intracranial or extracranial artery or multiple infarctions of atherosclerotic origin will be enrolled in the trial. Eligible subjects will be randomised 1:1:1:1 to one of four groups: (1) intensive antiplatelet therapy (combined clopidogrel and aspirin for days 1–21, then aspirin placebo and clopidogrel for days 22–90) plus immediate intensive statin therapy(atorvastatin at a dose of 80 mg daily for the first 21 days, then 40 mg daily for days 22–90); (2) intensive antiplatelet therapy plus delayed intensive statin therapy (atorvastatin placebo for days 1–3, followed by 40 mg per day of atorvastatin for days 4–90); (3) standard antiplatelet therapy (combination of clopidogrel placebo with aspirin for 90 days) plus immediate intensive statin therapy and (4) standard antiplatelet therapy plus delayed intensive statin therapy. The primary efficacy endpoint is any new stroke (ischaemic or haemorrhagic) within 90 days after randomisation. The primary safety endpoint is moderate to severe bleeding at 90 days.ConclusionThe INSPIRES trial will assess the efficacy and safety of intensive antiplatelet therapy and immediate intensive statin therapy begun within 72 hours of onset in decreasing the recurrent stroke at 90 days in patients with acute mild ischaemic stroke or high-risk TIA of intracranial or extracranial atherosclerosis origin.Trial registration numberNCT03635749.

Immediate- or Delayed-Intensive Statin in Acute Cerebral Ischemia

“…Details of the rationale and design of the INSPIRES study have been described previously. The protocol, statistical analysis plan, and information on committees, sites, and investigators are available in Supplement 1 , Supplement 2 , and the eAppendix in Supplement 3 , respectively. The trial was approved by the ethics committee at Beijing Tiantan Hospital and all other study sites.…”

“…Results of the intensive statin arm are presented here whereas results of an arm comparing the combination of clopidogrel with aspirin vs aspirin alone will be published elsewhere. Details of the rationale and design of the INSPIRES study have been described previously . The protocol, statistical analysis plan, and information on committees, sites, and investigators are available in Supplement 1, Supplement 2, and the eAppendix in Supplement 3, respectively.…”

“…3 Meta-analysis and observational studies have further indicated that early statin treatment is associated with good functional outcome and lower mortality. 10,18,19 Conversely, discontinuation of statin treatment after admission has been linked to poorer functional outcomes, increased mortality, and dependence. 18,20 However, there is a lack of high-quality RCTs providing evidence for the neuroprotective effects or for the effective improvement of functional outcomes in patients receiving acute statin treatment.…”

Dual Antiplatelet Treatment up to 72 Hours after Ischemic Stroke

“…There was no interaction between the results of the two components of the factorial trial (p= 0.16). Details of the rationale, design, and methods of the trial have been described previously 12 and are provided in the protocol, available at NEJM.org along with the statistical analysis plan. The trial was approved by the ethics committees of Beijing Tiantan Hospital and all other participating sites.…”