Liam Davenport June 09, 2023
MUNICH — Giving intensive statin therapy to patients with acute mild ischemic stroke or with high-risk for transient ischemic attack (TIA) immediately after onset significantly reduces the risk for a poor functional outcome compared with delaying treatment, without compromising safety, results of the INSPIRES trial show.
The research, presented at the 9th European Stroke Organisation Conference (ESOC) on May 26, also showed that intensive antiplatelet therapy reduced the risk for recurrent stroke albeit at an increased in bleeding risk vs standard treatment.
The study involved more than 6000 patients with acute mild ischemic stroke or TIA and intracranial or extracranial atherosclerosis (ICAS/ECAS), who were randomly assigned in a 2 x 2 factorial design to compare intensive vs standard antiplatelet therapy and intensive statin therapy within 24 hours vs waiting up to 72 hours after onset.
Intensive antiplatelet therapy with clopidogrel plus aspirin reduced the risk for recurrent stroke within 90 days by 21% vs standard single-agent therapy, although it also doubled the risk for moderate to severe bleeding.
Starting intensive statin therapy with atorvastatin within 24 hours of onset had no impact on recurrent stroke risk but did reduce the risk for a poor functional outcome vs waiting up to 72 hours by 16%.
Moreover, it was “safe, with no increased risk of bleeding, hepatotoxicity, or muscle toxicity,” said study presenter Yilong Wang, MD, Department of Neurology, Beijing Tiantan Hospital, National Clinical Research Center, Beijing, China.
There was, however, a suggestion of an interaction between intensive antiplatelet therapy and immediate intensive statin therapy, he noted, with a trend toward increased bleeding vs delaying the start of statin therapy.
Approached for comment, session co-chair Carlos Molina, MD, director of the Stroke Unit and Brain Hemodynamics in Hospital Universitari Vall d’Hebron, Barcelona. Spain, said that the study is “important because when we look at studies of minor stroke and TIA, they are just focused on long-term outcomes in terms of recurrent stroke.”
He told Medscape Medical News that “putting statins in the equation and looking at their impact on long-term outcomes, the study demonstrates that statins are associated…in particular with reductions in disabling stoke, and that’s good.”
Recurrence and Progression
Wang began by highlighting that acute mild stroke and high-risk TIA are common and underestimated, with a relatively high risk for recurrence and progression, often due to ICAS/ECAS.
Numerous guidelines recommend intensive antiplatelet therapy in the first 24 hours after the event, but Wang pointed out that there is little evidence to support this, and a meta-analysis suggested the window for effective treatment may be up to 72 hours.
In addition, intense statin therapy appears to be beneficial for the secondary prevention of atherosclerotic stroke in the nonacute phase, although there is no evidence for any neuroprotective effects in the acute phase nor for the optimal timing of starting the drugs.
Wang also noted that there is the potential for an interaction between intensive antiplatelet and statin therapy that could increase the risk for bleeding.
To investigate further, the researchers conducted a multicenter study involving patients aged 35-80 years with acute ischemic stroke or TIA.
The former was defined as an acute single infarction with 50% or greater stenosis of a major intracranial or extracranial artery that “probably account for the infarction and symptoms,” or multiple infarctions of large artery origin, including non-stenotic vulnerable plaques.
Patients were required to have a National Institutes of Health Stroke Scale score of 4-5 24 hours or less from acute stoke onset or 0-5 between 24 and 72 hours of onset.
TIA was defined as 50% or more stenosis of major intracranial or extracranial arteries that probably account for the symptoms, and an ABCD2 score for stroke risk of 4 or more within 24-72 hours of onset.
Patients were excluded if they had received dual antiplatelet therapy with aspirin and clopidogrel or high-intensity statin therapy within 14 days of random assignment or had intravenous thrombolysis or endovascular therapy after acute stroke or TIA onset.
Those included in the trial were randomly assigned in a 2 x 2 factorial design to receive:
- Intensive or dual antiplatelet therapy with clopidogrel and aspirin plus immediate high-intensity statin therapy with atorvastatin
- Intensive antiplatelet therapy plus delayed high-intensity statin therapy
- Standard antiplatelet therapy with aspirin alone plus immediate high-intensity statin therapy
- Standard antiplatelet therapy plus delayed high-intensity statin therapy
In all, 6100 patients were enrolled from 222 hospitals in 99 cities across 25 provinces in China. The mean age was 65 years, and 34.6%-37.0% were women. TIA was recorded in 12.2%-14.1% of patients; 19.5%-19.7% had a single acute infarction, and 66.4%-68.1% had acute multiple infarctions.
The time to randomization was 24 hours or less after event onset in 12.5%-13.2% of cases vs 24-48 hours in 41.2%-42.5% and 48 hours or more in 44.9%-45.7% of patients.
The primary efficacy outcome, defined as stroke at 90 days, was significantly less common with intensive vs standard antiplatelet therapy, at a cumulative probability of 9.2% vs 7.3%, or a hazard ratio of 0.79 (95% CI, 0.66-0.94; P = .007).
Clopidogrel plus aspirin was also associated with a significant reduction in a composite vascular event of stroke, myocardial infarction, or vascular death vs aspirin alone, at 7.5% vs 9.3%, or a hazard ratio of 0.80 (95% CI, 0.67-0.95, P = .01), as well as a reduction in rates of ischemic stroke (P = .002), and TIA (P = .02).
The primary safety outcome, defined as moderate to severe bleeding on the GUSTO criteria, was increased with intensive antiplatelet therapy, at 0.9% vs 0.4% for aspirin alone, with a hazard ratio of 2.08 (95% CI, 1.07-4.03; P = .02).
Turning to statin use, Wang showed that there was no significant difference in rates of stroke at 90 days between delayed and immediate intensive therapy, at a cumulative probability of 8.4% vs 8.1%, or a hazard ratio of 0.95 (P = .58).
There was also no difference in rates of moderate to severe bleeding, at 0.8% with immediate vs 0.6% for delayed intensive statin therapy, or a hazard ratio of 1.36 (95% CI, 0.73-2.54; P = .34).
Wang reported that there were no significant differences in key secondary efficacy and safety outcomes.
Analysis of the distribution of modified Rankin Scale scores at 90 days, however, indicated that there was a significant reduction in the risk for poor functional outcome, defined as a score of 2-6, with immediate vs delayed statin therapy, at an odds ratio of 0.84 (95% CI, 0.72-0.99; P = .04).
Finally, it was found that combining dual antiplatelet therapy with immediate intensive statin therapy was associated with an increase in moderate to severe bleeding vs delayed statin therapy, affecting 1.1% vs 0.7% of patients. The association nonetheless did not reach statistical significance, at a hazard ratio of 1.70 (95% CI, 0.78-3.71; P = .18).
The study was funded by the National Natural Science Foundation of China, the National Key R&D Program of China, the Beijing Outstanding Young Scientist Program, the Beijing Youth Scholar Program, and the Beijing Talent Project. The drug was provided by Sanofi and Jialin Pharmaceutical. No relevant financial relationships declared.
9th European Stroke Organisation Conference (ESOC) 2023. Presented May 26, 2023. Abstract 3116
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