DAPT Works When Started Up to 3 Days After Mild Stroke, TIA

Patients presenting with a mild ischemic stroke or high-risk TIA believed to be related to atherosclerosis derive a benefit from dual antiplatelet therapy (DAPT) even when it’s started up to 72 hours after symptom onset, the randomized INSPIRES trial shows.

Those treated with clopidogrel and aspirin had a lower risk of new stroke in the first 90 days compared with those treated with aspirin alone (7.3% vs 9.2%), researchers led by Ying Gao, MD, and Weiqi Chen, MD (both from Beijing Tiantan Hospital, China), report in a study published in the December 28, 2023, issue of the New England Journal of Medicine.

That benefit came at the cost of more moderate-to-severe bleeds, although the overall risk was low (0.9% vs 0.4%).

Currently, guidelines recommend using DAPT with clopidogrel and aspirin in patients with minor ischemic stroke when treatment can be started within 24 hours, based on the results of the CHANCE and POINT trials; the THALES trial provided similar results with the combination of ticagrelor and aspirin in a higher-risk group of patients. Exploratory analyses of all those trials suggested that initiating DAPT up to several days after the initial event might be beneficial, but the idea had not been tested in a dedicated trial before INSPIRES.

“The results of our trial potentially broaden the time window for the initiation of treatment, although there was more bleeding with the dual regimen than with the monotherapy,” the INSPIRES investigators write.

Extending the Treatment Window

INSPIRES, which was conducted across 222 hospitals in China, was a two-by-two factorial trial that included 6,100 patients (median age 65 years; 36% women) who had either a mild ischemic stroke or a high-risk TIA of presumed atherosclerotic cause and who had not undergone thrombolysis or thrombectomy. TIA was the qualifying event in 13.1% of participants.

Patients were randomized to DAPT or aspirin alone started within 72 hours and to immediate or delayed statin therapy; only the antiplatelet results were reported in the current paper. In the DAPT arm, patients received a 300-mg loading dose of clopidogrel on the first day followed by a 75-mg daily dose on days 2 to 90, in combination with aspirin at a dose of 100 to 300 mg on the first day followed by 100 mg daily on days 2 to 21. In the control arm, patients received a clopidogrel placebo in addition to aspirin at a dose of 100 to 300 mg on the first day followed by 100 mg daily on days 2 to 90.

The primary efficacy outcome was new ischemic or hemorrhagic stroke at 90 days, with a lower risk observed in the DAPT arm (HR 0.79; 95% CI 0.66-0.94).

On the safety side, DAPT increased the risk of GUSTO moderate-to-severe bleeding at 90 days (HR 2.08; 95% CI 1.07-4.04). Overall adverse events occurred in 21.3% of patients in each group, with higher rate of serious adverse events in the DAPT arm (3.5% vs 2.9%).

In an accompanying editorial, Anthony Kim, MD (UCSF Weill Institute for Neurosciences, San Francisco, CA), a member of the executive committee of the POINT trial, puts the balance of benefits and risks into perspective, calculating that for every 1,000 patients with TIA or mild stroke treated with clopidogrel plus aspirin versus aspirin alone up to 72 hours after the initial event, there would be about 19 fewer strokes and five additional moderate-to-severe bleeds.

Treat as Soon as Possible

Speaking with TCTMD, Kim noted that some physicians have started treating within that extended time window based on secondary analyses of the prior trials but said INSPIRES provides more confidence in that approach.

“With this new trial now specifically demonstrating that, I think it’s going to lead to more clinicians adopting a longer time window for these patients,” Kim said.

Although this is important for opening up treatment to more patients, it remains critical to initiate therapy as soon as possible, he stressed, pointing out that the risk of recurrent cerebrovascular events is highest early on.

“There’s still some urgency to treatment, so this is not a free pass to wait to 72 hours to start to treat someone,” Kim said.

In his editorial, he says the INSPIRES results cannot be generalized to patients with an increased bleeding risk, those with severe or cardioembolic stroke, or those expected to be treated with thrombectomy or thrombolysis, with uncertain applicability to populations that differ from the predominantly Han Chinese cohort studied here.

Nonetheless, “the incremental expansion of indications for dual antiplatelet therapy that was shown in this trial is welcome,” Kim writes. “Perhaps new, more targeted antithrombotic agents on the horizon may hold promise for delivering an even more favorable balance of benefits and risks among patients with stroke.”