IV Alteplase No Help for Minor, Nondisabling Strokes in PRISMS Trial

Patients with minor acute ischemic strokes and deficits that are not clearly disabling at presentation do not derive a benefit from IV alteplase, according to results of the PRISMS trial, which was stopped early by the sponsor for financial reasons.

The proportion of patients who had a favorable functional outcome at 90 days was 78.2% among those who received IV alteplase (Activase; Genentech) within 3 hours of symptom onset and 81.5% among those treated with oral aspirin, a nonsignificant difference, researchers led by Pooja Khatri, MD (University of Cincinnati, OH), report in the July 10, 2018, issue of JAMA.

No differences were seen for other secondary and exploratory efficacy endpoints, although there was a higher rate of symptomatic intracranial hemorrhage in the alteplase arm (3.2% vs 0).

Acknowledging that the trial was underpowered after enrolling only a third of the planned number of patients before being stopped, Khatri said the results still could be practice-changing, pointing out that a post hoc analysis indicated that the probability that alteplase would lead to a clinically meaningful improvement in outcomes in this patient population was just 1.9%.

“It’s the data that we’ve got, and it’s underpowered, but it certainly has swayed me towards typically not treating these patients,” Khatri told TCTMD. In discussions with her colleagues, she added, it’s “generally been the consensus that when you see these data, when you see that there’s a real hemorrhage risk and there isn’t any signal of benefit, it’s tough to justify treating them.”

William Powers, MD (University of North Carolina at Chapel Hill), who wrote an accompanying editorial, commented to TCTMD that there is a dilemma about whether to treat patients with mild strokes with alteplase because good data informing the question have been lacking. Even though many patients do well without alteplase, some develop significant functional disabilities, he pointed out.

The PRISMS trial showed that among the subset of patients with mild stroke who did not have clearly disabling deficits at presentation, alteplase does not seem to improve clinical outcomes, Powers said. “What we’ve got here is a study of 300 patients which doesn’t even show a hint that the treatment’s of benefit.”

Though the trial has limitations due to its premature termination, it could still have an impact on how physicians are managing this type of patient, he indicated. “It will affect my clinical practice,” Powers said. “I’ve agonized over this at times, and I think this will make me more confident in making the decision not to treat these patients.”

The findings, he notes in his editorial, suggest “that for these patients, treatment with aspirin along with close monitoring may be an appropriate course of action.”

Clinical Uncertainty

Alteplase is an established treatment for patients with acute ischemic stroke and disabling deficits, but nearly all of the major trials of the therapy excluded patients with the mildest deficits, resulting in uncertainty about how best to manage them. Guidelines from the American Heart Association/American Stroke Association (AHA/ASA) give a class IIb recommendation (“may be considered”) to use of alteplase in patients with mild ischemic stroke symptoms that are deemed nondisabling, and call for further research to better define the risk-benefit balance.

The PRISMS trial was designed to provide insight into that question. The initial plan was to enroll 948 patients with acute ischemic stroke—a National Institutes of Health Stroke Scale (NIHSS) score of 0 to 5 at presentation and deficits judged to be not clearly disabling—who could be treated within 3 hours of stroke onset. But Genentech stopped the trial early because it was not going to be completed in a timely manner with the allotted funds.

Ultimately, researchers randomized 313 patients at 53 US stroke networks to treatment with standard-dose IV alteplase (0.9 mg/kg) plus oral placebo or to oral aspirin 325 mg plus IV placebo. The mean age of the patients was 62, and 46% were women. Median NIHSS score at baseline was 2.

The primary efficacy outcome was favorable functional outcome, defined as a modified Rankin Scale score of 0 or 1 at 90 days. That and other efficacy outcomes did not differ between trial arms.

Safety outcomes favored the control arm, however. In addition to a higher rate of symptomatic intracranial hemorrhage, patients in the alteplase arm also had twice the rate of overall serious adverse events (26.0% vs 13.1%). One patient treated with alteplase died of volvulus at 90 days, but that was deemed unrelated to study treatment.

Don’t Apply Findings to Patients With Disabling Strokes

In their paper, Khatri and colleagues say that the findings should not be extrapolated to all patients with NIHSS scores of 0 to 5 because some have disabling deficits like isolated leg weakness that prevents walking and isolated aphasia that prevents communication.

“Furthermore, clinical guidelines and scientific statements regarding alteplase recommend ‘no exclusion for patients with mild but nonetheless disabling stroke symptoms,’” the authors write. “Additionally, patients with mild deficits who have large-vessel occlusions (a minority in this population) may be more prone to stroke progression and thus may require further study.”

Khatri pointed out that it has been difficult to get emergency departments to use IV alteplase since it was approved, and said she doesn’t want these findings to impede efforts to improve uptake. “It’s a therapy that hasn’t picked up as quickly as it should have, and what I wouldn’t want to have happen is these results to confuse people about patients with moderate or severe strokes because we have a ton of evidence in multiple trials as well as community cohorts that patients with disabling symptoms do benefit from alteplase,” Khatri said.

Asked about concerns that people might apply these data to patients with more severe strokes, Powers said, “I certainly would hope that people don’t infer from this that there is a group of people with more severe strokes who shouldn’t be treated. I think that would be an inappropriate reading of the data.”

As for whether the PRISMS data are strong enough to alter guideline recommendations for patients with nondisabling strokes, Powers, who is the lead author of the AHA/ASA guidelines for the early management of patients with acute ischemic stroke, said he could not comment because there is a revision in the works. That revision, he noted, takes into account data from the trial.