Triple antiplatelet therapy no better than guideline for stroke, TIA

Philip M. Bath, MD, discusses the TARDIS trial.

Triple antiplatelet therapy with aspirin, clopidogrel and dipyridamole is not superior to guideline-based agent treatment with aspirin + dipyridamole or clopidogrel alone for preventing recurrent strokes. Late-breaking results of the TARDIS (Triple Antiplatelets for Reducing Dependency in Ischemic Stroke) trial were announced during the Main Event at ISC 2017 in Houston.

The trial was stopped early in April 2016 at the recommendation of the data analysis committee.

“This was a neutral trial, overall no net harm or benefit from three antiplatelets for the prevention of subsequent stroke,” said lead author Philip M. Bath, MD, Stroke Association professor of stroke medicine and chair and head of clinical neuroscience at the University of Nottingham in the United Kingdom. “We now know that one antiplatelet is better than none, two is better than one and when you get to three, they are about the same. We certainly don’t want to start testing four drugs.”

TARDIS was intended to answer a very clear question, Bath said. There is evidence that one antiplatelet agent is superior to no antiplatelets for the prevention of recurrent stroke following an index ischemic stroke. There is also good evidence that two antiplatelets are better than one. Could three agents be better than two?

TARDIS used a simple prospective parallel group design to directly compare guideline therapy, aspirin + dipyridamole, against triple therapy of aspirin + dipyridamole + clopidogrel. All three agents were dosed at recommended levels. Dipyridamole is a phosphodiesterase inhibitor seldom used for stroke prevention in the United States.

The trial was broadly inclusive, open to patients within 48 hours of an index ischemic stroke of any acuity as long as the event was not cardioembolic, TIA, recurrent even if already on two antiplatelets and isolated dysphagia.

The primary outcome was recurrent stroke or TIA. The trial used a novel endpoint that accounted for both the number of recurrent events and the severity using an ordinal shift in score on the modified Rankin Scale or mRS. The scale is commonly used to assess outcome in acute stroke trials, but this is the first time it has been used in a secondary prevention trial, Bath said. The safety endpoint was the number and severity of bleeds.

Study design was somewhat complicated by a 2010 change in U.K. guidelines to include clopidogrel as a single agent for secondary stroke prevention, Bath said. The change was largely the result of approval of a generic version of clopidogrel and resulting price drops, he said. Patients in the guideline arm gradually switched from aspirin + dipyridamole to clopidogrel alone. In the U.S., patients generally receive either aspirin or clopidogrel for secondary prevention.

The trial population had a mean age of 69 and was 63 percent male. Only 11 percent had a prior stroke and 19 percent had diabetes. The index event was an ischemic stroke for 70 percent of participants and TIA for 30 percent.

A total of 3,096 patients were randomized before the trial was halted. The original target enrollment was 4,100 patients.

The primary endpoint, recurrent stroke or TIA, was not significantly different between the two treatment groups. The odds ratio for a recurrent event was 0.93, p=0.61. There was a trend toward fewer recurrent events on triple therapy, Bath said, but the difference was not statistically significant.

Differences in bleeding rates were significant. The odds ratio for bleeding in the triple therapy arm was 2.49, p<0.001.

“This is what the data monitoring committee was worried about,” Bath said. “Triple therapy shifted people to bleed and perhaps to more severe bleeding.”

Subgroup analyses by death, serious adverse events, stroke and major bleeding, death and stroke, myocardial infarction and major bleeding similarly showed no significant differences between the arms.

“In clinical practice, we should not be using intensive triple antiplatelet therapy,” Bath said. “We should carry on with guideline treatment.”

A similar trial, POINT, is currently underway in the U.S. to compare aspirin + clopidogrel versus aspirin alone for secondary prevention following TIA and minor stroke.