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PHOENIX -- Adjunctive thrombolysis with either argatroban or eptifibatide for acute ischemic stroke did not boost efficacy and contributed to risk, the MOST trial showed.

When given after starting alteplase (Activase) or tenecteplase (TNKase), placebo actually yielded the best 90-day utility weighted modified Rankin Scale (mRS) scores, with a mean of 6.8 compared with 5.2 on argatroban and 6.3 with eptifibatide, reported Opeolu Adeoye, MD, of Washington University in St. Louis, at the American Stroke Association's International Stroke Conference.

The probability of argatroban being better than placebo was just 0.2%, and wasn't much better for eptifibatide at 0.9%. Both easily met the futility threshold.

Jeffrey Saver, MD, of the University of California Los Angeles, called it the "disappointing end of a long journey."

Both the direct thrombin inhibitor argatroban and glycoprotein IIb/IIIa inhibitor eptifibatide have had a number of phase II trials over the past decade or so in combination with tissue plasminogen activator (tPA). It was finally time for a phase III trial.

Adeoye's group designed a response-adaptive randomized trial with three arms, allowing for greater randomization into the more successful arms after the first 150 and 500 patients enrolled. In total, the trial randomized 514 adults with a pre-thrombolysis NIH Stroke Scale (NIHSS) score of 6 or greater, of whom 421 completed the trial.

All patients received recombinant tPA -- alteplase at 0.9 mg/kg or tenecteplase at 0.25 mg/kg -- starting within 3 hours of stroke onset. Mechanical thrombectomy was done as well, when eligible. The randomly assigned treatment could begin within 60 minutes and no later than 75 minutes after starting the thrombolytic bolus.

The 59 patients randomized to argatroban received a 100-µg/kg bolus and a 12-hour infusion at 3 µg/kg/min. The 227 patients in the eptifibatide group got a 135-µg/kg bolus and a 2-hour infusion at 0.75 µg/kg/min followed by a 10-hour saline infusion. The 228 placebo-group patients got saline as a bolus and 12-hour infusion.

The included patients with an mRS of 0-3. Reflecting a shift in practice during the trial, about one-third of patients got tenecteplase.

Subgroup analysis by age, baseline NIHSS, thrombolysis type, and thrombectomy receipt all favored placebo over adjunctive thrombolysis.

Secondary efficacy findings again showed at least numerically better results with placebo, both for 90-day mRS score of 0-1 or return to pre-stroke mRS (40.4% with placebo vs 23.7% with argatroban and 36.1% with eptifibatide) and for an expanded definition with an mRS of 0-2 (61% vs 44.1% and 55.5%, respectively).

In terms of safety, all-cause mortality with argatroban was significantly more common than with placebo (24.1% vs 7.8%, P<0.001). The rate was numerically higher with eptifibatide as well (11.8%), although none of the deaths were deemed related to the study drug. Intracerebral hemorrhage rates trended in the wrong direction with both adjuncts as well.

Limitations of the trial included the single-blind design, low number of argatroban-treated patients, and unknown impact of adjunctive intra-arterial antithrombotic medications in endovascular thrombectomy patients.

The trial "shows that we need to do better at thrombolysis, because it's going to save more brain," Saver concluded. "But it's going to be a difficult challenge to improve upon what the current thrombolytics alone can do."

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