Background and Objective: Thrombin inhibitors such as Argatroban in combination with full-dose IV-tPA are currently being tested in a series of clinical trials for acute ischemic stroke. A single-arm, phase IIa study (ARTSS-1) of 65 patients treated with low-dose Argatroban + IV-tPA in either the 3 or 4.5 hour treatment window demonstrated an overall sICH rate of 4.6% and 40% complete recanalization within 2-hours. The objective of the study was to assess safety in a matched group of IV-tPA alone patients.
Methods: pPAIRS performs a post-hoc Euclidean matching of subjects on factors of choice and excludes outliers when no close match is found. We applied these techniques to compare outcomes of Argatroban+tPA treated subjects from ARTSS-1 with tPA treated subjects from NINDS. Matching factors were NIHSS, age, glucose, race, gender, hemisphere, and subtype. Outcomes were sICH, death and mRS 0-1, 0-2 at day 7 and 90.
Results: Of the 65 Argatroban+TPA patients, 55 and 44 had good NINDS matches at day 7 and 90, respectively. Rates of sICH were identical at both day 7 and 90 between ARTSS-1 and NINDS (3.6% and 2.3%). Mortality was not significantly different (5.5% vs. 3.6% at day 7; p=1.00; and 11.4% in each group at day 90). There was a non-significant trend for higher percent of mRS 0-1 (36.4% vs. 32.0%, p=0.814) and 0-2 (47.7% vs. 43.2%, p=0.823) at day 90 in the ARTSS-1 patients that was not present at day 7. The mRS 0-2 trend remained after excluding ARTSS-1 patients treated with tPA between 3-4.5 hours (see table).
Conclusion: There is no evidence for significantly increased mortality or symptomatic hemorrhage after addition of low dose Argatroban compared to a NINDS population with similar baseline characteristics particularly in those tPA-treated within 3 hours. A non-significant trend emerged at 90 days for 14% relative improvement in functional outcomes. A larger, Phase IIb, randomized trial (ARTSS-2) is ongoing to determine whether these trends reflect a true treatment effect.