The primary efficacy objective of the MOST trial is to determine if argatroban (100µg/kg bolus followed by 3µg/kg per minute for 12 hours) or eptifibatide (135µg/kg bolus followed by 0.75µg/kg/min infusion for two hours) results in improved 90-day modified Rankin scores (mRS) as compared with placebo in acute ischemic stroke (AIS) patients treated with standard of care thrombolysis (0.9mg/kg IV rt-PA or 0.25mg/kg IV tenecteplase or TNK) within three hours of symptom onset. Patients may also receive endovascular thrombectomy (ET) per usual care. Time of onset is defined as the last time the patient was last known to be well.

Inclusion Criteria:

1. Acute ischemic stroke patients
2. Treated with 0.9mg/kg IV rt-PA or 0.25mg/kg IV TNK within 3 hours of stroke onset or time last known well
3. Age ≥ 18
4. NIHSS score ≥ 6 prior to IV thrombolysis
5. Able to receive assigned study drug within 60 minutes but no later than 75 minutes of initiation of IV thrombolysis

Exclusion Criteria:

1. Known allergy or hypersensitivity to argatroban or eptifibatide

2. Previous stroke in the past 90 days

3. Previous intracranial hemorrhage, neoplasm, subarachnoid hemorrhage, or arterial venous malformation

4. Clinical presentation suggested a subarachnoid hemorrhage, even if initial CT scan was normal

5. Any surgery, or biopsy of parenchymal organ in the past 30 days

6. Trauma with internal injuries or ulcerative wounds in the past 30 days

7. Severe head trauma in the past 90 days

8. Systolic blood pressure persistently >180mmHg post-IV thrombolysis despite antihypertensive intervention

9. Diastolic blood pressure persistently >105mmHg post-IV thrombolysis despite antihypertensive intervention

10. Serious systemic hemorrhage in the past 30 days

11. Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with INR >1.5

12. Positive urine or serum pregnancy test for women of child bearing potential

13. Glucose <50 or >400 mg/dl

14. Platelets <100,000/mm3

15. Hematocrit <25 %

16. Elevated pre-thrombolysis PTT above laboratory upper limit of normal

17. Creatinine > 4 mg/dl

18. Ongoing renal dialysis, regardless of creatinine

19. Received Low Molecular Weight heparins (such as Dalteparin, Enoxaparin, Tinzaparin) in full dose within the previous 24 hours

20. Abnormal PTT within 48 hours prior to randomization after receiving heparin or a direct thrombin inhibitor (such as bivalirudin, argatroban, dabigatran or lepirudin)

21. Received Factor Xa inhibitors (such as Fondaparinaux, apixaban or rivaroxaban) within the past 48 hours

22. Received glycoprotein IIb/IIIa inhibitors within the past 14 days

23. Pre-existing neurological or psychiatric disease which confounded the neurological or functional evaluations e.g., baseline modified Rankin score >3

24. Other serious, advanced, or terminal illness or any other condition that the investigator felt would pose a significant hazard to the patient if rt-PA, TNK, eptifibatide or argatroban therapy was initiated

    a. Example: known cirrhosis or clinically significant hepatic disease

25. Current participation in another research drug treatment or interventional device trial - Subjects could not start another experimental agent until after 90 days

26. Informed consent from the patient or the legally authorized representative was not or could not be obtained

27. High density lesion consistent with hemorrhage of any degree

28. Large (more than 1/3 of the middle cerebral artery) regions of clear hypodensity on the baseline CT Scan. Sulcal effacement and/or loss of grey-white differentiation alone are not contraindications for treatment