Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue-Type Plasminogen Activator in Acute Ischemic Stroke-Full Dose Regimen Stroke Trial
Interview Conducted by Mark N. Rubin, MD

Dr. Rubin: If you do not mind, Dr. Adeoye, I would like to get down to brass tacks. Where is the best place to eat in Cincinnati? 
Dr. Adeoye: The important stuff! It’s a bit pricey but my favorite place by far is an Italian restaurant called Nicola’s. I don’t get to go often but always good for a special dinner, like every time colleagues visit Cincinnati and I get to pick where we go.

Dr. Rubin: What would you like readers to know about you? 
Dr. Adeoye: I’m a very proud father of two incredible children, ages 5 and 8. Maybe they won’t be so incredible in about 10 years but for now it’s pretty fantastic.

Dr. Rubin: What was the research question you wanted to answer with this trial? Please explain the interventions trialed and the rationale for getting at this question.  
Dr. Adeoye: Our goal was to estimate the safety of combining full dose tPA with eptifibatide in ischemic stroke patients treated with tPA within three hours of symptom onset. We had previously studied escalating doses of half dose (0.45mg/kg) and two thirds dose (0.6mg/kg) tPA combined with eptifibatide. Those combinations were safe with regard to symptomatic ICH rates. Being able to use full dose tPA (i.e., standard of care) in a phase III trial would be simplest to execute, and if safe may be most likely to show benefit given the possibility of improved lysis compared to lower doses of tPA. So, we sought to estimate whether such a combination would be safe enough to pursue in a large trial.

Dr. Rubin: How many sites were involved? Was enrollment protocol standardized across all sites? How did you herd so many cats (e.g., coordinate with so many physicians)? How did you ensure that participation in the study did not delay the use of standard tPA?  
Dr. Adeoye: Luckily, we were able to use eight hospitals in the Greater Cincinnati region to complete enrollment in the study. All hospitals had a standardized protocol for managing tPA treated patients. Fortunately, the monitoring and clinical care for the combination patients is essentially the same as that for tPA treated patients. To ensure we didn’t delay tPA administration, we encouraged treating physicians to proceed as rapidly as possible with initiation of tPA. Once the bolus was in and infusion started, THEN we approached the patient or family regarding participation in the study. 

Dr. Rubin: Why eptifibatide? Any reason other than it is not abciximab?
Dr. Adeoye: It’s definitely not abciximab which may have an anti-thrombotic effect for days after it’s been discontinued. There are multiple 2b/3a molecules beyond the ones that are well known. Eptifibatide was one of the early ones specifically developed to ensure rapid inhibition of platelet aggregation (within 15 minutes), a short half-life (~2 hours) and rapid dissociation from platelets with 50% restoration of platelet function within 2-4 hours of discontinuation. A series of papers by Drs. Robert Scarborough and David Phillips in the 1990s detail this development. In the context of stroke, these properties offer a quick on/quick off advantage that when combined with tPA allows augmentation of thrombolysis without a prolonged anti-thrombotic effect that may lead to symptomatic ICH.

Dr. Rubin: This study seemed to have relatively complex enrollment. Standard tPA was started in all patients soon after arrival to the hospital and you had 40 minutes to enroll the patient after tPA was started; how were you able to inform patients and get consent to participation within that time frame? What were the greatest challenges?
Dr. Adeoye: Actually, I think we were pretty fortunate in conducting this study. The protocol is fairly straightforward and investigators were able to adhere to the protocol without difficulty. As with any acute stroke trial, the challenge is in administering standard therapies rapidly while also obtaining consent and initiating study procedures in a timely manner.

Dr. Rubin: What is the one-sentence take-away for readers? Please comment on efficacy and safety of the intervention.  
Dr. Adeoye: The addition of eptifibatide to tPA in ischemic stroke appears to be safe in the doses we’ve studied and justifies a larger trial to determine it if improves stroke outcomes.

Dr. Rubin: What is the next step? 
Dr. Adeoye: We’ve submitted an application to the NIH for a Phase III trial called MOST (Multi-arm Optimization of Stroke Thrombolysis). This is a collaborative effort with me and Dr. Joe Broderick in Cincinnati and Drs. Andrew Barreto and Jim Grotta in Houston. We will use an adaptive design to determine whether eptifibatide plus tPA or argatroban plus tPA result in better outcomes than tPA alone for ischemic stroke.

Dr. Rubin: I understand that further studies looking at combinations of lytics are planned or underway. How does eptifibatide +tPA fit in the armamentarium in the era of data-supported efficacy of endovascular reperfusion therapies? 
Dr. Adeoye: That’s a great question. The aggregate data for the trials published in the past year showed that the overall TICI 2b/3 recanalization rate in endovascular patients was about 67%. That means a third of patients receiving endovascular therapy had inadequate recanalization/reperfusion. Our goal in the coming years is to determine whether eptifibatide may improve these recanalization rates. Hopefully, we can establish a role for eptifibatide in augmenting recanalization rates in patients treated with endovascular therapy.

Dr. Rubin: Can Andy Dalton win in the playoffs? 
Dr. Adeoye: It’s best not to tempt fate. No comments.