COMPARISON OF DUAL ANTIPLATELET THERAPIES POST INTERVENTION ON PATIENTS WHO PRESENTED WITH ISCHEMIC STROKE AND TANDEM CAROTID STENOSIS By Dalton Herbig B.S. RT(R)(VI) A thesis submitted to the School of Radiologic Sciences in collaboration with a research agenda team In partial fulfillment of the requirements for the degree of MASTER OF SCIENCE IN RADIOLOGIC SCIENCES (MSRS) WEBER STATE UNIVERSITY Ogden, Utah December 15, 2023 THE WEBER STATE UNIVERSITY GRADUATE SCHOOL SUPERVISORY COMMITTEE APPROVAL of a thesis submitted by Dalton Herbig B.S. RT(R)(VI) This thesis has been read by each member of the following supervisory committee and by majority vote found to be satisfactory. ______________________________ Dr. Robert Walker, PhD Chair, School of Radiologic Sciences ______________________________ Dr. Laurie Coburn, EdD Director of MSRS RA ______________________________ Dr. Tanya Nolan, EdD Director of MSRS ________________________________ Christopher Steelman, MS Director of MSRS Cardiac Specialist Abstract This study was conducted to see if there was any difference in mortality rates between one dual antiplatelet regimen over another in patients who have undergone thrombectomy for acute ischemic stroke (AIS) with tandem carotid artery stenting (CAS). Patients who have recently had carotid artery stenting require dual antiplatelet therapy (dAPT) to prevent recurrent stroke, and to prevent the stent from occluding. This study aims to see if one type of dual antiplatelet therapy affects patient mortality more than the other. At my facility between January 2019, to February of 2023, it was found that 30 patients have had acute ischemic stroke with carotid artery stenting. Within these 30 patients, the type of antiplatelet therapy, their mortality at 3,6 months, the restoration of flow, and if occlusion of the stent within 48 hours was observed. The data suggests that there is a reduced mortality rate with patients that were treated with clopidogrel and aspirin when compared to no, single, and ticagrelor and aspirin therapies. These results lack statistical power due to the limitation of the sample size and the variables surrounding the etiology of stroke and stroke patients. To gain further insight on the efficiency of different dAPT’s, larger extended trials with tighter parameters should be performed. Introduction Ischemic strokes occur when there is a sudden blockage of one or more of the arteries in the brain. This blockage can be a thrombus or an embolus. Most strokes are caused by an embolic blood clot. These embolics can be from a variety of sources, most commonly from patients with Atrial fibrillation, atherosclerosis, carotid artery disease, or other heart issues. Once the embolic travels up into the brain it eventually gets lodged when the vessels become smaller. The brain tissues distal to the occlusion are then starved of nutrients, mainly oxygen, and those tissues die. Brain cells and their neurons are typically unable to heal themselves and do not reproduce quickly. In the event of an acute neurological injury, damage is often irreversible. The evolution of stroke treatment is relatively new in the world of healthcare. In the 1980’s there were studies being performed for the use of intra arterial therapy agents for large vessel occlusion(LVO)(#1). In 1996, the FDA would approve intra arterial tPA to treat acute ischemic stroke within a small time window of 3 hours(#2). If the tPA didn't dissolve the clot, new techniques were being developed to physically remove it. In 2015, five randomized trials to show the effectiveness of stent retriever devices(#3). Since then there has been developments of the ideal “stent triever”, and developing techniques that involve guidance catheters, balloon occlusion, aspiration, and combinations of each. If a patient who is experiencing a strokes’ last known normal (LKN) was recent, they may receive a thrombolytic. Alteplase (tPA) is the most common thrombolytic and is given to a patient if their last known normal was within 3 hours. Tenecteplase (TNK) is given to stroke patients if their last known normal was within 4.5 hours. These thrombolytics are given in an attempt to dissolve the clot and restore blood perfusion. This does not always work and endovascular mechanical thrombectomy is still required. The carotid artery, the main artery feeding the brain, is where most ischemic stroke causing emboli travel. The Common carotid artery bifurcates at approximately the level of C3-4 into the internal carotid and external carotid artery. The internal carotid artery is responsible for providing the brain tissue with blood and can be affected by atherosclerotic disease. The buildup of plaque can affect the internal lumen of the vessel. Narrowing of the carotid artery can therefore affect blood supply to the brain as well. With the limited perfusion, patients can experience neurological deficits. The intraluminal plaque can also break off and cause a stroke. If a patient has significant carotid stenosis, a carotid endarterectomy can be performed or a carotid stent can be placed to restore normal flow. When compared to one another, there is no significant difference in outcomes after 10 years(#4). It is recommended that patients who have had a newly placed carotid stent be placed on dual antiplatelet therapy. This minimizes the change that the new stent thrombose, but also increases the potential risk of intracranial hemorrhage(#5). When a patient comes in emergently for stroke intervention and is found to also have a tandem carotid occlusion, it poses as a difficult combination of problems for physicians to deal with. Patients who present with acute ischemic stroke, and a tandem carotid occlusion are prone to unfavorable clinical outcomes(#6). Initially, the physician has to remove the emboli causing the stroke. Then they have to decide if the carotid stenosis is significant, or flow limiting, enough to stent. If they are unable to pass the carotid lesion to remove the ischemic blockage, they may opt to stent first. The decision to stent prior to, or after cerebral flow is restored is determined during the procedure, and on a case by case basis. Literature review Documentation: Search engine sources mainly included research articles that were within the last 10 years and also included the words: ischemic, large vessel occlusion, dual antiplatelet therapy, anticoagulation, carotid stenosis, carotid stenting, tandem, mortality, mortality rates, and other research of that sort. Primary search engine used was the Weber State “One Library” search engine along with Google Scholar. There were also references taken from within the found literature that were included. From 2010 to 2020, age adjusted stroke rates decreased by 0.8%(39.1 per 10,000 to 38.8 per 10,000), but deaths caused by strokes increased by 23.8% (129,476 to 160,264). This could be due to the large ratio of population reaching older ages(#7). Looking into the history of acute ischemic stroke has shown that it is rather new in the world of healthcare. Initial treatment of large vessel occlusion acute ischemic stroke was use of tPA within 3 hours of LKN, this was approved by the FDA in 1996. It wouldn't be until 2004 where the merci stent-triever device would be approved by the FDA as a treatment for acute ischemic stroke(#1). Since 2004 New stent-triever devices and new trials have been developed in order to treat acute ischemic stroke. Within the last 20 years, techniques including intra-arterial thrombolysis, stent-triever, and direct aspiration techniques have been developed in order to treat large vessel occlusion acute ischemic strokes(#8). During this timeframe there were studies being performed to determine whether surgical endarterectomy or carotid artery stenting would yield the best outcome for the patient. Subsequently, the role of antiplatelet or dual antiplatelet therapies were being considered and tested in the case of carotid artery stenting(#5,#9). Patients who have had either a CAS or carotid endarterectomy fare similarly when examined after 10 years, with respect to complications such as stroke, myocardial infarction, or death(#4). It has been observed that 10-20% in 2014,(#4,#10) now up to 20-30% in 2023, of patients who come in with acute ischemic stroke symptoms also have tandem carotid artery stenosis(#11). If there is a carotid lesion and there is already arterial access to treat the ischemic stroke, a carotid artery stent can easily be placed. Patients who develop acute stroke symptoms due to an acute carotid artery occlusion can benefit from increased flow from a stent and a direct intra-arterial injection of Urokinase plasminogen activator(#12). Acute stenting of the carotid stenosis during a stroke thrombectomy can be performed safely, this can lead to better patient outcomes(#13,#14). Patients who present with a LVO and a tandem carotid stenosis tend to do worse when compared to patients who present with only an isolated occlusion(#6,#15,#16). A combination of antiplatelet drugs versus a single antiplatelet drug is better in treating AIS or transient ischemic attacks(TIA) (#17,#18,#19,#20). The role of antiplatelet and dual antiplatelet therapies is still being researched with patients with tandem occlusions. Recent limited trials have indicated that patients who have undergone both intracranial stroke thrombectomy and CAS with dual antiplatelet therapy reduces acute recurrent stroke, but increases risk of intra and extra cranial hemorrhage(#3,#6,#11,#13,#14,#16,#21,#22). Patients who undergo mechanical thrombectomy and CAS that receive both dAPT and heparin treatment had significantly higher rates of symptomatic intracranial hemorrhage(#9). A retrospective study performed in Germany between 2007 to 2014 had an in house mortality rate of 19%(#3). Mortality rates from recent studies ranged from 10% up to 39%(#14,#21,#22). Recent developments with this specific etiology require more in-depth analysis and a larger encompassing study. At this point in time, it appears that it is beneficial for patients to receive dual antiplatelet therapy post carotid artery stenting to reduce recurrent stroke and stent occlusion(#23). Because of this, there is also an increased chance of hemorrhage both intracranial and extracranial. The increased length of time that the patient is on dual antiplatelet therapies runs a higher risk of hemorrhage(#23). Methods This study aims to determine if there is any advantage of one dAPT regime over another in the mortality rates at 3 and 6 months on patients who underwent intracranial thrombectomy with tandem carotid artery stenting. Other factors observed were; If TICI 2b flow restoration was obtained during the intervention, and if there was reocclusion of the stent within 48 hours. Patient selection: Patients were selected from a single institution from January 2019 to February of 2023. The patients were selected if they were brought into the interventional angio suite and a mechanical thrombectomy was performed along with a carotid artery stenting in a single session. Patients who received this procedure after February of 2023 were excluded because the 6 month mortality point would not have been reached at time of publication. Patients were prescribed one of the dual antiplatelet therapies to start within 48 hours after intervention. Patients were then separated into two groups, one group who was prescribed clopidogrel (Plavix) and aspirin, the other group prescribed ticagrelor (Brilinta) and aspirin. Those groups’ mortality rates at 3 and 6 months were measured. Based on the difference of mortality rates between the two types of dAPT indicates if one is better for patient outcomes compared to the other. After delving through our department's log of neurovascular interventions, it was found that 30 patients underwent mechanical thrombectomy for TIA and stent placement for CAS. Within those 30 patients, two of them did not receive any dAPT, one received single antiplatelet therapy, 16 patients received clopidogrel and aspirin, and 11 received ticagrelor and aspirin. Limitations: This study is limited due to its sample size. If there was a larger amount of patients that were treated with these specific problems, more of a trend might be observed. Additionally, there are several limitations involving the etiology of stroke; the brain is complex and depending on the area affected, the patient's native collateral system, and time since the stroke occurred can affect the patient's outcome. There was no limitation on patient age, gender, or initial presentation for this study. Patients who are specific to stroke etiology are generally older in age, but there were no restrictions in this experiment. With not eliminating patients on both potential ends of the age spectrum, it accurately reflects the population that requires TIA thrombectomy with tandem CAS. But, without restricting the sample size due to specific limitations can introduce other variables that can affect the outcome statistics. IRB approval was obtained through both the hospital and the academic facility. All patient data was stored on the facility server database, and no patient identifiers were used. In summary, within the last 3 years, 30 patients were selected that meet the criteria of being treated with a mechanical thrombectomy for AIS and a stent placed for carotid stenosis. One patient received a single antiplatelet therapy, two of them did not receive any antiplatelet therapy, and 27 of those patients received either clopidogrel and aspirin, or ticagrelor and aspirin. These patients’ mortalities were then recorded and compared to each other at the 3 and 6 month interval. The selection of patients was not restricted by age, gender, or initial presentation. Patient selection and information was approved by the facility and academic facilities’ IRB. Results Among the 30 patients that met the criteria, one patient received a single antiplatelet therapy, two of them did not receive any antiplatelet therapy, and 27 of those patients received either clopidogrel and aspirin, or ticagrelor and aspirin. 16 of the 27 patients received clopidogrel and aspirin as a dAPT treatment. 11 of the 27 patients received ticagrelor and aspirin. Within the total 30 patients, 5 patients were deceased after 3 months, and 6 patients were deceased at 6 months. Of the 5 patients that were deceased at 3 months, 2 of them did not receive dAPT, and one of them received a single antiplatelet therapy. The other two patients that passed away by 3 months received ticagrelor and aspirin as a dAPT regimen. The additional person who passed away at the 6 month time point was also on ticagrelor and aspirin (see Chart 1.1) It was also noted that post procedure 29 of 30 patients obtained TICI 2b flow restoration, and within 48 hours only 1 patient had stent occlusion. That correlates with a 6.66% mortality rate with patients who have received no antiplatelet therapy. A 3.33% mortality rate with single antiplatelet therapy. 0% mortality rate with Clopiogrel and aspirin dAPT, and mortality rate with ticagrelor and aspirin was 6.66% at 3 months, and 9.99% at 6 months. Overall mortality was 16.66% at 3 months, and 20% at 6 months. It appears that within each category of therapy there is some mortality involved except for the clopidogrel and aspirin dAPT. Overall mortality rate sits at 20% which is similar to the mortality rate found in recent literature(s). The rate of stent occlusion was also relatively low, which is on par with rates seen with other facilities. There was also a low rate (1/30) of stent reocclusion within 48 hours. TICI 2b flow restoration was achieved in all but 1 patient via aspiration, stent-triever thrombectomy, or a combination of both. Patients who present with TIA and a tandem carotid stenosis can be safely treated for both issues in a single intervention session. Restoration of cerebral perfusion can be achieved with a high success rate(#13,#14). Endovascular carotid stent placement can be performed with little occlusion rates given that the patient is placed on the proper antiplatelet therapy. Mortality rates of these patients are proportionate with other facilities(#14,#21,#22). This study is limited due the sample size, but appears to be comparable with other similar studies. Discussion Patients who present with TIA and a tandem carotid stenosis are at a high risk of mortality. Endovascular thrombectomy with carotid stenting can be performed to achieve a TICI 2b reperfusion and restore cerebral flow. dAPT regimes are recommended to these patients post stenting to reduce the risk of recurrent stroke and stent occlusion. This study compared dAPT therapies to see if one combination of antiplatelet drugs worked better in reducing patient mortality when compared to the other. From the presented data it appears that there is a reduced mortality in patients who received clopidogrel and aspirin as a dAPT. No antiplatelet therapy patients and patients who received ticagrelor and aspirin had similar mortality rates (ticagrelor and aspirin slightly more at the 6 month mark). Given that this study was limited in the sample size, this study has low statistical power and may be subject to a false discovery rate. Further research with a larger sample population is required to accurately observe a trend. Large facility or multi facility research should be performed with tighter qualifications to eliminate certain variables that could skew results. Patient mortality rates can have multiple contributors in these circumstances, not just due to which kind of dAPT they are on. In stroke patients the severity, onset, last known normal, and built in collaterals of the patient can affect the treatment path, recovery, and the mortality of the patient. Every patient is unique and each situation is unique. In general, patients with more comorbidities are more probable to have a worse outcome after any hospitalization. The general age of the population who are experiencing strokes are older in age and are more prone to health issues in addition to the TIA(#22). Physicians can achieve a TICI 2b flow restoration score but the patient may not recover as anticipated. Patients’ families may request that everything be done despite a developed stroke and a poor prognosis. The mortality probability of the patient can be affected by many factors, which all can affect one another. Initially, the severity of the stroke can range from minor to severe. The larger and more proximal the occlusion, the more brain tissue that will go without oxygen. Then the onset of the stroke and time to intervention will determine how much brain tissue can be recovered, and the last known normal of the patient can give medical personnel a time estimate of when the stroke occurred. This information can influence medical decisions, such as administration of clot busting medications(#1). The patient’s vessel collateral system can help buy time by taking over the main arteries duties and supply the infarcted tissues with oxygen, delaying cell death. All of these factors, in addition to the overall health of the patient with their comorbidities, can predict a patient's outcome both before and after intervention with restoration of flow. In order to narrow down patient outcomes and mortality rates due to dAPT regimes, the new study would have to be much more restrictive in patient selection. The patient's history and preexisting conditions should be taken into account. Along with that, the study would most likely have to encompass several large institutions or a national database. Selection and exclusion parameters would have to be much tighter, and performance techniques should be similar. For example, the flow restoration would have to be measurable such as a TICI score flow restoration. Also, and ideally, the stent parameters should be similar as well, like the same type of stent used, or the same material. There are many variables that should be considered. Necessary steps should be taken to try and remove as much of those as possible in order to accurately determine whether or not one of the dAPT’s is or is not trending towards more or less mortalities. 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