Research Question: Is the combination of once-daily Aspirin and once-daily rivaroxaban more effective in preventing recurrent stroke in patients with essential thrombocythemia in the first year after getting the first stroke as compared to twice-daily Aspirin therapy started one week following stroke?
P- People with Essential Thrombocythemia with acute stroke
I- Aspirin with rivaroxaban
C- Twice daily dose of aspirin
O- Recurrent stroke
T- One year after getting the first stroke
Patients with contraindications against taking apririn, rivaroxaban or hydroxylurea would be ineligible for this study. In addition, patients with a history of major bleed including hemorrhagic stroke would be excluded from this study, as would patients who use non steroidal anti inflammatory drugs (NSAIDs) more than 3 times per week to reduce the risk of bias because of their inhibition of platelet aggregation. Other exclusion criteria would be the use of heparin, fondaperinox, and any medical conditions contraindicating to the use of rivaroxaban; these medical conditions include advanced cirrhotic liver disease with Child Pugh B or C, kidney disease in the form of creatinine clearance less than 30 and pregnant and lactating woman (19, 20,16). Patients with contraindications to cytoreductive drug hydroxyurea would also be excluded because patients with these conditions would be at greater risk as a result of this study than benefit.
Patients will be allocated to different groups using a centralized web based interactive system. This process will make allocation concealment possible. The patients will be allocated to receive with aspirin and rivaroxaban or twice daily aspirin in 1:1 ratio. The study will begin seven days after getting the initial stroke. This aligns with the American Stroke Association guidelines (15) and also with the international consensus of starting anticoagulants after non-haemorrhagic stroke. (16) This study will continue for one year post randomization as the first year is the period of greatest risk for death or having a second stroke 17. The aspirin group patients will be given 100 mg of aspirin twice daily and in the rivaroxaban patients will be given 5 mg of rivaroxaban along with 100 mg aspirin once daily. Patients will not know what they were receiving. Treating clinicians and research assistants and adjudicators of the study will also not be aware of which the patients are receiving. The intervention will begin immediately after the randomization is complete. Patients will undergo follow up every 3 months after discharge from the hospital and information will be collected about TIA, any adverse event major bleeding, minor bleeding episode or general well being. Blood samples will be drawn for Lactate dehydrogenase, lipid profile, and serum creatinine every 3 months. This will ensure that patients are not suffering from adverse effects while they are taking these medications. Some of the adverse effects include suffering from additional kidney damage during their recovery.
When radiologists read MRIs, they will be aware of the category of the patients because the MRIs will show the occurrence or lack thereof of stroke, however both the groups are on oral medication, which will make it possible to blind patients. The data monitoring and safety board will be consulted regularly to ensure that the study ends when it reaches its end point. At the end of the study participants and clinicians will learn their categories, in case the patients incurred adverse effects
The MRIs will be read by radiologists who are located centrally. All the radiologists will receiving training to decrease inter-observer variability. The baseline MRI would be obtained to find out the presence of micrhemorrhages and to detect hemorrhagic strokes. First and second reports will be read by the same radiologist to decrease intra-observer variability. A new infarct would be defined as the incidence of newly diagnosed hypodense image on T1 weighted images or hyodendense image on T2 or FLAIR images of the MRI. T1-weighted, T2-weighted and fluid attenuated inversion recovery (FLAIR) MRI sequences would be completed for participants in the study. As this is a multicentral and multinational study, we would not specify an MRI protocol, but a local MRI protocol would be followed. The same MRI protocol will be followed at the end of the study to decrease within-participant variability. This second MRI at the end of one year after the stroke will be compared to the initial MRI done at the time of admission to the hospital. Radiologists (adjudication committee) reading the MRI will be blinded. The MRIs would be grouped into good and bad quality images. All the participants with good quality images at both stages of the study will be included in the final results.
Information will be collected about the presence or absence of JAK mutation, age, past deep vein thrombosis, diabetes, hypertension, smoking more than 5 cigarettes per day, obesity defined as body mass index more than 30, hyperlipedemia, heart disease including abnormal heart rhythm, high cholesterol and blood lipids. Post hoc analysis will be run on these different groups.
The written informed consent will be obtained from patients. In case of cognitive deficit in the principal, the consent will be obtained from the patient’s next of kin. The informed consent will be taken from patients who have the ability to consent before patients who are unable to consent will be included in the study. The consent will be taken into hospitals by the research assistants. The consent document will be in a simple, non-technical language. The consent document will briefly explain purpose and the purpose of the study, the risk and benefits, the additional testing requirements for this study. The research coordinators will answer all the concerns of the participants. It will be clearly explained that the participants can withdraw their consent to participate at any time during the study.
The risk of bleeding including life threatening bleeding including intracranial bleed and gastrointestinal bleed will be explained in the informed consent document. There is also a risk of discovering incidental finding of microhemorrhages and ischemia of clinical significance including meningiomas, or pituitary lesions by the MRI which will also be explained in the informed consent. If these incidental findings are found, then the information will be provided to the attending physicians and the physicians will be unblinded to the particular patient.
The primary outcome is the incidence of clinically apparent ischemic stroke, defined by standard guidelines, and confirmed by an MRI. The primary secondary outcome is composite cardiovascular mortality, which will measure the combined mortality due to stroke and myocardial infraction, and peripheral vascular disease which would also be defined by standard guidelines. The other secondary outcome would be the overall morality. As the stroke is an important risk for decrease in cognition, we included cognition as the other secondary outcomes would and will be assessed by MoCA and DSS, and standard assessment of global activities in the elderly (SAGE) scores both at the beginning and at the end of the study. (17)
Primary safety outcomes include intracranial haemorrhage, intraocular bleed leading to loss of vision, patients requiring two units or more units of red cells because of bleed, bleed requiring admission to a hospitalization or prolongation of stay in a hospitalization or death due to hemorrhage. (21) Our secondary safety outcomes measures would be hemorrhagic stroke, any other symptomatic bleed in brain except intracranial symptomatic hemorrhage and microhaemorrhages inside brain, gastrointestinal bleed not meeting criteria for primary safety outcome.
Increase in number of platelets in ET, which is associated with increased itching in patients. So change in subjective feeling of itching which would be graded in likert scale from 1-10 by the patients both in the beginning and end of the study.
The analysis will be run using SAS 9.1 version of software. Chi square and tests would be run to analyze categorical and for continuous variables. ANOVA would be used to run inter group comparisons.
This research could have significant clinical and policy implications. Preventing thrombosis is the goal of treatment for these patients. Not only are the patients of ET at much higher risk of developing thrombosis including ischemic stroke, but also stroke increases the likelihood of thrombosis to a great extent. Although some studies have shown the benefits of giving anticoagulants in patients of stroke, because of the lack of evidence in patients with ET these patients continued to be treated with twice daily aspirin and hydroxyurea. If the anticoagulants will prove to prevent additional strokes in these patients as compared to the commonly used aspirin therapy, it could have enormous clinical and economic benefits in healthcare. Furthermore, because the risks of morbidity and mortality increased during the year after patients have suffered from a stroke, it is important to determine the best way of decreasing that risk. If it is possible to ensure that patients will have a safe recovery after they have a stroke, it is likely that they will have better outcomes. When patients get additional strokes during their recovery period, they are less likely to recover lost function after they have suffered from the first stroke.
Future studies could focus on preventing covert stroke and cognitive decline both by clinical and covert stroke in patients with ET. Cost utility analysis and cost effectiveness analysis could be run on the use of anticoagulants with patients of ET.
The research findings could be useful only if they could be incorporated into clinical practice, which can be achieved by the translation of knowledge. The first step for knowledge translation would be identification of the stakeholders to whom we want to translate this knowledge. The main stakeholders would be the neurologists providing specialty care to these patients, the emergency room physicians who generally have the first contact with patients of stroke, family doctors who refer these patients for diagnosis of ET. The other stakeholders would be other researchers, high risk patients with ET and the kin of patients with acute stroke and ET. The researcher physicians will be reached by podcasts, writing blogs for neurology websites, presenting summaries of the research in neurology conerences and submitting the research findings in a Neurology Journal. Physicians would also be invited to teleconferences to disseminate our research finding. Patients of ET and kin of patients would be reached by preparing summaries in the plain language.