Reducing the Burden of Cardiovascular Events With Antiplatelet Therapy in Patients With IntraCerebral Haemorrhage

Reducing the Burden of Cardiovascular Events With Antiplatelet Therapy in Patients With IntraCerebral Haemorrhage.

BEAT ICH will be a pragmatic, randomised, placebo-controlled, blinded, superiority clinical trial aiming to recruit 5676 patients aged ≥18 years who survive ICH and assign them 1:1 to starting antiplatelet monotherapy (Aspirin 75 mg od) versus placebo for the entire duration of the trial for preventing MACE. Recruitment duration is for 2.5 years. The duration of the medication and follow-up will vary based on recruitment timeline. If recruited during the first year of the trial, the patient will take the medication for three years or until the trial ends or an event occurs, with a matching follow-up period. If recruited towards the end of the trial, he/she will take the medication for six months and be followed up for the same duration. The trial's follow-up duration is three years. The patients will be recruited for 2.5 years, and the last recruit will have a minimum follow-up of six months. No new patients will be recruited within the last six months of the trial, but all the patients will be followed up until the end of the trial.

Stroke is the second leading cause of death and disability globally. Intracerebral haemorrhage (ICH) accounts for 10% to 15% of strokes in high-income countries and 20% to 50% in developing countries. The proportion of ICH ranges from 19% to 41% in India and is higher in Eastern India. Recurrent stroke rates are high worldwide; 15% in India (Kolkata), 41% in China, 6 and 13% in Taiwan.

ICH patients are at a risk of recurrent stroke (ICH and ischaemic) and other serious cardiovascular events, and yet there is no consensus regarding starting antiplatelet drugs for secondary prevention. RESTART is the only trial (pilot) that studied antiplatelet therapy and showed a decrease in recurrent ICH compared to no antiplatelet therapy, with a median follow-up of 2 years (IQR [1·0-3·0]). The recurrence rates were 4% in the intervention group versus 9% in the control group. There is no large stroke trial which has addressed this question.

Hence, plan is to initiate the BEAT-ICH trial, a randomized placebo-controlled trial of ICH patients where intervention arm patients will receive antiplatelet monotherapy (Aspirin 75mg) and the control arm will receive a placebo. The primary outcome will be determining whether antiplatelet monotherapy provides a net reduction in major adverse cardiovascular and cerebrovascular events (MACE) in the long term in ICH patients.

Trial Population:

This multi-centric study will be conducted at 50 stroke centres in India associated with the INSTRuCT Network. All patients presenting with symptoms of stroke to the hospital and admitted to the stroke units will be screened for eligibility and if met, will be included in the study. The BEAT ICH trial intends to recruit 5676 patients.

Study design:

Each site will have a team of neurologists (Principal Investigator and Co-Investigators) and a site coordinator. All ICH patients admitted to stroke and neurology wards, Outpatient department (OPD) or Inpatient Department (IPD) after 24 hrs to 3 months will be screened for eligibility by the image-conformed haemorrhagic stroke by the site neurologist.

Investigators will collect complete information about patients' demographics, comorbidities, functional status (US National Institutes of Health Stroke Scale score (NIHSS) and the modified Rankin Scale mRS)), previous antithrombotic therapy, medical history, medication history (at the time of stroke and at the time of randomisation), and intracerebral haemorrhage (image confirmed), vitals and assessments and hematoma details into a database via a secure web interface with in-built validation to ensure complete baseline data before randomisation.

Each patient will undergo brain imaging by Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) as part of routine care at the time of ICH before enrolment. In case of any events, a second CT/MRI scan will be performed to assess for haematoma. All images will be saved in Digital Imaging and Communications in Medicine (DICOM) format and uploaded to the trial's Picture Archiving and Communication System (PACS) server.

After obtaining the consent form, Data will initially be recorded on paper case record forms (pCRF) and later entered into the electronic database. Patients not meeting the trial's eligibility criteria (screen failures) will also be captured in the database. All the recruited patients will be covered under comprehensive insurance for the entire trial duration. Randomisation will be initiated ≥24 hours after ICH onset up to 3 months, provided ICH growth has stopped by 24 hours after onset, followed by the investigational product (Aspirin/placebo) for the entire trial duration. All patients will receive additional standard care as per current gulidelines along with the intervention. Patients in the intervention arm will receive Aspirin 75 mg daily, and the control arm will receive a placebo tablet of similar shape, size, and colour daily. Both investigational products will be pills that look similar in appearance. Pharmaceutical company will centrally manufacture, label, and dispense the investigational products under the supervision of the pharmacologist at Christian Medical College and Hospital (CMCL). Since this trial is triple-blinded, the investigator, coordinator, and patient will be blinded to the allocated study treatment. Only the pharmacologist will decode in case of an event requiring a medication change in an emergency.

Each site will have a stock for a duration of one year, with new investigational products delivered yearly or based on prior consumption and follow-up requirements. Each site is expected to have a dedicated IP room for this purpose. Once delivered, the site will handle the storage, dispensing, and destruction of the investigational products, unused IP, and returned kits under the hospital's waste disposal management protocols with strict supervision.

The duration of the medication and follow-up will vary based on recruitment timeline. If recruited during the first year of the trial, the patient will take the medication for three years or until the trial ends or an event occurs, with a matching follow-up period. If recruited towards the end of the trial, he/she will take the medication for six months and be followed up for the same duration. The trial's total duration is three years. The patients will be recruited for 2.5 years, and the last recruit will have a minimum follow-up of six months. No new patients will be recruited within the last six months of the trial, but all the patients will be followed up until the end of the trial.

All patients will remain in the trial until the end of the study period (3 years to the max)/event/death/withdrawal. If a patient develops an event, the investigational product will be stopped, and treatment will be initiated based on the event and clinical guidelines. Unused investigational products will be returned to the site. If required, the trial pharmacologist will handle decoding after an event. Site research staff will capture all event-related data and submit it to the database and the site ethics committee for review. The central independent event adjudication committee will also review this data. In case of patient withdrawal or death, the investigational product will also be returned to the site. All patients will be analysed using the intention-to-treat principle, even if they withdraw at any point during the trial.

Patients will be called for face-to-face visits every 3 months to dispense the investigational product. Kits will be labelled as BEAT-ICH trial medication, with a unique kit number for identification for each patient. Each kit will contain 100 tablets, including a buffer of 10 tablets for delayed visits/buffer dose. The site coordinators will call the patient 15 days before the visit as a reminder to come to the hospital to take the next batch of IP. Monthly telephonic follow-ups will ensure medication adherence and detect events. Patients will be encouraged to report events during the interim follow-up period. At each visit, patients will return used kits and unused medication (expected return of approximately 10 tablets on every three-month visit) to monitor medication adherence.

The need for this study:

The BEAT-ICH trial has the potential to reduce the recurrent stroke rate and MACE after ICH. In addition, this trial will address the important question of the safety of antiplatelet use in ICH patients. If completed, this trial can change Clinical practice and guidelines globally, as aspirin is a low-cost drug that can be provided at all levels of healthcare in India.

Inclusion Criteria:

• Age ≥18 years
• First-ever Intracerebral Haemorrhage
• Presenting ≥24 hrs up to 3 months of stroke symptoms confirmed by brain imaging
• CT /MRI confirming Intracerebral Haemorrhage
• Alive ≥24 hours after non-traumatic ICH

Exclusion Criteria:

• ICH is known to be due to trauma, a structural cause (e.g., aneurysm, arteriovenous malformation, cerebral cavernous malformation, venous thrombosis, or tumour), or haemorrhagic transformation of cerebral infarction
• Glasgow coma score ≤5
• Taking any antiplatelet or anticoagulant therapy 15 days prior to randomization.
• Women pregnant, breastfeeding, childbearing potential, and not using contraceptives
• Enrolled in any other clinical trial
• Sick or compromised patients with life expectancy of less than a year
• Geographical or other factors that prohibit long-term follow-up