Title: Aspirin To Target Arterial Events In Chronic Kidney Disease (ATTACK)
Funder: Department of Health and Social Care

Abstract: TITLE Aspirin To Target Arterial events in Chronic Kidney Disease ACRONYM ATTACK CHIEF INVESTIGATORS Dr Hugh Gallagher Professor Paul Roderick OBJECTIVES To test the hypothesis that the addition of 75mg aspirin once daily to usual care reduces the risk of major vascular events in patients with chronic kidney disease (CKD) who do not have pre-existing cardiovascular disease (CVD) TRIAL CONFIGURATION Open label, multi-centre study SETTING Primary care SAMPLE SIZE ESTIMATE 24,684 patients (12,342 per arm). A total of 1,779 major vascular events overall are required. NUMBER OF PARTICIPANTS We expect to invite approximately 165,000 patients in order to recruit the 24,684 required. Of these 12,342 will be randomised to aspirin 75 mg once daily and 12,342 to no additional treatment. INCLUSION CRITERIA 1.Males and females aged 18+ at the date of screening 2.Subjects with diagnosed CKD (estimated glomerular filtration rate [eGFR] <60mL/min/1.73m2 for at least 90 days and/or urine albumin:creatinine ratio [ACR] >/=3mg/mmol for at least 90 days) 3.Subjects who are willing to give permission for their paper and electronic medical records to be accessed by trial investigators 4.Subjects who are willing to be contacted and interviewed by trial investigators 5.Subjects who can communicate well with the investigator or designee, understand the requirements of the study and understand and sign the written informed consent EXCLUSION CRITERIA 1.Subjects with CKD GFR category 5 2.Subjects with pre-existing cardiovascular disease (angina, myocardial infarction, stroke, transient ischaemic attack, significant peripheral vascular disease, coronary or peripheral revascularisation for atherosclerotic disease) 3.Subjects with a current pre-existing condition associated with increased risk of bleeding 4.Subjects currently prescribed anticoagulants or antiplatelet agent 5.Subjects who are currently taking drugs with a clinically significant interaction with aspirin 6.Subjects with a known allergy to aspirin or a previous clinically important adverse reaction 7.Subjects with poorly controlled hypertension (systolic blood pressure (BP) =180 mmHg and/or diastolic BP =105 mmHg) 8.Subjects with anaemia (haemoglobin [Hb] <100g/L or anaemia disproportionate to current level of kidney function) 9.Subjects who are pregnant or likely to become pregnant during the study period 10.Subjects with malignancy that is life-threatening or likely to limit prognosis, other life-threatening co-morbidity, or terminal illness 11.Subjects whose behaviour or lifestyle would render them less likely to comply with study medication 12.Subjects in prison 13.Subjects currently participating in another interventional clinical trial or who have taken part in a trial in the previous three months DESCRIPTION OF INTERVENTIONS Suitable participants will be randomised to: receive 75mg non-enteric coated aspirin once daily in addition to their usual medication; or no additional treatment DURATION OF STUDY The trial will continue until 1,779 major vascular events have occurred (this is anticipated 6 years after the recruitment start date, or 2.5 years following the recruitment end date) RANDOMISATION AND BLINDING Eligible participants, based on results of blood tests taken at screening, will be randomised (open label randomisation) 1:1 to general practitioner (GP) prescription of aspirin vs. no prescription, stratified by age, diabetes and CKD severity PRIMARY OUTCOME MEASURE Time to first major vascular event from the date of randomisation. A major vascular event is defined as a primary composite outcome of non-fatal myocardial infarction, non-fatal stroke and cardiovascular death (excluding confirmed intracranial haemorrhage). SECONDARY OUTCOME MEASURES 1.Composite outcome of intracranial haemorrhage (fatal and non-fatal), fatal extracranial haemorrhage and non-fatal major extracranial haemorrhage (adjudicated) 2.Fatal and non-fatal (reported individually and as a composite) intracranial haemorrhage comprising: i) primary haemorrhagic stroke (to distinguish from haemorrhagic transformation of ischaemic stroke); ii) other intracranial haemorrhage (adjudicated) 3.Fatal and non-fatal (reported individually and as a composite) major extracranial haemorrhage: i) vascular-procedural; ii) vascular-non-procedural; iii) gastrointestinal; iv) genitourinary; v) respiratory; vi) pericardial; vii) other viii) undetermined) (adjudicated) 4.Clinically relevant non-major bleeding 5.Death from any cause 6.Composite outcome of major vascular event or revascularisation (coronary and non-coronary) 7.Individual components of the primary composite endpoint 8.Transient ischaemic attack 9.Unplanned hospitalisation 10.New diagnosis of cancer (colorectal/other) 11.CKD progression 12.Health-related quality of life STATISTICAL METHODS The primary outcome measure of time to first major vascular event will be analysed for the intention-to-treat (ITT) population. Deaths from other causes (including fatal bleeding) will be treated as competing events. Patients who do not experience a major vascular event will be censored at the date of last follow-up. As non-fatal major bleeding and anticoagulation are events which, in the intervention arm, may lead to aspirin cessation, sensitivity analyses of the primary outcome measure (for the ITT population) will also include: 1.Censoring patients who experience non-fatal major bleeding, clinically relevant non-major bleeding , or anticoagulation at the date of the event (whichever occurs first). 2.Censoring patients who experience non-fatal major bleeding at the date of the event. All primary and secondary time to event outcomes will be described using Kaplan-Meier curves or Cumulative Hazard plots for time to event outcomes involving competing risks for the ITT population. Analyses of time to event outcomes will be performed using Cox proportional hazards models or Competing Risk regression models, both unadjusted and adjusted for stratification factors: age, diabetes and CKD severity. The adjusted Competing Risk regression model for time to first major vascular event, with deaths from other causes (including fatal bleeding) treated as competing events, and patients who do not experience a major vascular event censored, will form the primary endpoint analysis model. Other secondary endpoints will be assessed by arm using summary statistics (e.g. Pearson’s ?² tests) in the ITT population . The amount of missing data and reasons for the missingness will be explored and presented overall i.e. not by group. If the amount of missing data is deemed too high and if appropriate (i.e. assuming the missing data is either missing at random [MAR] or missing completely at random [MCAR] and censoring assumed to be non-informative), multiple imputation will be performed accordingly, for which all covariates included in the multivariable model, together with the censoring/event indicator and the cumulative baseline hazard will be included in the multiple imputation model.

Lay abstract: WHAT IS CHRONIC KIDNEY DISEASE (CKD)? CKD is a common condition where the kidneys don’t work as well as they should. The word “chronic” means long-term rather than serious. CKD affects as many as one in eight adults in the UK. It is particularly common in older people and in those with diabetes and high blood pressure. We diagnose CKD using a blood test (to measure kidney function) and a urine test (to measure if the kidneys are leaking protein). Most people are unaware of the early stages of kidney disease unless it their doctor mentions it. Few people have severe CKD that requires kidney dialysis or a transplant, but all people with CKD are at increased risk of heart attack and strokes (“cardiovascular disease”). 2-3% of people with CKD will have a heart attack or stroke every year. This is why CKD is so important, and why we urgently need to find ways to reduce these risks. WHEN DO WE USE ASPIRIN TO PREVENT CARDIOVASCULAR DISEASE? Heart attacks and strokes are usually caused by small blood clots. Aspirin reduces the chance that clots will form in the blood. Studies in people with previous heart attack or stroke show that aspirin prevents further attacks. As a result aspirin is recommended for people (both with CKD and without CKD) who have already had a heart attack or stroke. Treatment with aspirin can cause side effects and in particular an increased tendency to bleed. Before we can recommend aspirin treatment to prevent a first heart attack or stroke in people with CKD we need to be completely sure that the benefits of treatment outweigh any risks. We already have some evidence that aspirin is effective in preventing a first heart attack and stroke in people with CKD, but it is not conclusive. The risks of bleeding with aspirin may also be higher in people with CKD. The National Institute of Health and Care Excellence (NICE) therefore recommended that a definitive research study was needed. WHAT IS THE PURPOSE OF THIS STUDY? This study will tell us whether aspirin is effective in preventing a first heart attack or stroke in people with CKD and whether the benefits of treatment outweigh any risks. HOW WILL THE STUDY WORK? People with CKD who have not had a heart attack or stroke will be invited to their own practice to discuss the study. The research team will check their medical history and send a blood and urine test to assess the level of CKD. This is known as screening and is the only face-to-face visit. The test results will be reviewed by the study team. If people are suitable and consent to take part they will be allocated at random to: - be prescribed low-dose aspirin 75mg once daily (in addition to their regular medication), or - continue with their regular medication alone We will recruit around 24,500 people from across England and follow them for up to 6 years. The study investigators will analyse GP and hospital electronic records to find out whether people in the study have had a cardiovascular event or clinically significant bleeding. Study participants will also be contacted annually by letter/email and asked to report their health status. At the end of the study we will have information about a large group of people with CKD who have taken aspirin regularly and another group of people with CKD who have not taken aspirin regularly. If we find differences in the rates of heart attack, stroke or bleeding between these two groups we can put these differences down to the effects of aspirin. This will help us to decide how best to treat people with CKD in the future. WHY IS THE STUDY IMPORTANT We believe that the results of this trial (whether positive or negative) will be extremely important for the NHS: - if aspirin is beneficial, then treatment will be immediately available to about 3 million people with CKD. We estimate that this will prevent around 50,000 heart attacks and strokes over five years - we believe that 1 million people in the UK with CKD are already taking aspirin to prevent a first heart attack or stroke. If the study shows no benefit then we will have firm evidence that they should stop taking it We believe that this trial is also very important as it may save the NHS a large amount of money. This is because aspirin is an inexpensive medication and the costs to the country of heart attacks and strokes in people with CKD are extremely high (up to £1 billion every year). HOW HAVE PATIENTS/CARERS BEEN INVOLVED? A kidney patient who helped to choose the research topic at NICE is a member of the team who applied for funding. The funding application was reviewed with primary care patient representatives from the Wessex area and with kidney patients from St Helier Hospital, helping us to learn from the experiences of people with both early and advanced kidney disease. Patients and carers are represented on our Trial Steering Committee and Trial Management Group. A team of patients and carers has reviewed our Patient Information Sheet.

Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: CARDIOVASCULAR;RENAL AND UROGENITAL;STROKE