Aim 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)
Design Open label, multi-centre randomised controlled trial
Setting UK general practices
Sample size 25,210 patients (12,605 per arm). A total of 1,827 major vascular events overall are required.
Eligibility Inclusion Criteria
1. Males and females aged 18 years and over at the date of screening
2. Subjects with CKD (reduced eGFR and/or albuminuria) defined as: • estimated glomerular filtration rate \[eGFR\] \<60mL/min/1.73m2 for at least 90 days, and/or • kidney disease code on the GP electronic patient AND most recent eGFR in CKD-defining range (\<60mL/min/1.73m2), and/or • albuminuria or proteinuria (defined as urine albumin:creatinine ratio \[ACR\] ≥3mg/mmol, and/or urine protein:creatinine ratio \[PCR\] ≥15mg/mmol, and/or +protein or greater on reagent strip)
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 eGFR category 5
2. Subjects with pre-existing cardiovascular disease (angina, myocardial infarction, stroke, transient ischaemic attack (TIA), 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 other than CKD
4. Subjects currently prescribed anticoagulants or antiplatelet agent, or taking over the counter (OTC) aspirin continuously
5. Subjects who are currently and regularly taking other drugs with a potentially serious interaction with aspirin
6. Subjects with a known allergy to aspirin or definite 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 other conditions which in the opinion of their General Practitioner (GP) would preclude prescription of aspirin in routine clinical practice, for example significant anaemia or thrombocytopenia.
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 clinical trial of an investigational medicinal product or who have taken part in such a trial in the last three months (Covid-19 vaccine studies are acceptable)
Interventions Suitable participants will be randomised to receive: 75mg non-enteric coated or dispersible aspirin once daily in addition to their usual medication; or no additional treatment and avoidance of aspirin.
Duration The trial will continue until at least 1,827 adjudicated primary endpoint events (major vascular events) have occurred, or before if the trial is discontinued after the internal pilot or for any other reason.
Randomisation and blinding Eligible participants 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.
Follow-up Data on potential CVD and bleeding outcomes will be collected electronically from GP records and national hospitalisation and mortality records. An adjudication panel will assess the information blind to allocation.
Patients will complete an annual quality of life questionnaire (EQ5D).
Outcomes. 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 (MI), non-fatal stroke and cardiovascular death (excluding confirmed intracranial haemorrhage and other fatal cardiovascular haemorrhage).
Secondary outcome measures (all time to event except quality of life)
Efficacy
1. Death from any cause
2. Composite outcome of major vascular event or revascularisation (coronary and non-coronary)
3. Individual components of the primary composite endpoint
4. Health-related quality of life
Safety
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). Intra-cranial haemorrhage will be sub-categorised as traumatic or non-traumatic.
3. Fatal and non-fatal (reported individually and as a composite) major extracranial haemorrhage: i) upper gastrointestinal; ii) lower gastrointestinal; iii) sight-threatening ocular; iv) multiple trauma; v) other (adjudicated).
4. Clinically relevant non-major bleeding if hospitalised (adjudicated).
5. Composite outcome of fatal and non-fatal major extracranial haemorrhage and clinically relevant non-major bleeding (if hospitalised).
Tertiary (exploratory) outcome measures (all time to event except hospitalisation)
1. Transient ischaemic attack
2. Unplanned hospitalisation
3. Hospitalisation with heart failure
4. New diagnosis of cancer (colorectal/other)
5. Death due to cancer (where cancer is the underlying cause of death)
6. CKD progression
7. New diagnosis of dementia
8. Major non-traumatic lower limb amputation
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.
All primary, secondary and tertiary 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 and tertiary endpoints will be assessed by arm using summary statistics (e.g. Pearson's χ² tests) in the ITT population.
The amount of missing data and reasons for the incompleteness 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.
