Introduction
Background
Rationale
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Fatal bleeding events are uncommon overall. A 2016 meta-analysis found that although aspirin increased the risk of gastrointestinal (GI) bleeding by 60% there was no increase in fatal bleeds [32], although far higher rates of fatal or disabling bleeding in the elderly have been reported in an unselected high risk secondary prevention cohort (including some taking dual antiplatelet therapy) [33].
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It may be possible to mitigate the bleeding risk, but data on gastroprotection have not been reported consistently in the primary prevention literature. Proton pump inhibitors (PPI) reduce the risk of peptic ulcer in at-risk individuals treated with low-dose aspirin by approximately 80% [34]. There is also evidence that H2 antagonists reduce low-dose aspirin-associated bleeding in high risk users [35].
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Fatal CV events are more common. The 30-day day mortality in the survivors of a first MI is around 5% [36]. UK national data for 2010 indicate a 30-day case fatality rate for MI of 31% overall and 12% in those admitted to hospital [37]. However, in the general population, aspirin does not appear to reduce overall CV mortality [31, 38].
Objectives
Primary objective
Secondary objectives
Trial design
Methods: participants, interventions and outcomes
Study setting
Eligibility criteria
• Males and females aged 18 years and over at the date of screening • Subjects with CKD (reduced eGFR and/or albuminuria) defined as: o Estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2 for at least 90 days, and/or o Kidney disease code on the GP electronic patient AND most recent eGFR in CKD-defining range (< 60 mL/min/1.73 m2), and/or o Albuminuria or proteinuria (defined as urine albumin:creatinine ratio [ACR] inmg/mmol, and/or urine protein:creatinine ratio [PCR] inine mmol, and/or + protein or greater on reagent strip)* • Subjects willing to give permission for their paper and electronic medical records to be accessed and abstracted by trial investigators for the duration of the trial • Subjects willing to be contacted and interviewed by trial investigators should the need arise for adverse event assessment • Subjects able to communicate well with the investigator or designee, to understand and comply with the requirements of the study and to understand and sign the written informed consent * where albuminuria measurements are not available KDIGO state that measurements of urine protein:creatinine ratio or urine protein reagent strips can be substituted. Negative to trace on protein reagent strip is equivalent to ACR < 3 mg/mmol; trace to + is equivalent to ACR 3–30 mg/mmol [3]. The relationship between reagent strip measures and ACR depends upon urine concentration, and in this context for the purposes of ATTACK, we are regarding +protein or more as indicative of significant albuminuria. A single abnormal albuminuria/proteinuria test is required for entry to the trial: day-to-day variation in albumin excretion is substantial and the literature linking albuminuria to adverse outcomes is predicated upon single ACR readings; robust cohort data confirm that for urine ACR down to 1.7 mg/mmol multiple urine samples do not improve performance of CV mortality risk models beyond information achievable by implementation of one ACR value [57] |
• CKD GFR category 5 by KDIGO classification (eGFR < 15 mL/min/1.73 m2) • Pre-existing CVD: angina, MI, stroke (ischaemic or haemorrhagic [intracerebral/subarachnoid]), TIA, significant peripheral vascular disease, coronary or peripheral revascularisation for atherosclerotic disease; aortic aneurysm is not an exclusion criterion • Pre-existing condition associated with increased risk of bleeding other than CKD: upper GI bleed or peptic ulcer in the previous 5 years, lower GI bleed in previous 12 months, active chronic liver disease (such as cirrhosis), bleeding diathesis (investigator opinion) • Taking over the counter aspirin continuously • Currently prescribed anticoagulant or antiplatelet agent • Currently and regularly taking other drugs with a potentially serious interaction with low-dose aspirin, including non-steroidal anti-inflammatories (except topical preparations) and nicorandil • Known allergy to aspirin or definite previous clinically important adverse reaction to aspirin • Poorly controlled hypertension (latest recorded systolic blood pressure [BP] ≥180 mmHg and/or diastolic BP ≥105 mmHg) • Other conditions which in the opinion of the GP would preclude prescription of aspirin in routine clinical practice, for example significant anaemia or thrombocytopenia • Pregnant or likely to become pregnant during the study period • Malignancy that is life-threatening or likely to limit prognosis, other life-threatening co-morbidity, or terminal illness • Behaviour or lifestyle that would render subject less likely to comply with study medication (e.g. alcoholism, substance abuse, debilitating psychiatric conditions or inability to provide informed consent) • In prison • Currently participating in another interventional clinical trial or who have taken part in a trial in the last 3 months (Covid-19 vaccine studies are acceptable) |
Interventions
Description of investigational medicinal product
Criteria for discontinuing or modifying allocated interventions
Concomitant medications
Adherence to prescribed treatment
Outcomes
Primary endpoint
Secondary endpoints
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Death from any cause
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Composite outcome of major vascular event or revascularisation (coronary and non-coronary)
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Individual components of the primary composite endpoint
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Health-related quality of life
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Composite outcome of intracranial haemorrhage (fatal and non-fatal), fatal extracranial haemorrhage and non-fatal major extracranial haemorrhage (adjudicated)
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Fatal and non-fatal (reported individually and as a composite) intracranial haemorrhage comprising:
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Primary haemorrhagic stroke (to distinguish from haemorrhagic transformation of ischaemic stroke): (i) intracerebral and (ii) subarachnoid haemorrhage (reported individually and a composite) (adjudicated)
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Other intracranial haemorrhage: (i) subdural and (ii) extradural haemorrhage (reported as a composite) (adjudicated)
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Intracranial haemorrhage will be subcategorised as traumatic or non-traumatic [64]
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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)
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Clinically relevant non-major bleeding (if hospitalised) (adjudicated)
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Composite outcome of fatal and non-fatal major extracranial haemorrhage and clinically relevant non-major bleeding (if hospitalised)
Tertiary endpoints
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Transient ischaemic attack
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Unplanned (emergency) hospitalisations
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Hospitalisation with heart failure
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New diagnosis of cancer (colorectal/other)
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Death due to cancer (where cancer is the underlying cause of death)
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New diagnosis of dementia
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Major non-traumatic lower limb amputation
Recruitment
Recruitment system
Feasibility
Participant timeline
Summary schedule of enrolment, interventions and assessment
Consent consultation
Randomisation
Follow-up assessments
Sample size
Initial sample size estimate (not accounting for competing risks)
Definitive sample size estimate (accounting for competing risks)
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Proportional hazards assumption holds between the two arms
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A 2% annual major vascular event rate in the usual care arm
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An initial HR of 0.868 (equivalent to a 1.74% annual major vascular event rate in the aspirin arm)
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A 1.8% annual event rate in the usual care arm for deaths from other causes (including fatal bleeding)
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A 1.85% annual event rate in the aspirin arm for deaths from other causes (including fatal bleeding), i.e. assuming that patients in the aspirin arm will experience a 0.05% annual rate increase of fatal bleeding compared to patients in the usual care arm
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85% power, 5% two-sided alpha, 1% dropout rate
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3.5-year recruitment period and 2.5-year follow-up period
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Cumulative incidence at 5 years (in the presence of competing risks) for the usual care arm of 0.0911
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Cumulative incidence at 5 years (in the presence of competing risks) for the aspirin arm of 0.0796
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Subdistribution HR of 0.8692
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Proportion of main event failures in the usual care arm of 0.0782
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Proportion of main event failures in the aspirin arm of 0.0682
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Pooled proportion of main event failures of 0.0732
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Number of major vascular events required of 1827
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Number of patients required (prior to an allowance of dropout) of 24,958
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Number of patients required (after an allowance of dropout) of 25,210 (12,605 per arm)
Estimation of effect size
Estimation of vascular event rate
Methods: assignment of interventions
Allocation
Blinding
Methods: data collection, management and analysis
Data collection methods
Data sources
Endpoint adjudication
Participant retention
Data management
Data forms and data entry
Data coding
Status reports
Data storage and security
Data retention
Statistical methods
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Censoring patients who experience non-fatal major bleeding (adjudicated), clinically relevant non-major bleeding, or anticoagulation at the date of the event (whichever occurs first)
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Censoring only patients who experience non-fatal major bleeding (adjudicated) at the date of the event
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Deaths from other causes (excluding fatal bleeding) will be treated as competing events. Patients who experience a major vascular event will be censored at the date of the event. Patients who do not experience either a major vascular event or fatal/non-fatal major event will be censored at the date of last follow-up
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Major vascular events and deaths from other causes (excluding fatal bleeding) will be treated as competing events. Patients who do not experience a fatal/non-fatal major vascular event will be censored at the date of last follow-up
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Major vascular events and deaths from other causes (excluding fatal bleeding) will be treated as competing events. Patients who experience anticoagulation or clinically relevant non-major bleeding will be censored at the date of the event (whichever occurs first). Patients who do not experience either anticoagulation, clinically relevant non-major bleeding, or a fatal/non-fatal major vascular event will be censored at the date of last follow-up
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Deaths from other causes (excluding fatal bleeding) will be treated as competing events. Patients who experience anticoagulation, clinically relevant non-major bleeding, or a major vascular event will be censored at the date of the event (whichever occurs first). Patients who do not experience either anticoagulation, clinically relevant non-major bleeding, a major vascular event or a fatal/non-fatal major event will be censored at the date of last follow-up
Health economic analysis
Methods: monitoring
Trial management
Data monitoring
Interim analyses
Internal pilot
Subsequent interim analyses
Estimation of event rate
Harms
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Events meeting the definition of SAE but which are listed as undesirable effects in the current Summary of Product Characteristics for aspirin (with the exception of hypersensitivity/allergic reactions which will subject to expedited reporting)
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Anything that constitutes a trial endpoint, as this will be assessed as part of the trial
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SAE which in the opinion of the Investigator are with reasonable probability unrelated to aspirin