Study Endpoints

The ASPREE Clinical Trial primary endpoint was a composite endpoint of death from any cause or incident dementia or persistent physical disability. Secondary endpoints included cancer, cardiovascular events (specifically hospitalisation for heart failure, myocardial infarction (MI) and stroke), death from any cause, dementia, depression, major hemorrhage (including clinically significant bleeding events and hemorrhagic strokes), mild cognitive impairment and physical disability. To facilitate streamlined adjudication, these endpoints were operationally divided into the following component endpoints:

• Cancer
• Clinically significant bleeding
• Death (from any cause)
• Dementia
• Depression
• Hospitalisation for heart failure
• Mild cognitive impairment
• Myocardial infarction
• Physical disability
• Stroke

The definitions for each of these endpoints is included below.

Note: Mild Cognitive Impairment (MCI) was listed in the ASPREE protocol as an endpoint, and there was subclassification into amnestic MCI and non-amnestic MCI as part of the National Institute of Aging-Alzheimer’s Association sub-study (completed in December 2020). However, the definition used in the ASPREE Clinical Trial does not align with MCI as commonly used in the literature. As such, it is not recommended to use in publications and has not been included as an ASPREE endpoint.

Cancer

Cancer was defined as incident non-metastatic cancer (not present prior to randomisation), incident metastatic cancer, metastasis from pre-existing cancer (cancer present prior to randomisation), or incident blood cancer. Histopathological confirmation of cancers was required unless clear evidence of metastasis was present on imaging, or there was strong clinical evidence of metastasis. Specific decision rules developed for cancer adjudication during the ASPREE Clinical Trial continued in ASPREE-XT, as follows:

• Presentation of incident cancer without evidence of metastasis will be adjudicated as non-metastatic cancer.
• Presentation of local (local or regional) nodal disease will not be considered metastatic disease, whilst distant nodal disease represents metastatic disease.
• Presentation of metastasis without a prior diagnosis of the primary cancer will be adjudicated as incident metastatic cancer.
• Presentation of metastasis within three months of the primary diagnosis will be adjudicated as incident metastatic cancer i.e. will represent one ASPREE cancer endpoint.
• Presentation of primary diagnosis of cancer with metastasis greater than three months later will be adjudicated as one incident non-metastatic cancer followed by one metastatic cancer.

The above criteria apply for every cancer type e.g. if a participant with a history of adenocarcinoma of the colon is diagnosed with incident squamous cell carcinoma of the lung during study follow-up, they can meet both the non-metastatic and metastatic cancer endpoint for squamous cell carcinoma of the lung given that this cancer type was not present prior to randomisation. Recurrent non-metastatic cancer is not an ASPREE endpoint. Further information about the cancer endpoint has been published elsewhere (1).

NOTE: Basal cell carcinomas and squamous cell carcinoma of the skin were not considered to be cancer endpoints unless they resulted in death.

Clinically significant bleeding

Clinically significant bleeding events were defined as any non-stroke bleeding event that was substantiated and resulted in any one of the following:

• Transfusion of intravascular red blood cells
• Admission to hospital (hospitalisation for more than 24 hours, or prolongation of a hospitalisation for more than 24 hours)
• Surgery to stop the bleed
• Death

Further information about the clinically significant bleeding endpoint has been published elsewhere (2).

Bleeding was considered substantiated if it was observed (e.g. on gastroscopy or cystoscopy), there was a reasonable self-report of bleeding symptoms (e.g. melena or hematemesis), it was documented in a medical, nursing or paramedical report, or evident on imaging such as computerized tomography (CT)/magnetic resonance imaging (MRI) for intracerebral hemorrhage.

Note: Endoscopic procedures do not qualify as surgery.

Death

The death endpoint included all deaths that were confirmed with two independent sources (e.g. family, general practitioner/family physician or public death notice). Although not an ASPREE endpoint, trajectory to death was also collected according to the following categories (3):

• Cancer-related death
• Dementia-related death
• Coronary heart disease death (i.e. myocardial infarction, sudden cardiac death, rapid cardiac death, cardiac failure with coronary cause, other coronary death)
• Non-coronary vascular death (e.g. abdominal aortic aneurysm rupture, cardiomyopathy, or myocarditis)
• Stroke-related death
• Major hemorrhage-related death
• COVID-19-related death
• Death from other cause

Dementia

Dementia was defined according to the Diagnostic and Statistical Manual for Mental Disorders, American Psychiatric Association criteria - Version 4 (DSM-IV) (4). DSM-IV diagnostic features of dementia include memory impairment and at least one of the following: aphasia, apraxia, agnosia, disturbances in executive functioning (assessed via dementia assessment visit). In addition, the cognitive impairments needed to be severe enough to cause impairment in social and occupational functioning and represent a decline from a previously higher level of functioning. Further information about the dementia endpoint has been published elsewhere (5).

Depression

Depression was defined as a score of eight or more on the Centre for Epidemiologic Studies Depression Scale (CES-D 10) (6), or admission to hospital for greater than 24 hours where depression was either the primary reason for admission or one of the primary reasons for admission if multiple psychiatric diagnoses constituted the primary reason for admission. Further information about the depression endpoint has been published elsewhere (7).

Hospitalisation for heart failure

Hospitalisation for heart failure was defined as an unplanned admission to a hospital for greater than 24 hours where heart failure was the primary reason for admission. Heart failure was defined as typical symptoms (e.g. dyspnea, fatigue) occurring at rest or on effort supported by objective evidence of an underlying structural abnormality or cardiac dysfunction that impairs the ability of the ventricle to fill with or eject blood (particularly during exercise).

Physical disability

Persistent physical disability was defined as a participant self-reported (or proxy) response of ‘a lot of difficulty’, ‘unable to do activity’ or the requirement for assistance for the same basic Activity of Daily Living (ADL) (8) at consecutive administrations of six modified Katz ADL questions performed more than five months apart (not adjudicated). In cases where the modified Katz ADL questions could not be administered, eligibility or admission to care for assistance with ADLs was considered to be a physical disability endpoint. This endpoint was adjudicated. Therefore, if a participant was able to complete the modified Katz ADL questions, they could not trigger a physical disability endpoint through the eligibility or admission to care pathway. Further information about the physical disability endpoint has been published elsewhere (9).

Myocardial infarction

Myocardial infarction was defined as any cardiac event demonstrating typical rise in biochemical markers of myocardial necrosis (i.e. troponin or CK-MB) with at least one of: a) ischemic symptoms; development of pathologic Q waves on the electrocardiogram (ECG); b) ECG changes indicative of ischemia (ST segment elevation or depression) or; c) coronary artery intervention (e.g. coronary angioplasty) as per the American College of Cardiology & European Society of Cardiology definition (10). Development of proven new pathologic Q waves on serial ECGs, or evidence of acute, healed or healing MI on autopsy was also considered an MI endpoint. Further information about the cardiovascular disease endpoint has been published elsewhere (11).

Stroke

Stroke was defined as per World Health Organization criteria as ‘rapidly developing clinical signs of focal (or global) disturbance of cerebral function lasting more than 24 hours (unless interrupted by surgery or death) with no apparent cause other than of vascular origin'. Distinction between ischemic and hemorrhagic stroke was made based on CT/MRI imaging. Ischemic strokes were sub-classified according to the TOAST classification (12), and hemorrhagic strokes were sub-classified by anatomical location (11). Further information about the stroke endpoint has been published elsewhere (11) (13).

Endpoint Protocol Definitions

Table 1. ASPREE endpoint protocol definitions.

References

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2. Margolis KL, Mahady SE, Nelson MR, Ives DG, Satterfield S, Britt C, et al. Development of a standardized definition for clinically significant bleeding in the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Contemp Clin Trials Commun. 2018 Sep;11:30–6. doi: 10.1016/j.conctc.2018.05.015.

3. McNeil JJ, Nelson MR, Woods RL, Lockery JE, Wolfe R, Reid CM, et al. Effect of Aspirin on All-Cause Mortality in the Healthy Elderly. N Engl J Med. 2018 Oct;379(16):1519–28. doi: 10.1056/NEJMoa1803955

4. Guze SB. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV). Am J Psychiatry. 1995 Aug;152(8):1228–1228.

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6. Radloff LS. The CES-D Scale: A Self-Report Depression Scale for Research in the General Population. Appl Psychol Meas. 1977 Jun;1(3):385–401.

7. Berk M, Woods RL, Nelson MR, Shah RC, Reid CM, Storey E, et al. Effect of aspirin vs placebo on the prevention of depression in older people: a randomized clinical trial. JAMA Psychiatry. 2020 Oct 1;77(10):1012–20.

8. Katz S, Akpom CA. A Measure of Primary Sociobiological Functions. Int J Health Serv. 1976 Jul;6(3):493–508.

9. Woods RL, Espinoza S, Thao LTP, Ernst ME, Ryan J, Wolfe R, et al. Effect of aspirin on activities of daily living disability in community-dwelling older adults. The Journals of Gerontology: Series A. 2021 Nov 1;76(11):2007–14.

10. Alpert J, Thygesen K, Antman E, Bassand J. Myocardial infarction redefined - a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol. 2000;36(3):959–69.

11. McNeil JJ, Wolfe R, Woods RL, Tonkin AM, Donnan GA, Nelson MR, et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med. 2018 Oct 18;379(16):1509–18.

12. Adams HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993 Jan;24(1):35–41.

13. Wolfe R, Murray AM, Woods RL, Kirpach B, Gilbertson D, Shah RC, et al. The aspirin in reducing events in the elderly trial: statistical analysis plan. Int J Stroke. 2018 Apr;13(3):335–8.