Study Endpoints

The ASPREE Clinical Trial primary endpoint was death from any cause or incident dementia or persistent physical disability. Secondary endpoints included cancer, cardiovascular events (specifically hospitalisation for heart failure, myocardial infarction and stroke), death from any cause, dementia, depression, major haemorrhage (including clinically significant bleeding events and haemorrhagic 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.

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 ASPREE will continue in ASPREE-eXTension:

  • 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.

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

Clinically significant bleeding

Clinically significant bleeding events are defined as any non-stroke bleeding event that is substantiated and results in any one of the following:

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

Further information about the clinically significant bleeding endpoint has been published elsewhere (1).

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. melaena or haematemesis), it was documented in a medical, nursing or paramedical report, or evident on imaging such as CT/MRI for intracerebral haemorrhage.

Death

The death endpoint included all deaths that were confirmed with two independent sources (e.g. family, GP/family physician or public death notice). Although not an ASPREE endpoint, trajectory to death was also collected according to the following categories (2):

  • 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 death;
  • Major haemorrhage death; or
  • Death from other cause.

Dementia

Dementia was defined according to the Diagnostic and Statistical Manual for Mental Disorders, American Psychiatric Association (DSM-IV) criteria (3). 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 need to be severe enough to cause impairment in social and occupational functioning and represent must represent a decline from a previously higher level of functioning.

Depression

Depression was defined as a score of eight or more on the Centre for Epidemiologic Studies Depression Scale (CES-D) (4), 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.

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 is defined as a response of ‘a lot of difficulty’, ‘unable to do activity’ or the requirement for assistance for the same Katz ADL (5) at consecutive administrations of the ADL questions approximately six months apart (not adjudicated). In cases where the modified list of Katz ADL questions could not be administered, admission to care for assistance with activities of daily living was considered to be a physical disability endpoint. This endpoint was adjudicated.

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) ischaemic symptoms; development of pathologic Q waves on the ECG; b) ECG changes indicative of ischaemia (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 (6). Development of proven new pathologic Q waves on serial ECGs, or evidence of acute, healed or healing MI on autopsy was also be considered an MI endpoint.

Stroke

Stroke was defined as per World Health Organization (WHO) 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 ischaemic and haemorrhagic stroke will be made based on CT/MRI imaging. Ischaemic strokes were sub-classified according to the TOAST classification (7), and haemorrhagic strokes were sub-classified by anatomical location.

Endpoint Protocol Definitions

Table 1. ASPREE endpoint protocol definitions.

Endpoint Summary of evidence required to meet protocol criteria
Cancer Evidence of presence of cancer
Evidence of progression of cancer
Clinically Significant Bleeding Evidence of bleeding; AND
Evidence of significance (i.e. hospitalisation, surgery, transfusion or death from bleeding)
Death (cause of death) Evidence of date of death; AND
Evidence of cause of death
Dementia Evidence of cognitive decline; AND
Evidence of functional decline
Depression A score of eight or more on the CES-D
Evidence of depression as the primary reason for admission to hospital; AND
Evidence of admission for > 24 hours
Hospitalisation for Heart Failure Evidence of heart failure on admission; AND
Evidence of admission for > 24 hours
Myocardial Infarction Evidence of troponin rise; AND one of:
Ischemic symptoms, ECG changes, coronary artery intervention
Evidence of pathological changes of MI
Physical Disability Evidence of persistent loss of Katz ADLs for five+ months
Evidence of admission to care for physical disability
Stroke Evidence of symptoms of stroke; AND
Evidence that symptoms lasted for > 24 hours

References

  1. 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.

  2. 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

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

  4. 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.

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

  6. Antman E, Bassand JP, Klein W, Ohman M, Sendon JLL, Rydén L, et al. 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 Sep;36(3):959-69. doi: 10.1016/S0735-1097(00)00804-4

  7. 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.

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