FAQS FOR CLINICIANS

The primary objective is to determine whether low-dose aspirin prolongs life, or life free of dementia, or life free of significant, persistent physical disability in the healthy elderly.
Secondary objectives relate to the effects of low-dose aspirin on the key outcome areas of death, cardiovascular disease, dementia and cognitive decline, depression cancer, physical disability and major bleeding episodes.
Measures in addition to those included in the primary and secondary objectives will be examined. These include measures of cognitive and physical function and records of hospitalisations and pathology findings such as haemoglobin levels, urine albumin:creatinine ratios.

ASPREE study endpoints:
The composite primary endpoint of the trial is incident dementia or persistent physical disability or death.
Secondary endpoints of the trial include: all-cause mortality, cardiovascular events, cancer, dementia, physical disability, depression and major haemorrhagic events.

There is an increased risk of stroke and ischaemic heart disease after age 70. However, the United States Preventive Services Task Force (USPSTF) guidelines in 2009 specifically note that there is insufficient evidence to assess the balance of benefits and harms of aspirin for CVD prevention in older men and women. The April 2016 agency guidelines note insufficient evidence to assess the balance of benefits and harms of aspirin for CVD and colorectal cancer in the elderly. This is the primary reason for the need for ASPREE to answer the question: does aspirin have greater benefits than risks, such as bleeding, when used as primary prevention in ‘healthy’ independent older individuals. The elderly represent a cohort that may experience greater benefit of aspirin (because of co-morbid risk factors that increase risk of CVD events) but its use must be supported by adequate data on safety. Despite this absence of evidence, aspirin is often prescribed in this population based on evidence extrapolated from younger populations, which is coming under increased scrutiny. Thus, ASPREE is an important trial necessary to answer the fundamental question of risk vs benefit.

A series of publications led by a UK team, Rothwell et al[1] provided compelling findings about the aspirin/cancer link.  An overview of individual patient data from seven randomised cardiovascular trials of four years or more in over 23,000 patients showed that death from all solid cancers was reduced overall by about 15% by aspirin. Risk was unrelated to aspirin dose – 75mg daily or higher.

However, it is important to note that two very large trials, the Women’s Health Study[2] and the Physician’s Health Study[3], of almost 60,000 individuals followed up for 10-12 years, were excluded because they tested alternate day rather than daily aspirin. In these trials there was no effect on cancer.

Other studies by the same researchers published concurrently showed that aspirin had early short-term effects on cancer incidence and mortality[4] and that metastatic spread particularly of adenocarcinoma was reduced by about 40-50% in a few years[5]. His meta-analysis of 51 different studies published between 1968 and 2010, were of participants varying in age, health, the dose of aspirin and the duration of the studies. The average age in one study was 62 and unknown in other papers.

Adverse effects of aspirin reported in these papers were limited to ‘major’ bleeding outside the brain (e.g, gastro-intestinal bleeding) and not other potential side effects, such as anaemia, which may affect an older person’s quality of life.

Seshasai et al[6] later published an updated meta-analysis of nine placebo-controlled trials of primary prevention of CVD in over 100,000 people with mean age of 57 years. This attracted almost as much negative publicity as the cancer data captured public imagination. The overview showed a greater number of non-trivial bleeds (30% increase, and treatment of 73 people over mean six years caused one bleed) than cardiovascular events prevented, mainly non-fatal myocardial infarction (treatment of 120 people prevented one CVD event). Also, in contrast to Rothwell’s papers, there was no effect on cancer mortality.

While the evidence is not considered sufficiently robust to warrant recommendation of aspirin for cancer prevention; the papers do underscore the importance of ASPREE.  Only a large RCT trial like ASPREE will eliminate the biases and confounding associated with population-based studies and establish whether the benefits of aspirin (including cancer prevention) outweigh the risks specifically in people aged 70 and over. ASPREE’s composite endpoint of disability-free survival considers conditions in addition to cancer, which may reduce quality of life for older people, eg dementia.

1] Rothwell PM, Fowkes GR, Belch JFF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials, The Lancet, Volume 377, Issue 9759, 1–7 January 2011, Pages 31-41, ISSN 0140-6736, 10.1016/S0140-6736(10)62110-1.

2] Cook NR, Lee IM, Gaziano JM, Gordon D, Ridker PM, Manson JE, Hennekens CH, Buring JE. Low-dose aspirin in the primary prevention of cancer: the Women's Health Study: a randomized controlled trial. JAMA. 2005;294:47–55

3] The Steering Committee of the Physicians’ Health Study Research Group. Findings from the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med. 1988;318:262-264.

[4] Rothwell PM, Price FP, Fowkes FGR, Zanchetti A, Roncaglioni MC, Tognoni G, et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. The Lancet 2012; 379: 602-12.

[5] Rothwell PM, Wilson M, Price JFF, Belch JF, Meade TW,  Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. The Lancet.  28 April 2012 (Volume 379 Issue 9826 Pages 1591-1601 DOI: 10.1016/S0140-6736(12)60209-8)

[6] Seshasai SRK, Wijesuriya S, Sivakumaran R, Nethercott S, Erqou S, Sattar N, et al. Effect of aspirin on vascular and nonvascular outcomes meta-analysis of randomized controlled trials. Arch Intern Med. 2012;172(3):209-216. doi:10.1001/archinternmed.2011.628

It was not the intent or a goal of the study to screen patients for CV risk factors and recommend treatment plans. ASPREE is an effectiveness trial, testing whether aspirin provides benefit in a population that is relatively healthy, but does contain some level of risk factor burden primarily driven by age. These risk factors were identified and managed by the patient’s doctor.

Yes, as well as increased risk of MI and stroke, older people are at greater risk of bleeding. Click on summary of studies below to enlarge.
Aspirin’s influence on clinically significant bleeding is one of the questions that ASPREE is trying to address: do the benefits of aspirin outweigh the risks of GI bleeding and cerebral haemorrhage? An independent NIH-appointed Data Safety and Monitoring Board informed the continuation or termination of the ASPREE study based on benefit/harm data accrued throughout the study.
Of note, in the pilot phase of the ASPREE study, among 209 baseline subjects age ≥70 in Australia, there were no major GI bleeds or cerebral haemorrhages after 12 months of follow-up.

An ITT analysis means that participants randomised to a particular arm of the trial (aspirin or placebo) stay in that arm for all clinical outcomes, whether they remain on study medications or not.

The 3MS test is a modified Mini–Mental State Examination (MMSE) preferred by international experts for neuro-cognitive screening.

• The 3MS uses a 100 point scale rather than a 30 point scale, it is more sensitive to change than the MMSE and provides a broader assessment of the cognitive state of patients.
• The 3MS distinguishes more clearly between spontaneous retrieval and encoding problems in short term memory. The 3MS also measures semantic memory (verbal fluency—e.g, listing animals).
• The 3MS measures executive (frontal) function (e.g, similarities between things).
• The Pentagon test is graded from 1 to 10 in the 3MS rather than just as pass/fail.
• The confrontational naming test in the 3MS has more challenging items than the MMSE.

Professor Elsdon Storey, a Chief Investigator on ASPREE, has trained and accredited all ASPREE study staff in the administration of the 3MS. He also oversees the neuro-cognitive component of the trial.

Participants who ‘triggered’ the dementia investigation process were invited to undertake further cognitive assessments with specially trained research staff. ASPREE notified GPs of the 3MS test outcome for ongoing care and management of the participant, which at the GP’s discretion, may include a range of investigations for cognitive impairment. Referral to a suitable specialist or assessment clinic would often be indicated.
We sought medical documents relevant to dementia investigations from medical practices and other services for specialist adjudication on whether the participant had reached a dementia ‘endpoint’ in the ASPREE trial. Correct adjudication, and thus the accuracy of the study, was largely dependant on documentation obtained from the GP practice.

We asked all participants to continue in the study, attending scheduled study visits, even if he/she may be prescribed aspirin or other antiplatelet medication, eg for secondary prevention after a cardiovascular event.

The composite primary endpoint of the trial is incident dementia or persistent physical disability or death. Secondary endpoints of the trial include: all-cause mortality, cardiovascular events, cancer, dementia, depression and major haemorrhagic events. All health data from ASPREE participants collected for the duration of the trial, contributed to the study’s quality.

ASPREE research staff conducted the 3MS, the modified mini mental state examination, at baseline prior to enrolment and at years 1, 3 and 5. You will have been be notified by letter if your patient’s score is suggestive of cognitive decline.
If requested, ASPREE staff will send you details of dementia and memory service providers in your state. CDAMS (Cognitive, Dementia and Memory Service) in Victoria offers a free dementia service and will welcome referrals from ASPREE Co-investigator GPs. Services in other states may be fee-based.
If a specialist referral is not appropriate or possible, you may have been asked to provide your clinical opinion on a short questionnaire (DSM-IV proforma).
The provision of documentation for the dementia adjudication process helped maintain the integrity and quality of results in this very important study.

The literature highlights the value of early diagnosis of dementia, as there are now effective interventions that may improve patient quality of life. Recent research also shows a reversible cause may be present in some cases.

A large-scale clinical trial such as ASPREE takes many years and costs tens of millions of dollars. Because these studies arise rarely, it is an opportunity to capitalise on the availability of information with ancillary studies to provide important public health information. ASPREE’s 17 sub-studies are designed to supplement the principal trial. The participants largely find them interesting and engaging.

For more information on ASPREE sub-studies go to the sub-study menu.

To enrol in the ASPREE trial participants needed to be:

• Aged ≥70 years
• Generally well and able-bodied
• No history of a heart attack, stroke or a known bleeding risk
• Able to take 100 mg aspirin or a matching placebo tablet every day
• Able to undertake annual health measures

Recruitment for the ASPREE study closed in December 2014, with 19,114 participants in Australia and the USA.

Two meta-analyses have questioned the role of aspirin in primary prevention, and at this point, it is unclear whether the benefits of aspirin outweigh the risks in primary prevention. In the first meta-analysis (Antithrombotic Trialists’ (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual patient data from randomized trials. Lancet 2009;373:1849-60.), subgroup analyses indicated no evidence of net benefit in older people such as those who will be included in ASPREE (including those with diabetes, smoking status, elevated BP or dyslipidaemia).

In the second meta-analysis (De Berardis G, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomized controlled trials. BMJ 2009;339:b4531), no statistically significant reduction in the overall risk of major CV events was observed in patients with diabetes.

Without clear evidence of net benefit of aspirin in people with diabetes, it was not justified to exclude them from the ASPREE study. It is important that the ASPREE trial enrol individuals with diabetes, hypertension and those who smoke as it will be adequately powered to examine the effects of aspirin therapy in specific risk factor delineated subgroups (e.g. male vs female, age < or > than study median, diabetes, hypertension, and smoking). Given the paucity of evidence as to aspirin’s benefit in these populations, ASPREE will provide the definitive evidence to inform practice.

The benefits of aspirin in patients with peripheral artery disease are questionable. A recent primary prevention trial (Fowkes FG, et al. JAMA 2010;303:841-8) in a population with a low ankle brachial index failed to find benefit of aspirin in reducing vascular events. Although admittedly this was an asymptomatic population (but considered at high risk for vascular events from the ankle brachial index), the accompanying editorial noted the following: “Furthermore, the trial supports findings of a recent meta-analysis that failed to demonstrate a benefit of aspirin therapy for patients with peripheral artery disease. Thus, the clinical benefits of aspirin therapy for patients with peripheral artery disease remain unproven.” (Berger JS. JAMA 2010;303:880-2).

The meta-analysis citation referred to in the editorial is: Berger JS, et al. Aspirin for the prevention of cardiovascular events in patients with peripheral artery disease: a meta­analysis of randomized trials. JAMA 2009;301:1909-19. In this analysis of over 5,269 participants, CV events were experienced by 8.9% of 2823 patients taking aspirin (alone or in combination with dipyridamole) and by 11.0% of the 2446 in the control group (RR 0.88; 95% CI, 0.76-1.04).

Although the benefits of aspirin in patients with peripheral artery disease may be questioned based on recent data, we recognise that the vast majority of patients with symptomatic peripheral artery disease are likely to be already be taking aspirin under the direction/recommendation of their physician. Patients already taking aspirin for an appropriate indication as determined by their physician, should continue aspirin treatment. Patients already prescribed open label aspirin and advised to continue with treatment were not enrolled into the study.