FAQS FOR CLINICIANS

If your patient has reached an endpoint, please notify the ASPREE study staff. If the endpoint means that the patient has an indication for continuous low dose aspirin or other antiplatelet medication or anticoagulant, then stop study medication and manage accordingly. We ask your patient to remain in the study, attending all scheduled study visits. The composite primary endpoint of the ASPREE 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

More information on endpoints in the trial can be accessed in the ASPREE Protocol AUS Version# 9 Nov 2014

No, but If an ASPREE participant has a stroke or myocardial infarction, he/she has reached an ‘endpoint’ and we would like to know about this. Medical practitioners can contact the ASPREE research staff directly and assist by providing records of the event.

Your ASPREE patient ceases their study medication but remains in the study, attending scheduled study visits, even though he/she may be prescribed aspirin or other antiplatelet medication 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, contributes to the study’s quality.

ASPREE staff can be contacted on 1800 728 745 (toll free from a landline) or emailed on aspreegp@monash.edu.

It is not necessary to assume that anaemia is due to the study medication. It is best to treat as if your patient is on aspirin and investigate the anaemia according to clinical guidelines. A recommended strategy is to perform a full blood examination to determine RBC morphology. A hypochromic microcytic picture may suggest iron deficiency and warrants iron studies. If there is an iron deficiency, blood loss needs to be excluded on patient history, clinical examination and may require further investigations (FWTU, UGITE, colonoscopy). If investigations are negative, consider a dietary deficiency. A macrocytic anaemia suggests liver disease, a myelodysplastic disorder, vitamin deficiency, drugs or alcohol aetiology. Recommended investigations include LFTs, RBC folate, and serum B12. Other causes of anaemia are chronic disease (especially renal), haemolysis, and haemoglobinopathies such as thallasaemia and sickle cell anaemia.

Stop the study medication, prescribe aspirin or asasantin, update the medical history and please notify an ASPREE study staff member. As this is an intention-to-treat study, the patient would still continue in the study, attending further follow-up as planned.

In situations with a firm clinical indication for aspirin, stop the study medication, prescribe aspirin, and please notify an ASPREE study staff member. The patient would still continue in the study, attending further follow-up as per the ‘intention-to-treat’ study design.

Aspirin and NSAIDs do interact, with some NSAIDs reducing aspirin’s efficacy. To ensure ASPREE results are generalisable to a population, we do not give specific instructions about the timing of study medication, except to request that it is taken at the same time every day.
If your ASPREE patient is willing, we would recommend spacing the time between taking study medication and a NSAID eg, morning and night, with the lowest effective dose of NSAIDs taken for the shortest possible period.

ASPREE research staff conduct the 3MS, the modified mini mental state examination, at baseline prior to enrolment and at years 1, 3 and 5. You will be notified by letter if your patient’s score is suggestive of cognitive decline.
If requested, ASPREE staff will send 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, GPs may be asked to provide their clinical opinion on a short questionnaire (DSM-IV proforma).
The provision of documentation for the dementia adjudication process is appreciated and will greatly assist in maintaining 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.

Participants who ‘trigger’ the dementia investigation process are invited to undertake further cognitive assessments with specially trained research staff. ASPREE will also notify 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 seek to collect copies of pathology and other documents relevant to dementia investigations from medical practices and other services. A panel of clinical specialists will rely on these documents to determine whether the participant has reached a dementia ‘endpoint’ in the ASPREE trial. Correct adjudication, and thus the accuracy of the study, is largely dependant on documentation obtained from the GP practice.

No. Dementia is typically not a sudden drop in function, but rather an agreed level of significance in a gradual decline. Many people with very mild or mild dementia are quite capable of participating in the study and taking the medication from a dosette box or a Webster pack, if it is filled for them.
A carer can help ensure compliance. A patient with very mild or even moderate cognitive impairment can undertake further cognitive assessment and undertake the depression scale. Ongoing consent to participate is upheld throughout but they will typically also be able to give valid consent to undertaking all aspects of the study and associated assessments such as the ADL scales. A close informant is a good idea for these assessments.

Precautionary principles apply here. If you suspect your ASPREE patient has had a severe adverse reaction, stop the study medication. Please notify an ASPREE study staff member who will prepare a report for the Data and Safety Monitoring Board (DSMB) and supervising ethics committees. If the consensus is that the drug did not cause or contribute to the problem (for example, in traumatic blood loss) then the study drug can be recommenced.

The trial is to be analysed on an ‘intention-to-treat’ basis; therefore even if your patient stops taking their study medication, we still need to follow them for the duration of the study, asking them to attend all scheduled study visits. We do encourage your ASPREE patients to take their study medication unless you determine a firm clinical indication to cease.

ITT study design explained

Participants may present to GPs requesting advice about adverse events, which are perceived as drug ‘side-effects’. Intolerance is often unrelated to the study drug. For example, the PACE (Promoting Healthy Ageing with Cognitive Exercise) study and the ASPREE pilot study data suggested that only 20% of reported GI upsets were linked to aspirin.

If your ASPREE patient insists on ceasing study medication due to concern that they are experiencing a side effect, we would suggest a rechallenge after 2 weeks, looking for resolution or recurrence of symptoms. If symptoms of intolerance recur, it is reasonable to cease the trial drug.
Study medication would also be ceased if clinical events required prescribed open label aspirin or other antiplatelet agents or anticoagulants. Medical conditions or drugs where aspirin is contraindicated, will also mean trial drug termination.
Ultimately, the participant is at liberty to stop taking the study drug at any time. In all of these scenarios, the participant would continue to be followed up by the ASPREE staff as per an intention-to-treat (ITT) trial.

ITT study design explained

Yes, an enteric-coated product is used to maintain allocation blinding and to minimize gastric irritation, although there is no compelling evidence that enteric-coating does in fact reduce the risk of GI bleeding complications (Kelly JP, et al. Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product. Lancet 1996;348:1413-16).

Gastroprotective agents are prescribed at your discretion. Some participants initiate these medications of their own volition.

Pre-operative advice can be the same as per the recommendations for those who are taking open label aspirin. Guidelines in this area may be contradictory. Aspirin increases the rate of bleeding complications by a factor of 1.5, however, it usually does not increase “the severity of bleeding complications (exception: intracranial surgery and possibly transurethral prostatectomy)” Burger,W,.et al. (2005). Journal of Internal Medicine.

Recommendations for stopping aspirin vary from 3-10 days prior to surgery. Some recommend maintenance on aspirin intraoperatively if the cardiovascular risk is high, especially for cardiac surgery.
The trial is not compromised by patients who need to cease study medication for a short period (such as for surgery) but we do encourage recommencement as soon possible after surgery.

Emergency code breaking is reserved for critical circumstances such as a severe adverse reaction or when the information will impact on clinical outcome.
In an emergency situation, it should be assumed that the patient is taking 100 mg aspirin and should be treated accordingly. For more information on emergency unblinding, contact the ASPREE team on 1800 728 745.

The Medicare Benefits Branch, Department of Health and Ageing, has approved the ASPREE pathology test under Medicare under a principle that such “Medicare and pharmaceutical benefits would normally be consumed as part of on-going management of the subjects who could be enrolled in the proposed trial. This assumption is based on the relative age of the trial subjects as being in an age bracket that would have a normal expectation of appropriate testing for such conditions as hypertension, haemoglobin levels, and cholesterol levels etc.”
According to the guidelines in the Red Book (‘Guidelines for preventive strategies in general practice’ published by the RACGP), anyone at high CVD risk including all persons over 70 years of age, should have blood pressure measured and evaluation of absolute cardiovascular risk (including lipids). It should be noted that if lipids and haemoglobin have been measured in the previous 6 months, a new pathology test is not necessary for ASPREE.

A signature that the test was ordered by a registered medical practitioner is always needed

Your ASPREE patient can continue to participate fully in the trial. We will ask their new doctor to accept patient care and correspondence associated with the study.

Your ASPREE patient can continue to participate fully in the trial in the absence of clinical indications to review this arrangement. Residential facilities are able to administer ASPREE study medication to the patient if it is charted.
Admission to a RACF is not an endpoint unless it is triggered by permanent physical or cognitive impairment. Patients can be reviewed in the nursing home facility should they wish to continue involvement. Our research staff are trained to adapt study visits according to a participant’s circumstance.

We will continue to follow up your patients within the practice, hopefully with the good will of whomever they nominate as their new GP.

ASPREE patients may leave the study at any time for any reason. In practice, patients often leave trials because they imagine that a minor interruption renders them ineligible to continue (e.g. as a result of moving house, GP practice, or going on holidays). We ask that participants ring the ASPREE research staff on 1800 728 745 to discuss the options for follow up. Additionally, some ASPREE participants may feel that are automatically ‘withdrawn’ from the study if they can no longer take study medication. However, this is ‘cessation of study medication’ only.
As per ITT principles, all participants in the trial – both on and off study medication – are important to the accuracy of ASPREE findings. If your patient does wish to leave the study, without further involvement with ASPREE staff, please inform our study staff so that we can record their preference from that point. Data is still collected through medical records.

Intention-to-treat study design

In most cases we would strongly recommend patients decline other simultaneous intervention study opportunities (observational studies offer no conflict however). Nevertheless, we will consider advice regarding interventional studies on a case-by-case basis. For example, enrolment in an influenza vaccine trial has been deemed to be acceptable for the following reasons: annual influenza vaccine is a standard preventive medicine intervention in this population; in Australia, the over 70’s population is eligible to receive annual influenza vaccine; flu vaccines trials have been conducted annually for years at multiple US sites to develop appropriate flu vaccine strains, with no apparent significant adverse outcomes; individuals should be evenly distributed among our two groups and therefore involvement in an influenza vaccination trial will not impact on the study design.
You are always welcome to speak to ASPREE staff on 1800 728 745 or email aspreegp@monash.edu if you have any queries about other clinical trials.

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 is 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. It is important that these risk factors continue to be identified and managed by the patient’s primary care provider. We do not wish to be perceived as trying to usurp the role of the primary care physician.

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 will inform 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. ASPREE volunteers sometimes feel they are ‘withdrawing’ from the study if they have to stop taking their ASPREE tablet, however this is ‘cessation of study medication’ only, not withdrawn. We endeavour to collect clinical data for the remainder of the trial.

An intention-to-treat analysis

ASPREE staff are alerted to dementia as a possible event if:
1) You have prescribed medication for dementia or diagnosed dementia in the participant’s medical history (collected annually)
2) The participant self-reports dementia or ‘thinking problems’ to ASPREE staff, supported by documentation or testing
3) A significant deterioration in cognitive function is detected through the 3MS test during an ASPREE study visit.

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 ‘trigger’ the dementia investigation process are invited to undertake further cognitive assessments with specially trained research staff. ASPREE will also notify 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 seek to collect copies of pathology and other documents relevant to dementia investigations from medical practices and other services. A panel of clinical specialists will rely on these documents to determine whether the participant has reached a dementia ‘endpoint’ in the ASPREE trial. Correct adjudication, and thus the accuracy of the study, is largely dependant on documentation obtained from the GP practice.

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 15 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 has now closed, 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.