1Evidence Based Answers to Clinical Questions

Evidence Based Answers to Clinical Questions

Aspirin in Diabetics for Primary Prevention of Myocardial Infarction
Samuel Chan & Theodore Lau
Word Count: 1,798

CASE HISTORY
Mr JL, a 50 year old economics lecturer, presents to his GP for ongoing management of his Type II
Diabetes Mellitus (T2DM). JL has a BMI of 24 and was diagnosed with T2DM six years ago. He
has been taking Gliclazide-MR® tablets 30mg mane for the past five years and is adherent to
medication. JL’s GP manages his diabetes as per the Annual Cycle of Care. A random finger prick
blood glucose test revealed 5.5mmol/L and his latest HbA1C was 6%. Personal medical history and
family history is otherwise unremarkable. JL does not smoke or drink alcohol, and currently lives
happily with his wife and three children.

JL wishes to discuss with his GP whether he should be commenced on daily low-dose aspirin, as he
found an article on the internet1 stating that aspirin reduces the chances of him suffering from
myocardial infarction (MI). JL’s GP expressed uncertainty over this and JL opted to return in a
month to discuss this further. In the meantime, we resolved to investigate whether current literature
supports use of aspirin in patients of JL’s demographics.

RATIONALE FOR STUDY AND RELEVANCE TO GENERAL PRACTICE

MI contributes ~1% of Australia’s burden of disease and the direct healthcare expenditure of MI is
~$2.5 billion annually2,3. Recognition of the escalating costs and burden of MI have consequently
led to a need to identify effective approaches to prevention. General practice is an appropriate
setting for implementing such strategies.

An area in general practice which has received much debate is whether aspirin should be used for the
primary prevention of MI in diabetic patients. Various sources4-8 (Appendix 1) have recommended
low-dose aspirin in this demographic. However, since 2009, a multitude of clinical trials9-15 have
been conducted, the findings of which have raised questions about aspirin’s efficacy in primary
prevention of MI in diabetics. Consequently, this issue requires further exploration. The conclusions
drawn in this project will give GPs further insight into the role of aspirin in this population group.

CLINICAL QUESTION
We formulated JL’s query into a clinical question using the PICO (Patient, Intervention, Comparator,
Outcome) format.

“In 50 year old males with Diabetes Mellitus (P), will treatment with daily low-dose aspirin (I)
prevent primary myocardial infarction from occurring (O)?”

The comparator (C) is the absence of taking daily low-dose aspirin.

LITERATURE SEARCH
Choice of study type
A systematic review of randomised controlled trials (RCTs) is the preferred study type to answer
JL’s therapeutic query18. Controlled trials aim to isolate the effect of an intervention from other
variables18. Randomisation is performed to eliminate potential selection bias, while blinding
participants and observers decreases performance and observer (detection) bias respectively 18.
Hence, double-blinded RCTs are considered a reliable form of evidence in therapeutic studies18.

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2Evidence Based Answers to Clinical Questions

A systematic review with meta-analysis has advantages over a single RCT. Transferability or
robustness of results can be assessed by analysis of data from trials with different settings and
methods18,19. Statistical power is improved by combining results, permitting the detection or
confirmation of modest results which individual studies alone may be too undersized to verify18.
“Quality control” of included studies and protocols to protect against publication bias are often
utilised to improve reliability18.

Choice of database and Search strategy

Databases, such as Clinical Evidence, The Cochrane Library and PubMed, were used to answer JL’s
query. The search strategy employed (including history printouts) and exact search terms used are
documented in Table 1 and Appendix 2.

Clinical Evidence was accessed first. This database is recognised as high level evidence for
informing treatment decisions18-20. However, in answering JL’s question, the evidence in this
database does not include recent advances in the area (last updated in 2006), and hence was not
utilised in this assignment.

We then proceeded to Cochrane, which is limited to certain study types (e.g. systematic reviews)
which are arduously scrutinised for inclusion. Cochrane has a number of databases, such as the
“Cochrane Database of Systematic Reviews” (published by Cochrane) and the “Cochrane Database
of Review of Effects”, which includes non-Cochrane systematic reviews19-21. To search for JL’s
query, we matched each PICO element to relevant MeSH (Medical Subject Headings) headings
which also finds Index terms of its corresponding MeSH. These search entries were combined with
the Boolean operator “AND” for the final search. This Cochrane search returned no Cochrane or
systematic reviews. We thus accessed PubMed.

PubMed not only provides access to Medline, but it also automatically searches Medline Non-
Indexed Items, which is a database providing access to the latest published articles19,20. In contrast to
Cochrane, PubMed automatically maps keywords to MeSH terms, reducing the likelihood of relevant
studies being missed.

A broad search of our PICO terms was performed initially (Table 1; searches #1, #2, #3, #4) and our
search was narrowed to articles with matches in each broad category with the use of Boolean
operator “AND” (#5). Results were further constrained by selecting only RCTs (#6) and systematic
reviews (#7) through “Clinical Queries” (#8). “Limits” (#9) were then specified, restricting the
results to articles in English and from the past three years, the time period since Clinical Evidence
has been updated. This search yielded a final result of 9 articles appropriate to our PICO question.

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3Evidence Based Answers to Clinical Questions

ARTICLE SELECTION
The title and abstract of meta-analyses by Zhang16 (our key article) and Younis17 matched JL’s query.
These studies matched the highest level of evidence according to the NHMRC criteria18.

Zhang’s meta-analysis16 compared the effects of aspirin with no aspirin in diabetic patients across
various outcomes including MI, stroke, all-cause mortality and cardiovascular mortality. This
assignment will focus only on MI primary prevention, as this is JL’s outcome of interest.

Zhang’s article16 assessed all RCTs between 1950 and June 2009 from a collection of journal
databases. An exclusion/inclusion criterion was employed and seven RCTs, involving a total of
11,618 diabetic patients, were included in the meta-analyses.

Overall, results demonstrated negligible benefits of aspirin when compared with non-aspirin
regarding risk reduction of MI (relative risk (RR)=0.85, 95% CI 0.65-1.11, p=0.24). Zhang13 also
showed that the risk of major bleeding in aspirin compared with non-aspirin group was insignificant
(RR=2.46, 95% CI 0.70-8.61, p=0.16). These results were presented using forest plots and written
discussion.

Alternative Article
We chose the most recent meta-analysis that matched our PICO question, for comparison with
Zhang’s study16.

Similarly, Younis’ meta-analysis17 contrasted the role of aspirin with non-aspirin in primary
prevention of MI in diabetic patients, and found insignificant difference between the two groups.
Younis17 assessed publications up to December 2009. Six trials, totalling 7,374 patients, were
included in the analysis.

Although Younis’17 draws appropriate conclusions regarding aspirin in primary prevention of MI in

diabetics, by comparison it is not as powerful as Zhang’s16:
• The sample size in Zhang’s16 (11,618 patients) is much larger than Younis’17 (7,374). The
larger the sample size, the more likely it reflects the entire population in question, and less
likely that findings will be by chance alone.
• Zhang’s analysed an additional trial (ETDRS)12 not found in Younis’.
• Unlike Younis’, Zhang’s provided data on the adverse effects of aspirin and non-aspirin
groups, thus allowing calculation of NNH.
• Zhang’s provided a flow diagram for their selection process, an important component for
publishing a meta-analysis.
• Zhang’s formally assessed for publication bias. The Begg’s and Egger’s tests for asymmetry
were statistically insignificant16.

CRITICAL APPRAISAL
Using the appraisal guide taught by The University of Queensland22, Zhang’s meta-analyses
performed well (Table 2).

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4Evidence Based Answers to Clinical Questions

However, there are a few additional concerns regarding Zhang’s article:

• Data related to major bleeding was not available in all included studies and thus, there may be
reporting bias in this outcome. Only three trials reported major bleeding11-13, which may
suggest that this analysis was underpowered on major bleeding.
• There were differences in participant characteristics (e.g. gender), follow-up duration, and
doses of aspirin between individual trials. The dose range of aspirin, for example, varied
between 50-650mg daily. In two studies14,15, aspirin was given every second day. The failure
of higher doses to produce greater reductions in thrombotic events may be due to the fact that
the inhibitory effects of aspirin on platelets are permanent, and therefore relatively low daily
doses are able to to fully inhibit platelet COX-1.
• Some RCTs10-12 were conducted prior to statins being available on the market. Statins appear
to have antiplatelet activity which may negate the potential benefit of aspirin10-17.

For study results to be clinically significant, they must be statistically significant. When comparing
aspirin with non-aspirin, the results in Zhang’s are statistically insignificant (p=0.24; CI>1.0) and
hence clinically insignificant to support aspirin for primary prevention of MI in diabetic patients.

RELEVANCE TO PATIENT
We advised JL that recently published studies do not recommend daily low-dose aspirin in primary
prevention of MI in diabetic patients without the presence of additional cardiovascular risk factors.
Specifically, JL’s T2DM is well controlled. The absence of other cardiovascular risk factors such as
smoking, combined with his unremarkable family history, further reinforces aspirin may be
inappropriate for JL. Additionally, JL is supported by his wife and children, and has stable
employment. These psychosocial factors have been shown to be pivotal in managing patients such
as JL with chronic disease (e.g. maintaining adherence)22,23.

We also told JL that even if there was a proven benefit, it needs to be balanced with the potential for
harm. Based on the available data, 589 people need to take low-dose aspirin to prevent one MI each
year (NNT; Appendix 3). We also advised him when 396 people take aspirin, 1 person will
experience a major bleed each year (NNH). NNT is greater than NNH which suggests the harm
outweighs the benefit of taking aspirin for primary prevention of MI in diabetic patients. Whilst we
acknowledged aspirin is relatively inexpensive, JL was advised of the plethora of side-effects of
aspirin (e.g. gastrointestinal ulceration)23. JL was counselled on the potential surgical

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5Evidence Based Answers to Clinical Questions

complications23 and drug interactions, including over-the-counter and complementary medicines (e.g.
ginseng24), associated with aspirin.

IMPLICATIONS FOR GENERAL PRACTICE

Whilst current guidelines4-8 advocates routine prescribing of daily low-dose aspirin for primary
prevention of MI in diabetics, recently available evidence appears to be insufficient to support this
recommendation. Thus, the implications for general practice are to be vigilant in prescribing low-
dose aspirin to patients such as JL. Two ongoing trials, ASCEND25 and ACCEPT-D26, which are
aiming to recruit more than 15,000 participants, will provide additional clarification. Risks and
benefits should be appraised on a case by case basis, based on a thorough history of the patient, with
considerations to personal, family and social factors. Patients presenting to GPs may have additional
cardiovascular risk factors including smoking, hypertension and hyperlipidaemia, and hence
extrapolating the conclusions drawn here needs to be done with care. This project reinforces that
evidence is ever changing in medicine. It accentuates the need for GPs and students, such as
ourselves, to read widely and keep abreast of the latest medical developments.

ACKNOWLEDGEMENTS

The authors of this assignment would like to acknowledge the invaluable assistance of the academic
staff at the Discipline of General Practice at The University of Queensland, particularly Dr Rebecca
Farley, Dr David King, and Dr Ferdinandus Delooze, for their insightful feedback throughout various
drafting stages of this assignment and with the assistance of the various clinical calculations.
Additionally, the authors would like to thank our GP placement tutor, Dr Anita Sharma, for assisting
us with proofreading this project and offering clinical insight to this scenario.

The authors would also like to thank the library staff, Ms Jill McTaggart and Mr Justin Clark, for
assisting us with performing the literature search for this assignment. They have been invaluable in
providing us with the necessary skills that we will need in searching articles in Cochrane Library,
PubMed and Clinical Evidence when we graduate as clinicians.

We are indebted to these parties and we feel confident that we will be able to apply our EBM skills
beyond this course and into real-life situations.

REFERENCES

1. Science Codex. Research confirms aspirin’s role in primary prevention of cardiovascular events for diabetics.
http://www.sciencecodex.com/research_confirms_aspirin_s_role_in_primary_prevention_of_cardiovascular_events_for_di
abetics (accessed June 2010).

2. AIHW (Australian Institute of Health and Welfare): Mathers C, Vos T & Stevenson C 1999. The burden of disease and
injury in Australia. AIHW Cat. No. PHE 17. Canberra: AIHW.

3. Britt H, Miller GC, Charles J, et al. General practice activity in Australia 2007–08. General practice series no. 22.
Canberra: Australian Institute of Health and Welfare, 2008. (AIHW Cat. No. GEP 22; abstract item 115.)
http://www.aihw.gov.au/publications/index.cfm/title/10651 (accessed June 2010).

4. Diabetes Australia and Royal Australian College of General Practitioners. Diabetes management in general practice.
Guidelines for type 2 diabetes 2009/10. Canberra. Diabetes Australia, 2009 (Diabetes Australia Publication)
http://www.racgp.org.au/Content/NavigationMenu/ClinicalResources/RACGPGuidelines/Diabetesmanagement/200910dia
betesmanagementingeneralpractice.pdf (accessed June 2010).

5. National Health and Medical Research Council. National evidence based guidelines for the management of type 2 diabetes
mellitus. Part 5. Prevention and detection of macrovascular disease in type 2 diabetes. Canberra: NHMRC, 2004.
http://www.nhmrc.gov.au/publications/synopses/_files/di11.pdf (accessed June 2010).

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6Evidence Based Answers to Clinical Questions
6. Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention of cardiovascular events: a summary of
the evidence for the US Preventive Services Task Force. Ann Intern Med 2002; 136: 161-172.
7. Colwell JA, American Diabetes Association. Aspirin therapy in diabetes. Diabetes Care 2004; 27 Suppl 1: 72-73.

8. British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society, endorsed by the British
Diabetic Association. Joint British recommendations on prevention of coronary heart disease in clinical practice. Heart
1998; 80 Suppl 2: 1-9.

9. Antithrombotic Trialists’ Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative
meta-analysis of individual participant data from randomised trials. Lancet 2009;373:1849-60.

10. Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early treatment diabetic nephropathy study
report 14. ETDRS Investigators. JAMA. 1992; 268:1292-1300.

11. Ogawa H, Nakayama M, Morimoto T et al. Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes
(JPAD) Trail Investigators: Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2
diabetes: a randomised controlled trial. JAMA. 2008; 300:2134-41.

12. Sacco M, Pellegrini F, Roncaglioni MC, et al. Primary prevention of cardiovascular events with low-dose aspirin and
vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial. Diabetes Care 2003;26:3264-72.

13. Belch J, MacCuish A, Campbell I, et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial:
factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic
peripheral arterial disease. BMJ 2008;337:1840-50.

14. Physicians Health Study: aspirin and primary prevention of coronary heart disease. N Engl J Med 1989; 321: 1825-8.

15. Ridker PM, Cook NR, Lee IM et al. A randomised trial of low-dose aspirin in the primary prevention of cardiovascular
disease in women. N Engl J Med 2005; 352: 1293-304.

16. Zhang C, Sun A, Zhang P et al. Aspirin for primary prevention of cardiovascular events in patients with diabetes: a meta-
analysis. Diab Res Clin Prac. 2010;87:211-218.

17. Younis N, Williams S, Ammori B et al. Role of aspirin in the primary prevention of cardiovascular disease in diabetes
mellitus: a meta-analysis Expert Opin. Pharmacother. 2010; 11:1459-1466.

18. National Health and Medical Research Council. How to review the evidence: systematic identification and review of the
scientific literature. Canberra: Commonwealth of Australia. 2000.

19. Mulrow CD. Rationale for systematic reviews. BMJ (Clinical research ed). 1994 Sep 3;309(6954):597-9.

20. Glasziou P, DelMar C, Salisbury J. Evidence based medicine workbook. Finding and applying the best research evidence
to improve patient care. 2nd edn. London: BMJ Books Blackwell, 2007.

21. Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1. The Cochrane
Collaboration 2008.

22. The University of Queensland, School of Population Health. Evidence Based Medicine Workbook for Year 2 students,
2009.

23. Lanas A, Scheiman J. Low-dose aspirin and upper gastrointestinal damage: epidemiology, prevention and treatment. Curr
Med Res Opin. 2007; 23:163-73.

24. Elmer GW, Lafferty WE, Tyree PT et al. Potential interactions between complementary/alternative products and
conventional medicines in a medicare population. Ann Pharmacother. 2007;41(10):1617-1624.

25. A Study of Cardiovascular Events in Diabetes (ASCEND). Available from: http://www.cstu.ox.ac.uk/ascend/ (Last
accessed 10 June 2010).

26. De Berardis G, Sacco M, Evangelista V, et al. Aspirin and Simvastatin Combination for Cardiovascular Events Prevention
Trial in Diabetes (ACCEPT-D): design of a randomized study of the efficacy of low-dose aspirin in the prevention of
cardiovascular events in subjects with diabetes mellitus treated with statins. Trials 2007;8:21-30.

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 IEvidence Based Answers to Clinical Questions: Appendices

APPENDIX 1
Table 1.1 Guidelines for the use of aspirin for primary prevention of MI in diabetic patients

SOURCE RECOMMENDATION

Diabetes Australia and Royal Australian
College of General Practitioners (guidelines
updated annually)4
National Health and Medical Research
Council (NHMRC)5
United States Preventive Services Task Force6
American Diabetes Association and American
Heart Association7
British Cardiac Society and British Diabetic
Association8
Prophylactic aspirin (75–325 mg/day) for people with diabetes unless
contraindicated
Prophylactic aspirin (75–325 mg/day) should be considered for people
with type 2 diabetes unless contraindicated
Aspirin (75 mg/day) should be used for primary prevention in people
with diabetes who have a 5-year risk ≥ 3% of a CHD event
Aspirin (75–162 mg/day) strongly recommended for people aged
> 40 years with diabetes or with an additional risk factor for vascular
disease
Cardioprotective use of aspirin (75 mg/day) in people with diabetes or
other risk factors aged > 50 years with an absolute CHD risk ≥ 15%
over 10 years

APPENDIX 2

Image 2.1 PubMed search strategy and links to articles

A broad search of our key terms was performed initially and our search gradually narrowed with the
use of the Boolean operator “AND”, selecting only randomised controlled trials and systematic
reviews through “Clinical Queries”, and by using “Limits”, restricting the results to articles in
English and from the past three years. This search yielded a final result of 9 articles that matched our
PICO question.

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 IIEvidence Based Answers to Clinical Questions: Appendices

Image 2.2 PubMed search results

Results are ordered by publication date (descending). The two articles selected are boxed and
enlarged. Blue box (Zhang et al., 2009): Primary article appraised; Red box (Younis et al., 2010):
Alternative article.
Link to Zhang et al., 200916: http://www.ncbi.nlm.nih.gov/pubmed/19853947
Link to Younis et al., 201017: http://www.ncbi.nlm.nih.gov/pubmed/20429671

Image 2.3 Cochrane Library Search Strategy

A search of The Cochrane Library using the key terms of our PICO question. Search was restricted
to the title, abstract, and keywords. The wildcard * was used in the searches primary prevent* and
myocardial infarct* such that it would broaden the search. The search yielded 16 results (0 Cochrane
reviews, 0 other reviews, and 16 clinical trials). Our key article was found found in PubMed and not
found in Cochrane which is published quarterly.

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 IVEvidence Based Answers to Clinical Questions: Appendices

APPENDIX 3
Calculation of time-scale

Mean follow-up for the meta-analysis = 5.529 years (for calculation of NNT)
Mean follow-up for JPAD, POPADAD, and PPP = 4.933 years (for calculation of NNH)

Calculation of NNT (for primary prevention of myocardial infarction)

Experimental event rate (EER)

Control event rate (CER)
Absolute risk reduction (ARR)
Number needed to treat (NNT)

EER = 392/5828
CER = 444/5792
ARR = CER – EER = 0.00940

NNT = 1/AAR = 106.4 = 107

Thus, 107 people would need to be on low-dose aspirin therapy for 5.529 years to prevent one
myocardial infarction.

For one year: 106.4*5.529 = 588.3 = 589

Thus, 589 people would need to be on low-dose aspirin therapy to prevent one myocardial infarction
each year.
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 IVEvidence Based Answers to Clinical Questions: Appendices

Calculation of NNH (for major bleeding)

Mean follow-up for JPAD, POPADAD, and PPP = 4.933 years (for calculation of NNH)

Experimental event rate (EER)

Control event rate (CER)
Number needed to harm (NNH)

EER = 72/2419
CER = 42/2427

NNH = 1/(CER-EER) = 80.26 = 81

Thus, when 81 people take aspirin for 4.933 years, 1 person will experience a major bleed.

For one year: 80.26*4.933 = 395.95 = 396

Thus, if 396 people took low-dose aspirin, 1 person will experience a major bleed in a year.

General Practice, Rotation 3, 2010 Samuel Chan and Theodore Lau