This study evaluated the effects of low-dose aspirin (100 mg daily) for primary prevention of vascular events in 15,480 adults with diabetes but no known cardiovascular disease. It found that aspirin led to a 12% lower risk of serious vascular events but also a 29% higher risk of major bleeding. The number of vascular events prevented was similar to the number of major bleeding events caused. Therefore, the benefits of aspirin did not clearly outweigh the risks for primary prevention among adults with diabetes but no known cardiovascular disease.

1. Effects of Aspirin for Primary
Prevention in Persons with
Diabetes Mellitus
(The ASCEND Study Collaborative Group)
DOI: 10.1056/NEJMoa1804988
August 26, 2018
Dr. Shadab Ahmad

2. Background
• Patients with DM have a risk of vascular events 2-3 times higher than among those
without diabetes.
• Use of Aspirin reduces the risk of occlusive vascular events but increases the risk of
bleeding.
• In 2009 Antithrombotic Trialists’ Collaboration meta-analysis involving 95,000 patients in
six primary prevention trials showed that assignment to aspirin use led to a 12% lower
risk of serious vascular events than control however, 50% higher risk of bleeding with
aspirin use than with control (Only approximately 4% of participants in those trials had
diabetes).

4. • The ASCEND(A Study od Cardiovascular Events in Diabetes) randomized trial
was performed to assess the efficacy and safety of enteric-coated aspirin at a dose
of 100 mg daily, as compared with placebo, in person who had diabetes without
manifest cardiovascular disease.

5. Inclusion Criteria
• Men and women at least 40 years of age diagnosed as diabetes mellitus(any type)
and did not have known cardiovascular disease.

6. Exclusion Criteria
• Patients with a clear indication to aspirin.
• The presence of other clinically significant conditions that might limit adherence
to the trial regimen for at least 5 years.

8. Procedures
Potential Participants
Screening Questionnaire
Not willing to participate(excluded)
Willing to participate and eligible
(Aspirin group + Placebo group)
Pre-randomization run-in phase
(Blood & urine investigations, BP, Weight & height)
Randomization Questionnaire
Not willing to participate(excluded)
Willing to participate & eligible (15480)
Aspirin group (100 mg/d)(7740) Placebo group or n-3 fatty acid (7740)
Follow up questionnaires regarding all serious adverse events, adherence to trials, use of non-trial antiplatelet
or anticoagulation therapy, non serious adverse drug reactions resulting discontinuation of trial regimen and
symptomatic bleeding episodes every 6 monthly until end of the trial (i.e. 2.5 years)

9. Primary Efficacy Endpoints
• Nonfatal myocardial infarction,
• Nonfatal stroke(excluding confirmed intracranial hemorrhage)
• TIA
• Death from any vascular cause (excluding confirmed intracranial hemorrhage)

10. Primary Safety Endpoints
• Any confirmed intracranial hemorrhage
• Sight-threatening bleeding event in the eye
• Gastrointestinal bleeding
• Any bleeding events that resulted in hospitalization or transfusion or fatal events

11. Secondary Endpoints
• Any gastrointestinal tract cancer
• Any serious vascular event
• Any arterial revascularization procedure

12. Results
Effects on the Primary and Secondary Vascular outcomes
• In exploratory analysis, the risk difference was seen mainly in the first 5 years,
with no further gain subsequently in the number of participants avoiding an event.
• Pre-specified exploratory analyses showed no significant effect of aspirin use, as
compared with placebo, on the rate of death from all vascular cause combined,
which represented approximately 30% of all deaths.

13. Effects on the Primary Safety Outcome and another
bleeding
• There was a significant adverse effect of assignment to the aspirin group, as
compared with the placebo group, on the incidence of major bleeding.
• Exploratory analysis did not suggest an attenuation of the effect on bleeding over
time.
• Of the first major bleeding events, 41.3% were gastrointestinal(62.3% were in the
lower GIT, 2.2% were perforation and 2.6% were undetermined), 21.1% were
sight-threatening bleeding events in the eyes, 17.2% were intracranial bleeding
events, and 20.4% were bleeding events in other sites(mainly hematuria &
epistaxis).

14. • The incidence of fatal bleeding events & hemorrhagic stroke was similar among
those in the aspirin group.

15. Effects on Vascular events and Bleeding according to
baseline characteristics
• The proportional effects of aspirin use on the combined outcome of serious
vascular events or revascularization and on the safety outcome of major bleeding
did not show clear evidence of variation according to particular baseline
characteristics.

16. Effects on other Vascular and Microvascular outcomes
• The results regarding the vascular events show trends that are generally similar to
those regarding serious vascular events
• There was no apparent effect of aspirin use on selected microvascular events.

19. Discussion
• In this trial involving persons who had diabetes without manifest cardiovascular
disease, assignment to the use of aspirin at a dose of 100 mg daily for 7.4 years
resulted in a risk of serious vascular events that was 12% lower than that with
placebo but, also in a risk of major bleeding that was 29% higher.
• In contrast to previous trials where high rates cardioprotective treatments with
statins and blood pressure lowering therapy were used, the present trial provides a
direct assessment of the balance of the benefits and hazards of aspirin use.

20. • In this trial, the large number of participants, long duration of follow-up, the
randomized blinded design of the trial and the most complete follow-up of the
participants have allowed reliable detection of the incidence of the vascular events
(both the severity and incidence of bleeding).
• The predicted number of serious vascular events that would be avoided by
participants actually taking aspirin was closely balanced by the predicted number
of major bleeding events.

21. • Approximately half the excess of bleeding was in the GIT with approximately
1/3rd in the upper GIT and it is possible that bleeding rates among aspirin users
might be lower if PPIs were routinely used in these patients.

22. Conclusion
• The use of low dose aspirin led to a lower risk of serious vascular events than
placebo among persons with diabetes who did not have evident cardiovascular
disease.
• However, the absolute lower rates of serious vascular events were of similar
magnitude to the absolute higher rates of major bleeding, even among participants
who had a high vascular risk.

24. • ARRIVE is a randomized, double-blind, placebo-controlled, multicenter study
done in seven countries.
• Eligible patients were aged 55 years (men) or 60 years (women) and older and had
an average cardiovascular risk, deemed to be moderate on the basis of the number
of specific risk factors.
• Patients at high risk of gastrointestinal bleeding or other bleeding, or diabetes were
excluded.

25. • Patients were randomly assigned (1:1) with a computer-generated randomization
code to receive enteric-coated aspirin tablets (100 mg) or placebo tablets, once
daily.
• The primary efficacy endpoint was a composite outcome of time to first
occurrence of cardiovascular death, myocardial infarction, unstable angina, stroke,
or transient ischemic attack.
• Safety endpoints were haemorrhagic events and incidence of other adverse events,
and were analysed in the intention-to-treat population.

26. • Between July 5, 2007, and Nov 15, 2016, 12 546 patients were enrolled and
randomly assigned to receive aspirin (n=6270) or placebo (n=6276) at 501 study
sites.
• Gastrointestinal bleeding events (mostly mild) occurred in 61 (0·97%) patients in
the aspirin group versus 29 (0·46%) in the placebo group.
• The overall incidence rate of serious adverse events was similar in both treatment
groups (n=1266 [20·19%] in the aspirin group vs n=1311 [20·89%] in the placebo
group.

27. • The overall incidence of adverse events was similar in both treatment groups
(n=5142 [82·01%] vs n=5129 [81·72%] in the placebo group).
• The overall incidence of treatment-related adverse events was low (n=1050
[16·75%] vs n=850 [13·54%] in the placebo group; p<0·0001)
• Thus we can conclude that the role of aspirin in primary prevention among
patients at moderate risk could therefore not be addressed.

28. Thank You