Diabetes trial

1. Moderator- Speaker-
Dr. Dhiraj Kishore Satya Prasad Mahapatra

3. Aspirin (acetylsalicylic acid)
• Irreversibly blocks cyclo-oxygenase 1 and 2
• Low-dose aspirin (typically 75-162 mg) results
in inhibition of TXA2 and prostacyclin synthesis
– Inhibits platelet aggregation, vasoconstriction and
proliferation of vascular smooth-muscle cells
– Increased risk of GI bleed with long-term use

4. Mechanism of Action: Aspirin
Cardio protection GI bleed

5. Background
• Aspirin and cardiovascular disease
– Aspirin use is well established in secondary prevention of
cardiovascular disease.
– Diabetes is associated with increased cardiovascular risk 1
but it is unclear whether aspirin should be routinely
prescribed to prevent a first cardiovascular event 2-4
• Aspirin and cancer
– After analyses of selected randomized trials of aspirin
suggest reductions in the risk of cancer, particularly
gastrointestinal cancers, with effects apparent after
about 3 years 1. Lancet. 2010 Jun 26; 375(9733):2215-22
2.Lancet. 2009 May 30;373(9678):1849-60.
3. JAMA. 2014; 312:2510-2520
4.Am J Med. 2016; 129:e35-e36.

6. • Background( continue)
• 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).

7. Study Objective
• To assess the efficacy and safety of aspirin
compared to placebo in people who have diabetes
without any history of CV disease

8. Study Design
• Multicenter, randomized, two-by-two
factorial, double-blind, placebo controlled
trial
• Enteric coated aspirin 100 mg vs placebo
• Omega-3 fatty acid 1 g capsule vs placebo*
• Enrolment period: June 2005 - July 2011
• Setting: United Kingdom
• Follow-up: Mean 7.4 years
* Results reported separately

10. Study Population
• Inclusion Criteria:
• Men and women > 40 years of age
• Diagnosis of type 1 or 2 diabetes
• Absence of baseline CV disease

11. Exclusion Criteria:
• Clear indication for aspirin
• The presence of other clinically significant
conditions that might limit adherence
to the trial regimen for at least 5 years
• Contraindication to aspirin

12. Patient Enrolment and Follow-up
* Family doctor informed of potential participation
Requested to submit blood/urine samples and vitals

18. Statistical Analysis
• We used log-rank methods to conduct
intention-to-treat comparisons in time-to-
event analyses of the first occurrence of each
type of event of interest among participants in
the aspirin group as compared with those in
the placebo group.

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

20. 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

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

22. Results

23. Effects on the Primary and Secondary
Vascular outcomes:
• During the scheduled intervention period, the
primary efficacy outcome occurred in a significantly
lower percentage of participants in the aspirin group
than in the placebo group (658 [8.5%] vs. 743 [9.6%];
rate ratio, 0.88; 95% CI, 0.79 to 0.97; P = 0.01)

25. • 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.

27. • 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.

29. 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.
(314 participants [4.1%] vs. 245 [3.2%]; rate
ratio, 1.29; 95% CI, 1.09 to 1.52; P = 0.003)

31. • Exploratory analysis did not suggest an
attenuation of the effect on bleeding over
time.

32. • Of the first major bleeding events,
– 41.3% were gastrointestinal
• 62.3% were in the upper gastrointestinal tract,
• 32.9% were in the lower gastrointestinal tract,
• 2.2% were perforations
• 2.6% were undetermined
– 21.1% were sight-threatening bleeding events in eye
– 17.2% were intracranial bleeding events
– 20.4% were bleeding events in other sites
(mainly hematuria and epistaxis)

33. • The incidence of fatal bleeding events was similar among
persons in the aspirin group and among those in the placebo
group, as was the incidence of hemorrhagic stroke

34. 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.
• The incidence of a major bleeding event increased with
vascular risk.

36. 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 micro-vascular events.

37. Effects on Cancer and Other
Nonvascular Outcomes
• There was no difference in the risk of
gastrointestinal tract cancer, nor was there a
suggestion of an effect emerging with longer
follow-up.

39. • The trial groups also did not differ
significantly with regard to the risk of fatal or
nonfatal cancer overall or at particular sites.

42. 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

43. • In contrast to previous trials where high rates
cardio-protective 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.

44. • In this trial, the large number of participants, long
duration of follow-up, the randomized blinded
design of the trial and the almost complete
follow-up of the participants have allowed
reliable detection of the incidence of the vascular
events (both the severity and incidence of
bleeding).

45. • 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.

46. • Approximately half the excess of bleeding was
in the GIT, with approximately 1/3 rd 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.

47. • More than 7 years of aspirin treatment and
follow-up in ASCEND, we found no evidence of
a reduction in the incidence of gastrointestinal
tract cancer or of cancer at any other site,
even during the later years of follow-up.

48. 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.

50. Study Critique

51. Recommendations for Clinical Practice
COR: class of recommendation; LOE: level of evidence