Low-Dose Aspirin for the Primary Prevention of Atherosclerotic Events in Patients With Type 2 Diabetes A Randomized Controlled Trial

1
Low-Dose Aspirin for the Primary Prevention of
Atherosclerotic Events in Patients With Type 2
Diabetes A Randomized Controlled Trial

• Hisao Ogawa, MD, PhD
• Department of Cardiovascular Medicine Graduate
  School of Medical Sciences
• Kumamoto University Kumamoto, Japan

??.?.??????? ?????????? ??.?.????????
???????? ???.?????? ??????????? Ambulatory care
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Outline

• ?????????????????
• ???????????????????????
• Abstract
• Background
• Method
• Results
• Comment

3
?????????????????

• ???????????????? Aspirin ????????????
  Atherosclerotic ??????????????????????? 2
  ????????
• ?????? Aspirin ???????????????????????????
  Atherosclerotic ???????????????????????????

4
???????????????????????
Limit English
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(No Transcript)
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Impact factor 31.7
JAMA, November 12, 2008Vol 300, No. 18
7
Author

• Hisao Ogawa, MD, PhD
• Department of Cardiovascular Medicine Graduate
  School of Medical Sciences, Kumamoto University,
  Kumamoto, Japan

Coauthors Masafumi Nakayama, Takeshi Morimoto,
Shiro Uemura, Masao Kanauchi, Naofumi Doi,
Hideaki Jinnouchi, Seigo Sugiyama, Yoshihiko Saito
8
Financial Disclosures

• Grant support for JPAD from Ministry of Health,
  Labour and Welfare (Japan)
• Grant support from Astellas, AstraZeneca, Banyu,
  Bayer Yakuhin, Boehringer lngelheim, Cathex,
  Chugai, Daiichi Sankyo, Dainippon Sumitomo,
  Eisai, Get Bros., Guidant Japan, Japan Lifeline,
  Kaken, Kissei, Kowa, Kyowa Hakko, Mitsubishi
  Tanabe, Mochida, Nihon Kohden, Nihon Schering,
  Novartis, Otsuka, Pfizer, Pharmacia, Sankyo,
  Sanofi-Aventis, Sanwa Kagaku Kenkyusho,
  Schering-Plough, Sionogi, Sumitomo, Taisho
  Toyama, Takeda, Mitsubishi Tanabe, Teijin, Toa
  Eiyo, Torii, Toyama, Tyco Healthcare Japan,
  Vitatron Japan, Zeria, Novo Nordisk, Higo
  Foundation for Promotion of Medical Education and
  Research, Japan Foundation of Applied Enzymology,
  Japan Heart Foundation, Japanese Society of
  Interventional Cardiology, Kimura Memorial Heart
  Foundation, Kumamoto Medical Society, Smoking
  Research Foundation and Takeda Science Foundation
  for the past 5 years. No other potential conflict
  of interest relevant to this study was reported.

9
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??? ???????????????????????? ?????????????????????
?????????????????????????
1

• ????????????? ??????????????????????????????
  Journal of American Medical Association (JAMA)
  ??????????????????????????????????????????????????
  ??

10
????????????? ????????????????????????????????????
?????????????? ????????????????????????????
2
Low-Dose Aspirin for the Primary Prevention of
Atherosclerotic Events in Patients With Type 2
Diabetes A Randomized Controlled Trial

• ???????????????????????? ????????????????????????
  ?????? low-dose aspirin ????????????????????
  Atherosclerosis ???

11
????????????????????????? ????????????????????????
?????????????????????????????????????????
3

• Hisao Ogawa, MD, PhD
• Department of Cardiovascular Medicine Graduate
  School of Medical Sciences, Kumamoto University,
  Kumamoto, Japan

?????????????????????????? Cardiovascular
12
????????????????????????????????????????????
??????????????????????????????????????????
4

• Financial Disclosures
• Grant support for JPAD from Ministry of Health,
  Labour and Welfare (Japan)
• Grant support from Astellas, AstraZeneca, Banyu,
  Bayer Yakuhin, Boehringer lngelheim, Cathex,
  Chugai, Daiichi Sankyo, Dainippon Sumitomo,
  Eisai, Get Bros., Guidant Japan, Japan Lifeline,
  Kaken, Kissei, Kowa, Kyowa Hakko, Mitsubishi
  Tanabe, Mochida, Nihon Kohden, Nihon Schering,
  Novartis, Otsuka, Pfizer, Pharmacia, Sankyo,
  Sanofi-Aventis etc.

• ???????????????????????????????????
  ????????????????????????????????????????????????
  ????????? Aspirin ????????????????????????????????
  ???????????????

13
?????????????????????? Objective, Study design,
Setting, Patients, Intervention, Main outcome
measures, Results and Conclusion ???????
7
14
Background

• Risk of CV events is increased from 2- to 4-fold
  in type 2 diabetes
• Aspirin is recommended for primary prevention in
  patients with type 2 diabetes in many guidelines,
  including ADA

15
Background

• In subgroups with diabetes did not demonstrate a
  significant effect on reducing vascular events
  because they were underpowered.
• This trial was undertaken to examine the efficacy
  of low-dose aspirin therapy for the primary
  prevention of atherosclerotic events in patients
  with type 2 diabetes.

16
????????????????????????????????????????
???????????????????????????????????????????
??????????????????????????????????????????????????
???????????????????????????????????????
6

• ??????????????? Guideline ??? ADA 2003
  ??????????????? aspirin ???? primary prevention
  ??????????????????????????????????????????????????
  ??? ???????????? Guideline ?????????????????
  aspirin ???? primary prevention ????????????????
  ??????????????? 2002-2008

17
??????????????????????????????????????????????????
????????????????? ????????????????????????????????
?????????????????????
8

• ????????????????????????????????????????
  ??????????????????????????????????????????
  low-dose aspirin ???????????????????
  atherosclerosis ??????????? power ??????????
• ????????????????????????????????? ?????????????
  Guideline ??????????? aspirin ???? primary ???
  secondary prevention ?????????????????????????????
  ??????? aspirin ???? primary prevention ??????????

18
??????????????????????????????????????????????????
????????????????
9

• ????????????????????????????? ????????????????????
  ???? low-dose aspirin ???????????????????
  atherosclerosis ??????????????????????? 2

19
Method

• Design Prospective, randomized, open-label,
  controlled trial with blinded end point
  assessment
• 163 institutions in Japan from December 2002 to
  May 2005 with follow-up to April 2008
• The institutional review board at each
  participating hospital approved this trial, and
  written informed consent was obtained from each
  patient.

20
Trial Population

• Inclusion Criteria Type 2 diabetes between ages
  30 and 85 years
• Exclusion Criteria
• electrocardiographic changes
• a history of coronary heart disease confirmed by
  coronary angiography
• a history of cerebrovascular disease
• a history of arteriosclerotic disease
• atrial fibrillation
• pregnancy
• use of antiplatelet or antithrombotic therapy,
• a history of severe gastric or duodenal ulcer
• severe renal and liver dysfunction
• allergy to aspirin.

21
Trial Protocol

• Enrolled patients were randomly assigned to the
  aspirin group (81 mg or 100 mg of aspirin OD) or
  the nonaspirin group by nonstratified
  randomization from a random number table.
• Follow-up visits were scheduled every 2 weeks for
  patients seen in a clinic setting and every
  4weeks for patients seen in a hospital setting.
• Data for patients who were lost to follow-up were
  included at the day of last follow-up.
• Patients in the non aspirin group were also
  allowed to use antiplatelet/thrombotic therapy,
  including aspirin, if needed.

22
End Points

• Primary end point any atherosclerotic event
• death from coronary, cerebrovascular, and aortic
  causes
• nonfatal acute myocardial infarction
• unstable angina
• newly developed exertional angina
• nonfatal ischemic and hemorrhagic stroke
• transient ischemic attack
• nonfatal aortic and peripheral vascular disease
• Secondary end points Each primary end point and
  combinations of primary end points and death from
  any cause
• Adverse events analyzed included gastrointestinal
  events and any hemorrhagic events other than
  hemorrhagic stroke

23
Sample size calculation

• The incidence of cardiovascular death 7.5,
  myocardial infarction 7.5, and cerebrovascular
  events 8.0 events per 1000 patients-year
  (Hisayama-cho study and Funagata study).
• The atherosclerotic events, including peripheral
  arterial disease, was suggested to be 3 times
  (HOT study).
• Discounted 25 of the estimated 69 events that
  were expected to occur and estimated that 52
  events per 1000 patients-year.

24
Sample size calculation

• Based on a 2-sided a level of .05, a power of
  0.95, an enrollment period of 2 years, and a
  follow-up period of 3 years after the last
  enrollment.
• We estimated that 2450 patients would need to be
  enrolled to detect a 30 relative risk reduction
  for an occurrence of atherosclerotic disease by
  aspirin.

25
Statistical Analyses

• Efficacy comparisons were performed on the basis
  of time to the first event, according to the
  intention-to-treat principle.
• Safety analyses were performed on data from all
  enrolled patients.
• Following the descriptive statistics, cumulative
  incidences of primary and secondary end points
  were estimated by the Kaplan-Meier method and
  differences between groups were assessed with the
  log-rank test.
• We used the Cox proportional hazards model to
  estimate hazard ratios (HRs) of aspirin use along
  with 95 confidence intervals (CIs).
• We used the x2 test or Fisher exact test to
  evaluate adverse events.

26
Statistical Analyses

• We also conducted subgroup analyses for
  predetermined subgroups
• Using the Cox proportional hazard model
• P values of less than .05 were considered
  statistically significant.

27
??????????????????????????????????
5

• ??????? ????????? 163 ????????????????????????????
  ?????? ?????????????????? ????????????????????????
  ????????????????

28
??????????????????????? (Study design)
????????????????????????? ?????????????????
10

• ??????????????? Prospective, randomized,
  open-label, controlled trial with blinded end
  point assessment ??????? ????????????????????????
  ????????????????? ?????????????? RCT
• ?????????????????????????????????????????????????
  ??????????????????????????????????????

29
??????????????????????????????????????????????????
???????? ???????????????????????????
11

• ????????????????????????????????????????????
• Inclusion Criteria Type 2 diabetes between ages
  30 and 85 years, and ability to provide informed
  comsent.
• Exclusion Criteria electrocardiographic changes
  consisting of ischemic ST-segment depression,
  ST-segment elevation, or pathologic Q waves a
  history of coronary heart disease confirmed by
  coronary angiography a history of
  cerebrovascular disease consisting of cerebral
  infarction, cerebral hemorrhage, subarachnoid
  hemorrhage, and transient ischemic attack a
  history of arteriosclerotic disease necessitating
  medical treatment atrial fibrillation
  pregnancy use of antiplatelet or antithrombotic
  therapy, defined as aspirin, ticlopidine,
  cilostazol, dipyridamole, trapidil, warfarin, and
  argatroban a history of severe gastric or
  duodenal ulcer severe liver dysfunction severe
  renal dysfunction, and allergy to aspirin.

30
?????????????????????????????????????????
?????????????????????????????????????????????????
12

• ??????????????????????? ??????????????????????????
  ????????? 2450 ???
• ????????????????? enrolled ???????????????? 2539
  ??? ??????????????????????????????????????????????
  ????????????

31
??????????????????????????????????????????????????
?????????????
15

• Enrolled patients were randomly assigned to the
  aspirin group or the nonaspirin group by
  nonstratified randomization from a random number
  table.
• The study center prepared the sealed envelopes
  with random assignments and distributed them by
  mail to the physicians in charge at the study
  sites.

32
??????????????? ??????? ??????????????????????????
?????????????????????????????????????????
16

• ????? aspirin ?????? aspirin ???? 81 ???? 100 mg
  ??????????????? ?????????????????????????? ADA
  2003 ??????????????? aspirin 81-325 mg
  ??????????????????????????????????????????????????
  ??????????
• ?????????????????????? 2002-2005
  ????????????????????????????????????? aspirin
  ??????????????????? atherosclerosis
  ??????????????????????????????? 2008

33
????????????????????????????????????????????????
???????????????????? (Washout period)
??????????????
17

• ??????????????????????????????????????????????????
  ????????????????? ????????????????????????????????
  ? (Washout period)

34
????????????? (???????????????????????????)
????????????????????????????????????
??????????????????????????????????????????????
18

• ???????????????????????????????????????????
  ????????????????????????????? ??????
  ?????????????? 2 ??????????????? ???????????????

35
??????????????????????? (???? single blind,
double blind ???????) ???????
19

• ??????????????? open-label ???????????????????????
  ????????????????????????? (blinded end-point
  assessment)

36
??????????????????? ??????????????????????????????
???????????????? ?????????????????????? (blind
technique) ????????????????????????
20

• ????????????????????????????????????
• ?????????????????????????????????????????????
  (blinded end-point assessment)

37
????????????????????????????????????????
21

• ????????????????????????????????????????????
  ?????????????? atherosclerotic events
  ????????????????????????????????

• Primary end point any atherosclerotic event
• Secondary end points Each primary end point and
  combinations of primary end points and death from
  any cause
• Adverse events analyzed included gastrointestinal
  events and any hemorrhagic events other than
  hemorrhagic stroke

38
??????????????????????????? subjective ????
objective ???????
22

• ??????????????????????????? Objective ??????
  ??????? atherosclerotic events

39
??????????????? ????????????????
???????????????????????????????????????????
??????????????????????????????????????????????????
??????
23

• ??????? atherosclerotic events ???????????????????
  ????? ????????????????????????????????????????????
  ????????

40
?????????????????????????????? ?????????????????
24

• ???????? aspirin 2002-2005 ????????????????????
  2008 ?????????????????????????????????????????????
  ??

41
?????????????????????????????????????????
28

• ???????????????????????? ????????????????????????

42
Results

• Study population
• Baseline clinical characteristics
• Efficacy analysis
• Subgroup analysis
• Safety

43
Study population
2567 Patients were screened
28 Excluded 6 Withdrew consent 10 History of
atherosclerotic disease 10 Aged gt85 years 1 No
diabetes 1 Receiving warfarin
2539 Randomized
1262 Randomized toreceive aspirin
1277 Randomized to nonaspirin group
9 Received aspirin or other antiplatelet
therapy 6 Received aspirin 3 Received other
antiplatelet medication
1139 Received aspirin through completion of
trial 123 Stopped taking aspirin
1181 Followed up through end of study 96 Lost to
follow-up
1165 Followed up through end of study 97 Lost to
follow-up
1262 Included in efficacy and safety analyses
1277 Included in efficacy and safety analyses
44
Baseline Clinical Characteristics
Baseline Clinical Characteristics
45
Baseline Clinical Characteristics
46
??????????? ????????????? (???? ???????? ???
???????????????? ???????) ????????????????????????
?????? ??????????????????? ??????????? ???????
??????????????????????????????????????????????????
?????????
13

• ????????????????????????????????????????
  ??????????????????????????????????????????????????
  ???????????????????

47
????????????????????????????????????
14

• ??????????????????????????????????????????????????
  ????????????????????????? ????????????????????????
  ???????????????????????

48
Efficacy analysis
49
Primary End Point Total Atherosclerotic Events
According to the Treatment Groups
10
8
Log-Rank Test, P 0.16 HR (95 CI) 0.80
(0.581.10)
6

4
Aspirin Group
Nonaspirin Group
2
0
Years
0
1
2
3
4
5
50
Subgroup Analysis
Events, No./Total No.
Favors No Aspirin
Favors Aspirin
Age, y Aspirin Group Nonaspirin Group Hazard Ratio (95 CI) Hazard Ratio (95 CI)
65 45/719 59/644 0.68 (0.460.99) 0.68 (0.460.99)
lt65 23/543 27/633 1.0 (0.571.70) 1.0 (0.571.70)

Gender Gender Gender Gender Gender
Male 40/706 51/681 0.74 (0.491.12) 0.74 (0.491.12)
Female 28/556 35/596 0.88 (0.531.44) 0.88 (0.531.44)

Hypertensive Status Hypertensive Status Hypertensive Status Hypertensive Status Hypertensive Status
Hypertensive 49/742 55/731 0.88 (0.601.30) 0.88 (0.601.30)
Normotensive 19/520 31/546 0.64 (0.361.13) 0.64 (0.361.13)

Lipid Status Lipid Status Lipid Status Lipid Status Lipid Status
Dyslipidemia 38/680 43/665 0.88 (0.571.37) 0.88 (0.571.37)
Normolipidemia 30/582 43/612 0.71 (0.451.14) 0.71 (0.451.14)

Smoking Smoking Smoking Smoking Smoking
Current or past smoker 36/565 42/494 0.73 (0.471.14) 0.73 (0.471.14)
Nonsmoker 32/697 44/783 0.83 (0.531.31) 0.83 (0.531.31)
0.3
Hazard Ratio (95 CI)
51
Adverse Events
52
Adverse Events

• No difference between aspirin group (10 patients)
  and nonaspirin group (7 patients) for composite
  of hemorrhagic stroke and severe GI bleeding
• 4 cases of severe gastrointestinal (GI) bleeding
  that required transfusion in aspirin group
• 6 hemorrhagic strokes (1 fatal) in aspirin group
  and 7 hemorrhagic strokes (4 fatal) in nonaspirin
  group

53
???????????????????????????????? ???????
?????????????????
25

• ????????????????????? ?????? Baseline clinical
  characteristics, Efficacy analysis, Subgroup
  analysis ??? Safety ???????????
  ???????????????????????

54
???????????????????????????????????
26

• ????????????????????? ?????? Baseline clinical
  characteristics, Efficacy analysis, Subgroup
  analysis ??? Safety

55
??????????????????????????????????????????????????
????????????????? (drop out) ???????
27

• ????????? Drop out 193 ??? (97 ????? aspirin
  group, 96 ????? nonaspirin group)
  ?????????????????????????????? drop out

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Comment

• This trial the sample size was the largest among
  the previous primary prevention studies in
  respect to the number of diabetic patients
  enrolled.
• However, no difference was found in the effect of
  aspirin on the primary end point or most
  secondary end points.
• A benefit of low-dose aspirin on the primary end
  point also was suggested in the subgroup of
  patients aged 65 years or older, which had a
  significant 32 relative reduction in total
  atherosclerotic events (P.047).

57
Comment

• The interpretation of these results is
  challenging because the overall event rates were
  low17 in 1000 Japanese diabetic patients.
• This is one-third of the event rate anticipated
  in our sample-size calculations, which were based
  on the Hisayama-cho and Funagata epidemiologic
  studies conducted in Japan in the 1990s.

58
Comment

• A meta-analysis of primary prevention trials
  showed that aspirin therapy
• significantly reduced the risk of total coronary
  heart disease, nonfatal myocardial infarction,
  and total cardiovascular events
• nonsignificant trend for decreased risk of
  stroke, cardiovascular mortality, and all-cause
  mortality.
• Previous studies investigating the effects of
  low-dose aspirin on primary prevention of
  cardiovascular events did not enroll solely
  diabetic patients.

59
Comment

• The study design may be considered a limitation
  of the JPAD trial (prospective, randomized,
  open-label, controlled trial with blinded
  end-point assessment), as it did not have the
  advantages of a double-blind, randomized trial.
• However, the end-point classification was
  conducted by a blinded, independent committee on
  validation of data and events that was unaware of
  the group assignments.

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Summary

• Low-dose aspirin as primary prevention did not
  reduce the risk of cardiovascular events.
• Aspirin was well tolerated in these patients, as
  there was no increase in hemorrhagic strokes and
  a small increase in serious GI hemorrhagic.

61
??????????????????????????????????????????????????
? ????????????????????????????????????????????????
29

• ????????????????? ????????????????????????????????
  ?????????
• ?????????????? Coronary and cerebrovascular
  mortality ???????? Secondary end point
  ????????????????? aspirin (P0.0037)
• ???????????? Subgroup analysis ???????????????????
  ????????? 65 ???????????? aspirin
  ??????????????????????????? Atherosclerotic
  events ??? 32 ??????????????????????????????
  (P0.047)

62
??????????????????????????????????????????????????
??
30

• ????????????????????????????? ??? ?????? Low-dose
  aspirin ??????????????????????? 2
  ???????????????? Atherosclerotic
  events????????????????????????????????????????????
  ???? Low-dose aspirin

63
??????????????????????????????????????????????????
??????????
31

• ???????????????????????????????????
  ??????????????????????????????????????????????
  Low-dose aspirin ??????????????????????? 2
  ????????????? Atherosclerotic events ???
• ??????????????? ?????? Low-dose aspirin
  ??????????????????????? 2 ?????????
  Atherosclerotic events ????????????????

64
??????????????????????????????????????????????????
?????????????????????? ???????????????????????????
??? ??????????????????????????????????????????????
??????????????????????
32

• ?????????????????????????????????????????
  Hisayama-cho ??? Funagata ?????????????????
  Atherosclerotic events ??????????????????????? 2
  ???? 52 ?? ??? 1000 person-years
  ??????????????????????????????????????????????????
  ????????????????????????????????????????????????
• ??????????????????????????????????? ??????
  British Doctors Trial, the Physicians Health
  Study, the Thrombosis Prevention Trial, the
  Hypertension Optimal Treatment (HOT) study, the
  Primary Prevention Project (PPP) trial, and the
  Womens Health Study

65
????????????????????????? ????????????????????????
???????????????
33

• ???????????????????????? Underpower
  ??????????????????????????????????????????????????
  ????????????