: .

. , MD, FESC, FAHA

- .
-

-
-



, ab,

AstraZeneca, Bayer, Sanofi, Pfizer,
Vianex, MSD, Unilever, Boehringer,
Novartis, Abbott, Galenica, Amgen,
Specifar, Menarini, Merck,
Pharmaswiss, Winmedica

PLATELET ORIGIN

Role of Platelet Activation and Aggregation in Ischemic Syndromes

Bhatt D. N Engl J Med 2007;357:2078-2081

The formula of aspirin is C9H8O4

Aspirin: modern medicine with ancient roots

Analgesic and antipyretic properties of willow bark
first recognised by Hippocrates
Natural salicin isolated from willow bark and used to yield
salicyclic acid; aspirin (acetylsalicylic acid) was derived from this
Aspirin first discovered by Bayer

Section 1

1897: acetylsalicylic acid first synthesised

1899: patented and marketed in tablet form
1900: first water-soluble tablets introduced by Bayer
1915: aspirin available without prescription
1993: enteric-coated Aspirin Cardio developed by Bayer

Aspirins mechanism of action

COX, cyclooxygenase.
Patrono C et al. N Engl J Med 2005;353:237383.

Section 2

Improvements in Primary Prevention

Physicians Health Study: 44% RRR in MI

HOT trial: 36% RRR in MI
PPP: 56% RRR in CV death
Metanalysis of 55.580 patients: 32% RRR
for 1st MI

Aspirin Evidence: Primary Prevention in Men

Physicians Health Study (PHS)
22,071 men randomized to aspirin (325mg every other day) followed for an
average of 5 years

End point
Myocardial infarction
Fatal
Nonfatal
Total

Relative Risk (95% CI)

P value

0.34 (0.15-0.75)
0.59 (0.47-0.74)
0.56 (0.45-0.70)

0.007
<0.00001
<0.00001

1.51 (0.54-4.28)
1.20 (0.91-1.59)
1.22 (0.93-1.60)

0.43
0.20
0.15

Stroke
Fatal
Nonfatal
Total

Aspirin significantly reduces the risk of MI in men

CI=Confidence interval, MI=Myocardial infarction
Physicians Health Study Research Group. NEJM
1989;321:129-35

Thrombosis Prevention Trial (TPT): design

TPT trial (1998)
Design

Randomised, factorial, double-blind

Objective

To evaluate low intensity oral anticoagulation with warfarin and

aspirin in the primary prevention of IHD

Patients

5499 men (aged 4569 years) at high risk of IHD (2025% of the
risk score distribution) included

Regimen

1272 received aspirin 75 mg/day and placebo warfarin, 1272

patients received placebo warfarin and placebo aspirin, 1268
patients received active warfarin INR: 1.5 and active aspirin, and
1277 received active aspirin and active warfarin

Primary endpoint

All IHD, defined as the sum of coronary death and fatal and
nonfatal MI

Mean follow-up

6.8 years

IHD, ischaemic heart disease; MI, myocardial infarction.

1. Medical Research Councils General Practice Research Framework, Lancet 1998; 351:233-41.

Section 4

11

Thrombosis Prevention Trial (TPT): results

20% reduction in all IHD

(p=0.04)

32% reduction in nonfatal

IHD events (p=0.004)

IHD, ischaemic heart disease; MI, myocardial infarction.

The Medical Research Councils General Practice Research Framework. Lancet 1998;351:233241.

Section 4

12

Hypertension Optimal Treatment (HOT) trial:

design
HOT trial (1998)
Design

Randomised, double-blind

Objective

To assess whether aspirin, in addition to antihypertensive

therapy, reduces the incidence of major CV events

Patients

18 790 men and women (aged 5080 years; mean 61.5 years)
9399 patients received aspirin and 9391 received placebo

Regimen

Aspirin 75 mg/day was randomly added to antihypertensive

treatment (felodipine and if necessary stepwise ACE inhibitors in
3545% cases, beta-blockers, diuretics)

Mean follow-up

3.8 years (range 3.34.9 years)

ACE, angiotensin converting enzyme; CV, cardiovascular; MI, myocardial infarction.

1. Hansson L, et al. Lancet 1998;351:175562.

Section 4

13

Hypertension Optimal Treatment (HOT) trial:

results

CV, cardiovascular.
1. Hansson L, et al. Lancet 1998;351:175562.

Section 4

14

Hypertension Optimal Treatment (HOT) trial:

results

MI, myocardial infarction.

1. Hansson L, et al. Lancet 1998;351:175562.

Section 4

15

Primary Prevention Project (PPP): design

PPP trial (2003)
Design

Randomised, open-label, factorial trial

Objective

To test whether chronic treatment with aspirin and vitamin E

reduces the frequency of major CV events

Patients

4495 patients (mean age 64.4 years) with one or more of the
following: hypertension, hypercholesterolaemia, diabetes,
obesity, family history of premature MI, or individuals who are
elderly

Regimen

2226 patients received aspirin 100 mg/day and 2269 patients

did not receive aspirin

Primary endpoint

Cumulative rate of CV death, nonfatal MI and nonfatal stroke

Mean follow-up

3.6 years (terminated early)

CV, cardiovascular; MI, myocardial infarction.

1. Sacco M, et al. Diabetes Care 2003;26:326472.

Section 4

16

Primary Prevention Project (PPP): results

The Primary Prevention Project1 was stopped early because of
positive trends for aspirin in other trials2,3
Aspirin lowered the frequency of all endpoints, being significant
for CV death (from 1.4 to 0.8%; relative risk=0.56) and total CV
events (from 8.2 to 6.3%; relative risk=0.77)
The authors concluded that in men and women at risk of having a
CV event, aspirin contributes an additional preventive role, with
an acceptable safety profile

CV, cardiovascular.
1. Sacco M, et al. Diabetes Care 2003;26:326472;
2. Medical Research Councils General Practice Research Framework, Lancet 1998; 351:23341;
3. Hansson L, et al. Lancet 1998;351:175562.

Section 4

17

Aspirin Evidence: Primary Prevention

RR of MI
in Men

BDT, 1988
PHS, 1989

RR of CVA
in Men

TPT, 1998
HOT, 1998
PPP, 2001

RR = 0.68 (0.54-0.86)
P=0.001

Combined
0.2

0.5

1.0

2.0

5.0

RR = 1.13 (0.96-1.33)
P=0.15
0.2

0.5

1.0

2.0

RR of MI
in Women

HOT, 1998

5.0

RR of CVA
in Women

PPP, 2001
WHS, 2005

RR = 0.99 (0.83-1.19)
P=0.95

Combined
0.2

0.5

Aspirin Better

1.0

2.0

Placebo Better

CVA=Cerebrovascular accident, MI=Myocardial

infarction, RR=Relative risk

Ridker P et al. NEJM 2005;352:1293-304

5.0

RR = 0.81 (0.69-0.96)
P=0.01
0.2

0.5

Aspirin Better

1.0

2.0

Placebo Better

5.0

Aspirin is recommended in a range of US

guidelines
Guidelines

Recommendations

USPSTF, 20091

Aspirin therapy is recommended for prevention of first MI in men aged 4579 years
and for stroke prevention in women aged 5579 years

ACCF/AHA,
20092

These recommendations confirm the use of aspirin as primary prevention

ACCP, 20083

Aspirin 75100 mg/day is recommended in patients at moderate risk of a coronary

event

AHA (women),
20074

Aspirin 75325 mg/day is recommended in high-risk women unless contraindicated

AHA/ASA,
20075

Oral aspirin 325 mg is recommended within 2448 hours after the onset of a stroke

AHA, 20026

Aspirin 75160 mg/day is recommended for persons at higher risk (especially with
10-year risk of CHD of 10%)

ACCF, American College of Cardiology Foundation; ACCP, American College of Chest Physicians; AHA, American
Heart Association; ASA, American Stroke Association; CHD, coronary heart disease; MI, myocardial infarction.
1. USPSTF. Ann Intern Med 2009;150:396404; 2. Redberg RF, et al. Circulation 2009;120:1296336;
3. ACCP. Chest 2008;133:776S814S; 4. Mosca L, et al. Circulation 2007;115:14811501;
5. AHA/ASA. Stroke 2007;38:16551711; 6. AHA. Circulation 2002;106:388391.

Section 7

19

Aspirin is recommended in a range of

European and international guidelines
Guidelines

Recommendations

ESO, 20081

Aspirin is recommended for women aged 45 years who are not at increased risk for
intracerebral haemorrhage and who have good GI tolerance; aspirin may be
considered for men for the prevention of a first MI

ESH, 20092

the prudent recommendations of the 2007 ESH/ESC guidelines can be reconfirmed:

antiplatelet therapy, in particular, low-dose aspirin, should beconsidered in
hypertensive patients without a history of cardiovascular disease with reduced renal
function or with a high cardiovascular risk.

NICE, 20073

Aspirin should be offered to all patients who had had an acute MI

JBS 2, 20054

Aspirin 75 mg/day is recommended for people >50 years with a total CV disease risk
>20% and in patients with diabetes once blood pressure has been controlled to 150
mmHg systolic and 90 mmHg diastolic

WHO, 20075

Aspirin should be given to patients with a CV risk 30%

CV, cardiovascular; ESC, European Society of Cardiology; ESH, European Society of Hypertension; ESO, European Stroke
Organization; GI, gastrointestinal; JBS, Joint British Societies; NICE, National Institute of Clinical Excellence;
MI, myocardial infarction; WHO, World Health Organization.
1. ESO. http://www.eso-stroke.org/pdf/ESO08_Guidelines_Original_english.pdf; 2. Mancia G, et al. J Hypertens 2009;27:212158;
3. NICE. http://www.nice.org.uk/ nicemedia/pdf/CG48NICEGuidance.pdf; 4.JBS 2. Heart. 2005;91:v1v52;
5. WHO. http://www.who.int/publications/en/.

Section 7

20

Aspirin is consistently recommended in

patients with diabetes
Guidelines

Recommendations

ACC/ADA/AHA
20101

Consider aspirin therapy (75162 mg/day) for adults with diabetes and no previous
history of CVD, at increased CV risk (10-year risk >10%) with no risk for bleeding
Aspirin (75162 mg/day) might be used for those with diabetes at intermediate CVD

ADA, 20102

Consider aspirin therapy (75162 mg/day) as a primary prevention strategy in those

with type 1 or type 2 diabetes at increased CV risk (10-year risk >10%)

Diabetes UK,
20093

Aspirin should be offered to patients with diabetes and a history of CV disease;

patients with no known CV history should consult their physician

NICE, 20084

Aspirin 75 mg should be offered to people with type 2 diabetes aged 50 years if

blood pressure is <145/90 mmHg or to people with type 2 diabetes aged 50 years
with other significant CV risk factors

ESC and
EASD, 20075

Aspirin should be given for the same indications and in similar dosages to diabetic
and non-diabetic patients for CV risk management

AHA/ADA,
20076

Aspirin 75162 mg/day is recommended in patients with diabetes at increased CV

risk, including those >40 years or with additional risk factors

IDF, 20057

Aspirin 75100 mg/day is recommended for people with evidence of CV disease or

at high risk (unless aspirin-intolerant or with uncontrolled blood pressure)

ADA, American Diabetes Association; AHA, American Heart Association; CV, cardiovascular; EASD, European Association for the Study of
Diabetes; ESC, European Society of Cardiology; IDF, International Diabetes Federation; NICE, National Institute for Clinical Excellence.
1. Join Statement ACC/ADA/AHA: http://content.onlinejacc.org/; 2. ADA. Diabetes Care 2010;33(suppl 1):S11S61;
3. Diabetes UK. https://www.diabetes.org.uk/; 4. NICE. http://www.nice.org.uk/; 5. ESC/EASD Task Force. Eur Heart J 2007;28:88136;
6. Bluse JB, et al. Diabetes Care 2007;30:16272; 7. IDF. www.idf.org/.

Section 7

21

USPSTF recommendations for aspirin

USPSTF1 advocates an individualised patient- and sex-based
approach to treatment
Men aged 4579 years to use aspirin when the potential benefit of
a reduction in MI outweighs the potential harm of an increase in GI
haemorrhage
Women aged 5579 years to use aspirin when the potential benefit of
a reduction in ischaemic strokes outweighs the potential harm of an
increase in GI haemorrhage
Aspirin recommended in patients aged 80 years who are without
additional risk factors for GI bleeding/able to tolerate a GI bleeding
episode

The ACCF/AHA (2009) also acknowledges the USPSTF

algorithm2
ACCF, American College of Cardiology Foundation; AHA, American Heart Association; GI, gastrointestinal; MI, myocardial
infarction; USPSTF, US Preventive Services Task Force.
1. USPSTF. Ann Intern Med 2009;150:396404;
2. Redberg RF, et al. Circulation 2009;120:12961336.

Section 6

22

The USPSTF (2009) guidelines recommend

aspirin in primary prevention
The USPSTF found good evidence
that aspirin decreases the incidence
of MI in men and ischaemic strokes
in women1
Clinicians should inform patients
about GI bleeding because they
might be mitigated by a patients
early recognition of the signs and
symptoms1
The incidence of MI and stroke is
high in persons 80 years or older,
and thus the potential benefit of
aspirin is large1

CHD, coronary heart disease; CVD, cardiovascular disease; GI, gastrointestinal; MI, myocardial infarction;
USPSTF, US Preventive Services Task Force.
1. USPSTF. Ann Intern Med 2009;150:396404.

Section 7

23

The ADA (2010) reconfirm the role of aspirin

in diabetes
The ADA (2010) guidelines1 recommend aspirin
75162 mg/day as primary prevention in those with type 1 or 2
diabetes at increased CV risk >10%
The guidelines1 add that although two recent randomised
controlled trials (JPAD, POPADAD) failed to show significant
reductions in CV endpoints in diabetes, the ATTC (2009) metaanalysis found that aspirin reduced the risk of vascular events by
12% in primary prevention these findings were based on six key
trials involving 95 000 patients with 4000 diabetic patients

ADA, American Diabetes Association; ATTC, Antithrombotic Trialists Collaboration; CV, cardiovascular; JPAD,
Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes; POPADAD, Prevention Of Progression
of Arterial Disease And Diabetes .
1. ADA. Diabetes Care 2010;33(suppl 1):S11S61.

Section 7

24

25

Benefit of low-dose ASA therapy increases with

increased risk for CHD events

Outcome

Estimated 5-year risk for CHD

events at baseline
1%

3%

CHD events avoided

3 (14)

8 (412)

14 (620)

Haemorrhagic stroke caused

1 (02)

1 (02)

1 (02)

Major gastrointestinal bleeding

events caused

3 (24)

3 (24)

3 (24)

CHD = coronary heart disease

5%

US Preventive Services Task Force. Ann Intern Med 2002;136:15760

JPAD study: design

JPAD trial (2008)

Design

Multicentre, prospective, randomised, blinded, endpoint trial

Objective

To examine the efficacy of aspirin for the primary prevention of

atherosclerotic events in patients with type 2 diabetes

Patients

2539 patients (mean age 65 years; 55% males) with type 2

diabetes without a history of atherosclerotic disease

Regimen

1262 patients randomised to receive aspirin 81100 mg/day and

1277 patients randomised to receive placebo

Primary endpoint

Atherosclerotic events, including fatal or nonfatal IHD, fatal or

nonfatal stroke, and PAD

Mean follow-up

4.4 years

IHD, ischaemic heart disease; JPAD, Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes; PAD, peripheral artery disease.
1. Ogawa H, et al. JAMA 2008;300:213441.

Section 4

27

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

Nonaspirin Group (n)

Aspirin Group (n)

1277
1262

1220
1210

1165
1159

1117
1095

813
806

135
140

Years

 ASA was not

effective in the
primary of CV
events in pts with
asymptomatic PAD

Antioxidants
BMJ 2008, 337: 1840

showed no benefit
as well

Did they have PAD? (ABI

0,99)
ASA <
was
not effective
Asymptomatic diabetics,
aged
> 40 of CV
in the
primary
No benefit of aspirin in events
this population
in pts with
asymptomatic PAD

BMJ 2008, 337: 1840

Antioxidants showed
no benefit as well

AAA trial
Aspirin for Asymptomatic Atherosclerosis

among participants
without clinical CV
disease, identified
with a low ABI based
on screening a
general population,
the administration of
ASA did not reduce
vascular events

AAA trial
Aspirin for Asymptomatic Atherosclerosis

most pts with borderline ABI

70% of
participants women
among
participants
the rate
of events
without
clinical
CV lower than expected
- limitedidentified
power of the study
disease,
enteric
acetylsalicylic acid
with
a lowcoated
ABI based

on screening a
general population,
the administration of
ASA did not reduce
vascular events

AAAT, JPAD and POPADAD how to interpret

the findings?
Six key primary prevention trials involving ~95 000 participants,
660 person/years and 3500 vascular events have established the
role of aspirin in primary prevention16
The AAAT, JPAD and POPADAD79 have yielded mixed results
These trials have been criticised for a number of reasons:
All studies were underpowered (the event rate was less than assumed)
The event rate in JPAD was ~third of that anticipated
In the AAAT trial ~15% in the placebo group used aspirin and compliance was
low in the treated group (~60% used aspirin)

It is also possible that diabetic patients may respond to a different

dosing regimen

1. Peto R, et al. BMJ 1988;296:3136; 2. Steering Committee of the Physicians Health Study Research Group. N Engl J Med 1989;32112935;
3. The Medical Research Councils General Practice Research Framework. Lancet 1998;351:23341; 4. Hansson L, et al. Lancet 1998;351:175562;
5. Sacco M, et al. Diabetes Care 2003;26:326472; 6. Ridker PM, et al. N Engl J Med 2005;352:1293304;
7. Ogawa H, et al. JAMA 2008;300:213441; 8. Belch J, et al. BMJ 2008;337:a1840;
9. Fowkes FGR, et al. JAMA 2010;303:8418.

33

The benefits of aspirin in primary prevention

are consistent in meta-analyses (19942002)
Metaanalysis

Trials
(n)

Patients
(n)

Outcomes with aspirin

APTC
(1994)1

145

96 316

34% reduction in nonfatal MI (2p<0.00001)

25% reduction in nonfatal stroke (2p<0.00001)
15% reduction in fatal stroke
17% reduction in vascular deaths (2p<0.00001)

ATTC
(2002)2

287

135 000

28% reduction in nonfatal reinfarction

15% reduction in vascular death
25% reduction in nonfatal stroke (p<0.0001)
23% reduction in stroke in patients with previous stroke/TIA*
19% reduction in stroke in patients with previous acute stroke**

*p<0.0001; **p=0.0002.
APTC, Antiplatelet Trialists Collaboration; ATTC, Antithrombotic Trialists Collaboration; MI, myocardial infarction;
TIA, transient ischaemic attack.
1. APTC. BMJ 1994;308:81106; 2. ATTC. BMJ 2002;324:7186.

Section 4

34

The benefits of aspirin in primary prevention

were shown in the recent ATTC meta-analysis
Metaanalysis

Trials
(n)

Patients
(n)

Outcomes with aspirin

ATTC
(2009)1

95 000

First events
12% reduction in serious vascular events (p=0.0001)
18% reduction in major coronary events
23% reduction on nonfatal MIs
14% reduction in ischaemic stroke

ATTC
(2009)1

16

17 000

Recurrent events
20% reduction in major coronary events
31% reduction in nonfatal MIs
13% reduction in coronary mortality
22% reduction in ischaemic stroke
9% reduction in vascular death
19% reduction in serious vascular events*

ATTC, Antithrombotic Trialists Collaboration; MI, myocardial infarction.

1. ATTC. Lancet 2009;373:184960.

Section 4

36

Aspirin and statins have an additive effect in

the prevention of recurrent CV events
In meta-analyses, relative risk reductions for fatal and non-fatal MI
were
31% for aspirin + pravastatin vs aspirin alone
26% for aspirin + pravastatin vs pravastatin alone
40% for aspirin + pravastatin vs placebo

Benefits of combined therapy are greater than the sum of benefits

of each alone, with a synergy probability of 0.92

MI, myocardial infarction;.

Hennekens CH, et al. Arch Intern Med 2004;164:404.

Section 12

37

CAPRIE: Clopidogrel in Diabetes

Ischemic Stroke, MI, Vascular Death, Hospitalization for
Ischemic Events/Bleeding
Overall Benefit P=.032; Multivariate Analysis
38

Annual Event Rate (%)

25

Aspirin
Clopidogrel

21
21.5%

20
9

17.7%
17.7%

15

15.6%
12.7%

10

Events
Prevented/1000
Patients
Over Aspirin

11.8%

5
0

Nondiabetic

All Diabetic
Patients

With Insulin

CAPRIE, Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events; MI, myocardial infarction.
Bhatt DL, et al. Am J Cardiol. 2002;90:625-628. (with permission)

TRial to Assess Improvement in

Therapeutic Outcomes by Optimizing
Platelet InhibitioN with Prasugrel
TRITON-TIMI 38
AHA 2007
Orlando, Florida
Disclosure Statement:
The TRITON-TIMI 38 trial was supported by a research grant to the
Brigham and Womens Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.

Primary Endpoint
CV Death,MI,Stroke
Primary Endpoint (%)

15
Clopidogrel
12.1
(781)
9.9
(643)

10
Prasugrel

HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46

HR 0.80
P=0.0003

HR 0.77
P=0.0001

ITT= 13,608

0 30 60 90

180

270
Days

LTFU = 14 (0.1%)

360

450

Clopidogrel
(%, n=1,570)

Prasugrel
(%, n=1,576)

UA/NSTEMI (%)

79

79

STEMI (%)

21

21

()
75 (%)

63
15

63
15

36

31*

29

29

<70kg (%)
70-90kg
>90kg

15
45
40

15
45
40

*p=0.004

Wiviott SD et al. Circulation 2008; 118: 1626-1636

Diabetic Subgroup
N=3146
18

Clopidogrel

Endpoint (%)

16

17.0

CV Death / MI / Stroke

14
12.2
12

Prasugrel

10

HR 0.70
P<0.001
NNT = 46

8
6

TIMI Major
NonCABG Bleeds

Clopidogrel

2.6
2.5

Prasugrel

0
0

30 60 90

180

Days

270

360

450

August 30, 2009 at 08.00 CET

PLATO study design

NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)
Clopidogrel-treated or -naive;
randomised within 24 hours of index event
(N=18,624)

Clopidogrel
If pre-treated, no additional loading dose;
if naive, standard 300 mg loading dose,
then 75 mg qd maintenance;
(additional 300 mg allowed pre PCI)

Ticagrelor
180 mg loading dose, then
90 mg bid maintenance;
(additional 90 mg pre-PCI)

612-month exposure
Primary endpoint: CV death + MI + Stroke
Primary safety endpint: Total major bleeding
PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid;
CV = cardiovascular; TIA = transient ischaemic attack

Primary efficacy endpoint over time

(composite of CV death, MI or stroke)
8

Clopidogrel

5.43
4.77

Ticagrelor

Cumulative incidence (%)

Cumulative incidence (%)

HR 0.88 (95% CI 0.771.00), p=0.045

0
0

10

20

30

6.60

Clopidogrel

5.28
4

Ticagrelor

2
HR 0.80 (95% CI 0.700.91), p<0.001

31

90

150

210

270

330

Days after randomisation*

Days after randomisation

No. at risk
Ticagrelor

9,333

8,942

8,827

8,763

8,673

8,543

8,397

7,028

6,480

4,822

Clopidogrel 9,291

8,875

8,763

8,688

8,688

8,437

8,286

6,945

6,379

4,751

*Excludes patients with any primary event during the first 30 days

PLATO: Diabetes substudy

Of the 18,624 patients with ACS enrolled in the PLATO study,
4662 had a diagnosis of diabetes[Wallentin 2009:B; James 2010:A]
In the diabetic subgroup of patients with ACS, outcomes were
compared between:[James 2010:A,B]
Diabetic vs. non-diabetic patients
96% of diabetic patients presented with type 2 diabetes

Patients with below-median vs. above-median HbA1c (median

HbA1c = 6.0%)
HbA1c is a composite, long-term measure of plasma glucose control

Patients with below-median vs. above-median non-fasting serum

glucose (median non-fasting serum glucose = 6.8 mmol/L)

ACS, acute coronary syndromes.

Wallentin L, et al. N Engl J Med 2009;361:10451057;
James S, et al. Eur Heart J 2010;31:30063016.

PLATO diabetes:
Key patient characteristics

During initial hospitalisation[James 2010:A,C]

84% of diabetic patients were treated with antidiabetic medication
55.2% of diabetic patients received insulin
Almost one in four patients continued to receive insulin treatment throughout the
duration of the PLATO study

Diabetic patients were more likely than non-diabetic patients to suffer

from:[James 2010:D]
Hypertension
Dyslipidaemia
Obesity
Diabetic patients were less likely than non-diabetic patients to be[James 2010:D]
A habitual smoker
Considered for invasive treatment

James S, et al. Eur Heart J 2010;31:30063016.

PLATO diabetes:
Primary composite endpoint
CV death, MI, or stroke (%)

20

[James 2010:F,H]

Diabetes
Ticagrelor (n=2326)
Clopidogrel (n=2336)
HR (95% CI) = 0.88(0.761.03)

15

16.2%
14.1%
p for interaction = 0.49

10

10.2%
8.4%

No diabetes
Ticagrelor (n=6999)
Clopidogrel (n=6952)
HR (95% CI) = 0.83(0.740.93)

0
0

60

120

180

240

300

360

Days after randomisation

Primary endpoint benefit with ticagrelor was consistent with the

overall PLATO trial results[Wallentin 2009:J]
No interaction between diabetes status and treatment was observed (p=0.49)[James 2010:G,H]
CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction.
James S, et al. Eur Heart J 2010;31:30063016.

PLATO diabetes:
All-cause mortality
All-cause mortality (%)

10

[James 2010:H,I]

Diabetes
Ticagrelor (n=2326)
Clopidogrel (n=2336)
HR (95% CI) = 0.82(0.661.01)

8.7%
7.0%

6
p for interaction = 0.66
5.0%
4

3.7%
No diabetes
Ticagrelor (n=6999)
Clopidogrel (n=6952)
HR (95% CI) = 0.77(0.650.91)

0
0

60

120

180

240

300

360

Days after randomisation

All-cause mortality benefit with ticagrelor was consistent with the

overall PLATO trial results[Wallentin 2009:J]
No interaction between diabetes status and treatment was observed (p=0.66)[James 2010:G,H]
CI, confidence interval; HR, hazard ratio.
James S, et al. Eur Heart J 2010;31:30063016.

Summary of PLATO diabetes substudy:

Efficacy and safety of ticagrelor
Efficacy of ticagrelor in the diabetic patient subgroup is consistent
with that observed in the overall PLATO study
population[James 2010:G,H]
Incidence of CV death, MI or stroke and all-cause mortality in
diabetic patients with ACS was numerically lower in patients
treated with ticagrelor compared with clopidogrel
No definitive efficacy conclusion between the treatment groups
can be drawn due to the small sample size
No significant increase in major bleeding was observed in diabetic
patients treated with ticagrelor compared with clopidogrel[James 2010:L,M]
However, it should be noted that in the PLATO main analysis,
there were higher rates of non-CABG major bleeding.

ACS, acute coronary syndromes; CV, cardiovascular; MI, myocardial infarction.

James S, et al. Eur Heart J 2010;31:30063016.

View inside an atherosclerotic artery with severe

plaque and a thrombus partially occluding the
lumen (light microscopy)

Unstable Plaque