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HOT LINE PRESENTATION

World Congress of Cardiology 2006

Barcelona, Spain September 5, 2006

Warfarin Antiplatelet Vascular Evaluation- 2161 PAD Patients

Dr. Sonia Anand Associate Professor of Medicine

McMaster University

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Rationale

• Atherosclerosis is a systemic disease• PAD patients suffer the highest rates of CV

death, MI, and ischemic stroke• Antiplatelet therapy reduces CV events in

broad spectrum of patients with vascular disease (CAD, CBVD, PAD)

• Role of Oral anticoagulants (OAC) together with antiplatelets in CAD appears promising

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Primary Objectives

• To determine if moderate intensity OAC (INR 2-3), in combination with antiplatelet therapy, is superior to antiplatelet therapy alone in preventing– cardiovascular death, MI, or stroke, and– cardiovascular death, MI, stroke, or severe

ischemia of the coronary or peripheral arterial circulation

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Study Design

Follow-up - q 3 mo. x 30-42 mo.

AP only(1,081 patients)

AP + OAC(1,080 patients)

6 m

o.

9 m

o.

42 m

o.

or F

inal

Vis

it

3 m

o.

Day

35

PAD Patients

2-4 weeksAP + OAC

(INR 1.8-3.5)

Rand

AP o

nly

Run-In

AP +

OAC

• Central Randomization, Open trial, Blinded adjudication, 80 Centres, 7 Countries

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Key Inclusion/Exclusion Criteria

• Men and women, 35-85 years plus >1 of– Intermittent claudication with objective evidence of PAD

(e.g. ABI <0.9)– Previous vascular reconstruction (including amputation)

or angioplasty of a peripheral artery – Significant carotid artery disease– Prior Vascular disease and ABI < 0.9

Inclusion:

Exclusion:- Active bleeding or high-risk for bleeding- Clear indication for long-term OAC use - Clear indication for long-term (> 3 months) daily NSAIDs- Recent Stroke < 6 months

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Key Outcomes

• Co-Primary 1: CV death, MI, or stroke• Co-Primary 2: CV death, MI, stroke, or severe

ischemia of the coronary or peripheral arterial circulation

• Life-threatening bleeding: Fatal or intra-cranial, or requiring surgical intervention, or transfusion of at least 4 units of blood products

• Moderate bleeding: < 3 units of blood products

Efficacy

Safety

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Flow of Patients

2,417 eligible patients enter active run-in

256 stopped Run-in 115 patient decision 66 minor bleeding or unstable INR values 50 poor adherence 25 other reasons

2,161 patients randomized

1,080 allocated to oralanticoagulation therapy plus antiplatelet therapy

1,081 allocated to antiplatelet therapy alone

Mean INR = 2.2 2 lost to follow-up 319 permanently discontinued

oral anticoagulants 126 bleeding 129 patient / physician decision 64 other reasons

1,080 analyzed

21 permanently discontinued antiplatelet therapy 1 bleeding 20 other reasons 45 began oral anticoagulants 12 atrial fibrillation 10 venous thromboembolism 12 patient / physician decision

2 prosthetic heart valves

9 other reasons

1,081 analyzed

0 lost to follow-up

Mean INR = 2.2

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Baseline Characteristics

OAC/AP AP

N Randomized 1080 1081

Age –years 63.9 (9.4) 63.8 (9.5)

Sex-women (%) 284 (26.3) 286 (26.5)

Current Smokers 318 (29.4) 315 (29.1)

History Coronary artery disease n (%) 483 (44.7) 539 (49.9)

History of Stroke n (%) 166 (15.4) 177 (16.4)

Qualifying Condition PAD Limbs Other PAD

880 (81.5)200 (18.5)

887 (82.1)194 (17.9)

Mean Blood Pressure (Sys/Dias)

Ankle Brachial Index [median (IQR)] 0.83 (0.7-1.0) 0.84 (0.7 – 1.0)

Antiplatelet therapy 98.5 99.0

As of July6, 2006As of July 6, 2006

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Primary Outcomes

OAC/APN=1080 (%)

APN=1081 (%)

RR 95%CI P-value

P1:Cvd/MI/Stk 132 (12.2) 144 (13.3) 0.92 0.73-1.16 0.49

P2: P1+SI 172 (15.9) 188 (17.4) 0.91 0.74-1.12 0.38

CV Death 66 (6.1) 65 (6.0) 1.04 0.74-1.46 0.84

MI 54 (5.0) 66 (6.1) 0.82 0.57-1.18 0.28

Stroke 38 (3.5) 38 (3.5) 1.01 0.65-1.59 0.96

Severe ischemia

62 (5.7) 59 (5.5) 1.06 0.74-1.51 0.76

Note: P1 =composite of CV death, MI, stroke; P2= CV death, MI, stroke, SI of limb or coronaries

10Day

Ka

pla

n-M

eie

r R

ate

s

0.0

0.0

50.1

00.1

5

0 100 300 500 700 900 1100 1300

W/A

Anti

WAVE: CVD/MI/Strk

Figure 2aCo-Primary 1: CV Death, MI, Stroke

OAC+APAP

11Day

Ka

pla

n-M

eie

r R

ate

s

0.0

0.0

50.1

00.1

50.2

0

0 100 300 500 700 900 1100 1300

W/A

Anti

WAVE: CVD/MI/Strk/si

Figure 2bCo-Primary 2: CV Death, MI, Stroke,

Severe Ischemia

OAC+APAP

As of July6, 2006As of July 6, 2006

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Safety Outcomes

OAC/APN=1080 (%)

APN=1081 (%)

RR 95%CI P-value

Life-threat bleed

43 (4.0) 13 (1.2) 3.41 1.84-6.35 <0.001

Hem stroke 14 (1.3) 0 (0) 15.2 2.0-115.6 <0.001

Fatal Bleed 10 (0.9) 3 (0.3) 3.34 0.92-12.1 0.0513

Moderate Bleeding

31 (2.9) 11 (1.0) 2.82 1.43-5.58 0.0018

LT or Mod Bleed

74 (6.9) 24 (2.2) 3.21 2.02-5.08 0.0001

Cvd/MI/stk

(-bleeds)

117 (10.8) 143 (13.2) 0.82 0.64-1.05 0.11

13Day

Ka

pla

n-M

eie

r R

ate

s

0.0

0.0

10.0

20.0

30.0

40.0

5

0 100 300 500 700 900 1100 1300

W/A

Anti

WAVE: Life-threatening

Life-Threatening Bleeding

OAC+APAP

14Day

Ka

pla

n-M

eie

r R

ate

s

0.0

0.0

20.0

40.0

60.0

8

0 100 300 500 700 900 1100 1300

W/A

Anti

WAVE: Life-thr./Mod Bleed

Life-Threatening or Moderate Bleeding

Life-Threatening or Moderate Bleeding

OAC+APAP

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Summary

1) Oral anticoagulants (targeting an INR range of 2 to 3) added to Antiplatelet therapy do not lower the rate of cardiovascular events, and increase life-threatening bleeding compared to Antiplatelet therapy alone in patients peripheral arterial disease.

2) Other antithrombins with a better safety profile or dual antiplatelet agents should be evaluated in this population

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Australia: Eikelboom, 1 centre, 16 patients; Canada: Anand, 26 centres, 880 patients; China: Liu, 18 centres, 347 patients; Hungary: Keltai, 8 centres, 85 patients; Netherlands: van Urk, 1 centre, 18 patients; Poland: Budaj, 15 centres, 566 patients; Ukraine: Parkhomenko, 11 centres, 249 patients.

DSMB chair: Dagenais; Adjudication chair: Sussex.

Project office: Anand, Yusuf, Chin, Joldersma, Xie, Antaya, Sloane, Nowacki, Parkinson

Study Organization