HOT LINE PRESENTATION World Congress of Cardiology 2006
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Transcript of HOT LINE PRESENTATION World Congress of Cardiology 2006
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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