i.v. enoxaparin or unfractionated heparin in primary pci: acute and long-term results
DESCRIPTION
G. Montalescot, M. Cohen, P. Goldstein, K. Huber, C. Pollack, U. Zeymer , E. Vicaut for the ATOLL investigators. I.V. Enoxaparin or Unfractionated Heparin in Primary PCI: Acute and Long-term results. - PowerPoint PPT PresentationTRANSCRIPT
I.V. Enoxaparin or Unfractionated Heparin in Primary PCI: Acute and Long-term results
G. MONTALESCOT, DISCLOSURE: Research Grants to the Institution or Consulting/Lecture Fees from Abbott Vascular, Astra-Zeneca, Bayer, Biotronik, Boehringer-Ingelheim, Boston Scientific, Cleveland Clinic Foundation, Cardiovascular Research Foundation, Cordis, Daiichi-Sankyo, Duke institute, Eli-Lilly, Europa, Fédération Française de Cardiologie, Fondation de France, GSK, ICM, INSERM, Lead-up, Medtronic, Menarini, Nanospheres, Novartis, Pfizer, Sanofi-Aventis Group, Servier, Société Française de Cardiologie, The Medicines Company, TIMI group.
ATOLL: Acute STEMI Treated with primary PCI and intravenous enoxaparin Or UFH to Lower ischemic and bleeding events at short- and Long-term follow-up (Investigator-driven study)
G. Montalescot, M. Cohen, P. Goldstein,
K. Huber, C. Pollack, U. Zeymer, E. Vicaut
for the ATOLL investigators
Intravenous enoxaparin vs. UFH in PCI
Primary PCI of STEMI (ATOLL)Secondary PCI of STEMI
(ExTRACT-PCI)Elective PCI (STEEPLE) 57%
Major Bleeding(p=0.004)
23%Death or re-MI
(p<0.001)
Montalescot G et al. N Engl J Med 2006;355:1006 –17Gibson MC et al. J Am Coll Cardiol 2007;49:2238–46
?
ATOLL Trial design
STEMI Primary PCI
30-day and 6-month results
Randomization as early as possible (MICU +++)Real life population (shock, cardiac arrest included) No anticoagulation and no lytic before RxSimilar antiplatelet therapy in both groups
ENOXAPARIN IV0.5 mg/kg
with or without GPIIbIIIa
UFH IV 50-70 IU with GP IIbIIIa
70-100IU without GP IIbIIIa(Dose ACT-adjusted)
IVRS
Primary PCI ENOXAPARIN SC UFH IV or SC
Trial organization
ACTION Study Group (Academic Research Organization, Paris):
1-Coordinating Center: Institute of Cardiology, Pitié-Salpêtrière Hospital, Paris 2-Sponsor: AP-HP (Assistance Publique-Hôpitaux de Paris) 3-Data center, Statistics: Unité Recherche Clinique, Lariboisière Hospital, Paris 4-International CRO: Pierrel-Hyperphar 5-Funding: AP-HP and unrestricted research grant from Sanofi-Aventis Group
Steering Committee: G. Montalescot (Chair, France), M. Cohen (USA), P. Goldstein (France), K. Huber (Austria), C. Pollack (USA), E. Vicaut (France), U. Zeymer (Germany)
Data Safety Monitoring Board: A. Cohen (Chair, France), M. Cucherat (France), A. Gitt (Germany)
Core Laboratory: R. Dumaine, A. Samadi
Clinical Event Committee: F. Philippe, P. Sabouret, F. Boccara, A. Bellemain, O. Gournay
Main objectives
• 1° EP:– All-cause mortality at D30, – Complications of MI at D30 [resuscitated cardiac arrest,
recurrent MI/ACS, urgent revascularization, stroke, peripheral or pulmonary embolism],
– Procedure failure [definite stent thrombosis; B.O. use of GpIIB/IIIa; Non-TIMI 3 flow after PCI; ST resolution < 50% after PCI],
– Non-CABG major bleeding during hospitalization
• Main 2° EP: All-cause mortality, Recurrent ACS or Urgent revascularization at D30
• Main safety EP: Non-CABG major bleeding (STEEPLE definition) during hospitalization
FINAL 30-DAY RESULTS
Selected Baseline Characteristics
UFH (n=460)
ENOXAPARIN (n=450)
Age, median (Q1;Q3) Age > 75
60 (52; 70)17% (80)
59 (52; 71)19% (85)
Pre-hospital randomization 71% (325) 71% (318)
Shock and/or cardiac arrest before sheath, % (n) 5% (24) 4% (17)
Time from symptom onset to randomization—hr, median (Q1;Q3)
2h19(1h26; 4h37)
2h33(1h29; 4h50)
Radial artery access, % (n) Other artery access, % (n)
66% (305)34% (155)
69% (309) 31% (141)
Glycoprotein IIb/IIIa inhibitors,% (n) 83% (382) 77% (347)Clopidogrel < 300mg > 300 and < 600mg > 600 and < 900mg > 900mg
37% (171) 37% (172) 25% (113)
1% (4)
37% (168)39% (174) 22% (101)
2% (7)
Primary EndpointDeath, Complication of MI, Procedure Failure or Major Bleeding
33.7
28
0
5
10
15
20
25
30
35
40
UFHENOX
RRR = 17% P = 0.07
% o
f pat
ient
s
0.06
Main Secondary Endpoint (ischemic) Death, Recurrent ACS or Urgent Revascularization
0 5 10 15 20 25 30
0.00
0.05
0.10
0.15
Days
Mai
n se
cond
ary
EP
rate UFH
ENOXLog-Rank Test
p=0.01 11.3%
6.7%
30d rate (%)
41%
Consistent therapy Pre-specified analysis: no protocol violation (88%)
0.1 1.0 10
Only one heparin
More than one heparin
Only one heparin
More than one heparin
Relative Risk
IV 0.5mg/kg Enoxaparin better IV UFH better
0.76 (0.61-0.94)
1.51 (0.91-2.50)
RR (95%CI)
0.76 (0.61-0.94)
1.51 (0.91-2.50)
1 � end point
Main 2� end point
Death or Complication of MIDeath, resuscitated cardiac arrest, recurrent ACS, Urg Revasc,
stroke, peripheral or pulmonary embolism
0 5 10 15 20 25 30
0.00
0.05
0.10
0.15
Days
Dea
thor
Com
plic
atio
n of
MI r
ate
UFHENOX
Log-Rank Test
p=0.02 12.4%
7.8%
30d rate (%)
37%
Death or resuscitated cardiac arrest
Death (any)
0 5 10 15 20 25 30
0.00
0.02
0.04
0.06
0.08
0.10
DaysDea
thor
resu
scita
ted
card
iac
arre
stra
te
UFHENOX Log-Rank Test
p=0.049 7.0%
4.0%
30d rate (%)
0 5 10 15 20 25 30
0.00
0.02
0.04
0.06
0.08
0.10
Days
Dea
thra
te
UFHENOX Log-Rank Test
p=0.08 6.3%
3.8%
30d rate (%)
40% 42%
6.3%
3.8%
7.0%
4.0%
Safety Endpoints
Protocole definitions (STEEPLE)
NS
Death, Complication of MI or Major bleedingNet clinical benefit
15
10,2
0
2
4
6
8
10
12
14
16
UFHENOX
RRR = 32% P = 0.03
% o
f pat
ient
s
6-month Follow-up
6-month results
• Follow-up on mortality• 100% follow-up• We used a Cox regression model to identify
independent predictors of death at 6 months. We firstly performed univariate analysis and significant variables were introduced into a stepwise cox regression model
Death over 6 months
0 1 2 3 4 5 6
0.00
0.02
0.04
0.06
0.08
0.10
Months
Dea
th
ENOX
UFH
Log Rank Test: p=0.11
6.3%7.0%
7.2%
3.8%4.5%
4.7%r=2.5%
r=2.5%r=2.5%
Independent correlates of death at 6 months
Variables HR[95%CI] Pvalue
Beta blockers, yes vs. no 0.16 [0.08;0.32] <.0001
KILLIP II,III,IV vs. I 3.87 [2.02;7.4] <.0001
Age >75 vs. <75 4.01 [2.2;7.29] <.0001
ACE yes vs. no 0.32 [0.16;0.66] 0.0021
MI location, anterior vs. other 2.24 [1.27;3.94] 0.0052
Prior heart failure, yes vs. no 4.57 [1.37;15.31] 0.0137
Prior COPD, yes vs. no 3.15 [1.05;9.39] 0.0401
Systolic BP [mmHg] (10 units increase) 0.87 [0.77;0.97] 0.0149
Prior stroke, yes vs. no 3.10 [1.14;8.48] 0.0273
Conclusions
In this 1st head-to-head comparison between two anticoagulants in primary PCI, i.v. enoxaparin:
• Reduced serious ischemic events, on top of intense antiplatelet therapy
• Had a good safety profile, with a superior net clinical benefit
• Tended to reduce mortality over 6 months
Special Thank to:
INVESTIGATORS – Austria: WR. Benzer, K. Huber, F. Leisch, F. Weidinger – France: F. Adnet, M. Angioi, B. Barberon, JF. Benezet, JL. Bonnet, J. Boschat, B. Boulanger, D. Carrie, T. Chouihed, P. Coste, Y. Cottin, H. Courcoux, C. Cuvier, N. Danchin, JL. Ducasse, F. Duclos, P. Ecollan, S. Elhadad, E. Filippi, M. Freysz, F. Funck, S. Gallula, B. Gelée, A. Greffet, P. Henry, A. Jacquemin, T. Joseph, JM. Lablanche, H. Lardoux, H. Le Breton, B. Lederman, A. Margenet, G. Mehu, O. Nallet, F. Paganelli, M. Pansieri, L. Payot, C. Pouges, E. Salengro, C. Spaulding, G. Steg, O. Stibbe, E. Teiger, M. Thicoipe, C. Thuaire, J. Treuil, O. Wittenberg, O. Wolf – Germany: D. Andresen, C. Axthelm, Fischer, E. Girth, E. Hauptmann, U. Zeymer – USA: M.Cohen, F. ShamoonCOMMITTEES – A Appaix-Bellemain, F Boccara, A Cohen, M. Cohen, M Cucherat, R Dumaine, A Gitt, P Goldstein, O Gournay, K Huber, F Philippe, C Pollack, P Sabouret, A Samadi, E Vicaut, U ZeymerPIERREL Research– L. Basso, L. Merlini, M. MazzoleniACTION study Group – ME. Assossou, M. Aout, B. Bertin, D. Brugier, JP. Collet, M. Courreges-Viaud, V. Gallois, P. Gallula, V. Jouis, S. Kabla, C. Misse, G. Ngouala, A. Pena, S. Paulsrud, N. Vignolles