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