Three-year duration of benefit from abciximab in patients receiving stents for acute myocardial infarction in the randomized double-blind ADMIRAL study

The ADMIRAL Investigators*

Received 4 April 2005; revised 13 September 2005; accepted 6 October 2005; online publish-ahead-of-print 25 October 2005.

* Corresponding author. Gilles Montalescot, Institut de Cardiologie, Bureau 2-236, Centre Hospitalier Universitaire Pitié–Salpêtrière, 47 Boulevard de l'Hôpital, 75013 Paris, France. Tel: +33 1 42 16 30 06; fax: +33 1 42 16 29 31. E-mail address: gilles.montalescot{at}psl.ap-hop-paris.fr

See page 2479 for the editorial comment on this article (doi:10.1093/eurheartj/ehi553)


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 Appendix
 References
 
Aims The Abciximab Before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-term Follow-up (ADMIRAL) study demonstrated that early inhibition of the platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor with abciximab led to improved coronary patency, left ventricular function, and clinical outcomes. The current long-term follow-up study evaluated the durability of the positive outcomes.

Methods and results The randomized double-blind ADMIRAL trial enrolled 300 patients who received either abciximab plus stenting or placebo plus stenting for the treatment of ST-elevation myocardial infarction (STEMI). Abciximab (bolus of 0.25 mg/kg body weight, followed by 12 h infusion of 0.125 µg/kg per min) was administered to 149 patients, whereas 151 patients received placebo. Long-term follow-up was conducted in a blinded manner by either patient chart review or telephone interview. Long-term follow-up data were obtained on 288 patients (96%). After 3 years, using an intent-to-treat analysis, the outcome of all-cause mortality occurred in 9.1% of abciximab-treated patients when compared with 12.2% of placebo patients, absolute and relative risk reductions of 3.1 and 25%, respectively (P=0.36). Parallel Kaplan–Meier curves were observed for the cumulative incidence of death or re-infarction, which was reduced from 16.9% in the placebo group to 11.8% in the abciximab group, absolute and relative risk reductions of 5.1 and 30%, respectively (P=0.20). Rates of recurrent ischaemia were significantly reduced from 21.7 to 11.5% (P=0.05).

Conclusion Adjunctive abciximab to primary stenting for STEMI elicits favourable clinical outcomes with the same absolute risk reductions of hard clinical outcomes from 30 days up to 3 years of follow-up.

Key Words: STEMI • Long-term follow-up • Abciximab


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 Appendix
 References
 
Stent placement in primary percutaneous coronary intervention (PCI) for evolving ST-elevation myocardial infarction (STEMI) has been shown to reduce mainly the incidence of target vessel revascularization (TVR), but has not demonstrated a reduction in ischaemic complications.1 Among the randomized clinical trials evaluating adjunctive therapy with platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor antagonists in conjunction with primary PCI, only five were sized to examine clinical endpoints,26 four looked at stented patients,36 ADMIRAL being the only double-blind study of these four trials.4 All four stent trials were conducted with abciximab and have consistently shown a significant reduction of ischaemic complications at 30 days, but limited follow-up has been available for these studies. Sustained long-term efficacy with GP IIb/IIIa receptor antagonists in primary stenting of STEMI cannot be presumed without clinical evidence.

In the Abciximab Before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-term Follow-up (ADMIRAL) study, we examined the effect of abciximab in primary stenting for STEMI.4 When compared with placebo, the primary endpoint of death, MI, or urgent TVR was significantly reduced from 14.6% (placebo group) to 6.0% (abciximab group) at 30 days. This benefit persisted through 6 months. This report represents a clinical follow-up to the third year after randomization.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 Appendix
 References
 
The 30-day and 6-month outcomes from the ADMIRAL trial as well as the details of the experimental design, definitions, and methods have been published previously.4 The clinical protocol was approved by the Ethics Review Board of the Pitié–Salpêtrière Hospital, and all patients provided informed consent for the initial trial and long-term follow-up study. Briefly, 300 patients with STEMI, scheduled to undergo primary stenting at 26 centres throughout France, were enrolled in the study. Patients were deemed eligible for this study if the time from initial onset of symptoms of STEMI was <12 h preceding randomization. The primary exclusion criteria included the concurrent administration of thrombolytic agents for the current event or any known contraindications to aspirin, ticlopidine, or heparin. Study drug was administered immediately after randomization in a double-blind manner, either in the mobile intensive care unit before arrival at the hospital, the emergency department, the intensive cardiac care unit, or in the catheterization laboratory.

Patients were randomized into two groups and administered either abciximab (ReoPro®, Centocor, Malvern, PA, USA) or placebo in advance of the PCI procedure. Of the 300 patients enrolled, 78 (26%) were administered either abciximab or placebo early in the mobile intensive care unit before hospital arrival or in the emergency room. All patients received aspirin. Heparin was administered as an initial bolus of 70 U/kg and adjusted with additional boluses, if necessary, to achieve an activated clotting time (ACT) of 200 s. All patients received ticlopidine 250 mg twice daily for 30 days. The stent of choice for the ADMIRAL study was the Saint-Côme stent (Saint-Côme-Chirurgie, Marseilles, France), although the ultimate decision was at the discretion of the investigator providing the stent was approved.

The 3-year data were collected on a separate long-term follow-up questionnaire. Data collection was conducted by either patient chart review or telephone interview by physicians or study coordinators who were unaware of treatment assignments. All-cause mortality was evaluated at 3 years in all patients. In addition to survival status, data on re-infarction (new Q-waves or STEMI event), recurrent ischaemia [any recurrent myocardial infarction (MI) or ischaemic episode], revascularization, coronary artery bypass surgery, stroke, and re-hospitalization were also collected. The combined endpoints of death or MI, death, MI or urgent revascularization were evaluated at 3-year follow-up.

Statistical analysis
The data were analyzed according to the intention-to-treat principle using SAS statistical software version 8.02 (SAS Institute, Inc., Cary, NC, USA). The Kaplan–Meier method was used for the estimation of the probability of death, death or MI, and re-infarction alone over the 3-year follow-up period in each treatment group. Comparative analyses of the percentages between the two groups for the pre-specified 3-year secondary endpoints were conducted using Fisher's exact test. All tests were two-sided and conducted at the unadjusted {alpha}=0.05 level.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 Appendix
 References
 
Patient disposition
At the time of enrolment, there were no significant differences, with respect to the baseline demographic and angiographic characteristics, between the 149 patients assigned to abciximab and the 151 patients assigned to placebo.4 After 3 years, follow-up mortality data were available for a total of 288 (96%) patients; 145 (97.3%) randomized to treatment with abciximab and 143 (94.7%) randomized to placebo. Other 3-year follow-up data were available for 261 (87%) patients.

Mortality
At 3 years, using an intent-to-treat analysis, the cumulative incidence of all-cause mortality had occurred in 9.1% of abciximab-treated patients when compared with 12.2% of placebo patients (P=0.36) (Figure 1). The absolute benefit of 3.1% (95% CI: –3.9%; 10.1%) measured with abciximab at 3 years in an intent-to-treat analysis was comparable with the absolute benefit of 3.2% (95% CI: –1.7%; 8.1%) measured at 30 days.



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Figure 1 Cumulative incidence of all-cause mortality at 3 years after randomization. The absolute difference at 3 years was 3.1% (95% CI: –3.9%; 10.1%), P=0.36.

 
Combined endpoints
The cumulative incidence of death or re-infarction was reduced to the rate of 11.8% (P=0.20) in the abciximab-treated group when compared with that of 16.9% in the placebo group by the end of the third year (Figure 2). The absolute benefit in death or MI was 3.2% (95% CI: –2.3%; 8.7%) and 5.1% (95% CI: –2.8%; 13.0%) at 30 days and 3 years, respectively.



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Figure 2 Cumulative incidence of death or MI at 3 years after randomization: the absolute difference was 5.1% (95% CI: –2.8%; 13.0%) (P=0.20).

 
Although not statistically significant, re-infarction alone was reduced by abciximab to 3.6%, when compared with placebo with 7.2% (P=0.18), over the 3-year follow-up period. The divergence in occurrence of MI was evident early on, widened rather considerably between 6 months and 1 year post-event and was preserved throughout the 3-year period (Figure 3). The reduced incidence of re-infarction was a major factor that led to the reduction in the composite endpoints.



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Figure 3 Cumulative incidence of recurrent MI at 3 years after randomization: the absolute difference was 3.6% (95% CI: –1.5%; 8.7%) (P=0.18).

 
The primary end-point of the ADMIRAL study was the composite endpoint of death, re-infarction, and urgent TVR at 30 days. Rates of this composite triple endpoint remained lower in the abciximab group (13.8%) when compared with the placebo group (21.6%) over the 3-year time period (P=0.07). Again, the absolute benefit for this triple endpoint was well preserved from 30 days (8.6%, 95% CI: 1.8%; 15.4%) to 3 years (7.8%, 95% CI: –0.8%; 16.4%). The need for any revascularization also trended favourably for the abciximab-treated group.

Additional 3-year pre-specified endpoints were the onset of recurrent ischaemia, CABG, stroke, and re-hospitalization (Figure 4). There was a significant reduction in the incidence of recurrent ischaemia in the abciximab group (11.5%) when compared with the placebo group (21.7%, P=0.05).



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Figure 4 Cumulative incidence of 3-year pre-specified endpoints.

 

    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 Appendix
 References
 
At 3 years, fewer patients, who received abciximab as adjunctive therapy to primary stenting for the treatment of STEMI, experienced the endpoint of death when compared with patients who received placebo. Although not statistically significant, this 3.1% absolute survival benefit is quite considerable in the field of reperfusion of STEMI and confirms the results observed at both 30 days and 6 months. Similarly, the 30% relative risk reduction of the composite endpoint of death and MI with abciximab throughout the 3-year follow-up period is consistent with both the early results of the trial and the recently reported 34% relative risk reduction of death and MI at 30 days in the meta-analysis of the five primary angioplasty trials evaluating abciximab.7 In this long-term follow-up ADMIRAL study, the most impressive results were observed on re-infarction and recurrent ischaemia, especially during the first year of follow-up, suggesting a sustained effect of the drug on coronary patency. This information supports the initial angiographic results of our study, which was the only trial to systematically evaluate the culprit artery patency at 24 h and 6 months after coronary intervention. In this angiographic analysis, abciximab was associated with significantly more frequent TIMI 3 flow and less reocclusions at 6 months, which translated into a significant improvement of global left ventricular function.4

Evidence from several trials, meta-analyses, and registries suggests that the administration of abciximab can provide a long-term survival benefit, possibly through anti-platelet but also anti-inflammatory effects.6,812 Although still debated, this point is of the utmost importance when long-term follow-up studies are performed. Although not powered for mortality, the present data bring the important information of a 3-year preservation of the initial survival benefit and go along the same line as the 52% reduction of mortality with abciximab at 1-year follow-up in the Abciximab and Carbostent Evaluation (ACE) study, although other studies showed neutral effects of abciximab on mortality.13 The latter study, ISAR-2, did not show a mortality benefit with abciximab after 5 years.

Inherent in long-term follow-up studies, the increasing number of deaths of other origins and the increasing impact of risk factors of poor survival, such as age, diabetes mellitus, or heart failure which are self-aggravating, may mask the acute benefit of the drug. This catch-up phenomenon, in addition to atypical features of this particular primary angioplasty trial such as late enrolment (<48 h after symptom onset), enrolment of non-Q-wave MI (31.2%), and failed thrombolysis AMI patients, could explain the absence in ISAR-2 of a long-term benefit observed by others.

Above and beyond the high-risk characteristics of its population and its double-blind design, another specificity of the ADMIRAL study when compared with the other primary stenting studies in STEMI was the early administration of abciximab. The study drug was administered in the emergency room or in the ambulance in one-fourth of the population, whereas all the other patients had the treatment started in the catheterization laboratory always before sheath insertion and the coronary angiogram. In a subgroup analysis, comparing those patients who received early pre-catheterization initiated drug administration with those who received in-laboratory administration, there was a significantly larger clinical benefit for the patients treated before they reached the catheterization laboratory.4 This time component of STEMI treatment has been recently confirmed with a significant benefit on coronary patency of the early vs. late administration of GP IIb/IIIa inhibitors: the rate of TIMI 2+3 flow before angioplasty increased from 25 to 37% in the group pre-treated with abciximab (P=0.006).14,15 This reperfusion benefit improves visualization of both the arteries and the lesions, facilitates and shortens the procedure, reduces distal embolization, and finally impacts clinical outcomes. Such favourable trends, although non-significant, were observed on all clinical endpoints including a 28% reduction of mortality when Gp IIb/IIIa inhibitors were given at the point of initial contact (emergency room or ambulance).14 This time component may clearly play a role in the acute and long-term benefits observed in the ADMIRAL study.

In conclusion, the current long-term data from the ADMIRAL trial demonstrate that adjunctive medical therapy with abciximab to inhibit the GP IIb/IIIa receptor in advance of and concurrent with primary stent implantation for STEMI elicits favourable clinical outcomes through the third year with similar absolute benefits along follow-up for hard clinical outcomes, although statistical significance is lost with accumulation of events over time in both groups.


    Acknowledgements
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 Appendix
 References
 
We are indebted to Dr A.C. Potocka for technical support, R. Hegedus for statistical assistance, and R. Achenbach for expert advice on the present study. The 3-year follow-up of the Admiral patients was made possible through a research grant from Lilly Critical Care Europe, Geneva, Switzerland for monitoring by the CRO PharmaResearch/Inveresk, Paris, France.

Conflict of interest: G.M. has been a consultant for Eli Lilly.


    Appendix
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 Appendix
 References
 
ADMIRAL trial organization
Steering Committee: Gilles Montalescot (Chairperson), Groupe Hospitalier Pitié Salpêtrière, Paris; Paul Barragan, Clinique Beauregard, Marseille; and Philippe Pinton, Eli Lilly and Company, Saint Cloud.

Clinical EndPoint and Safety Monitoring Committee: Alain Leizorovicz (Chairperson), Hôpital Louis Pradel, Lyon; Alain Cribier, Hôpital Charles Nicolle, Rouen; and Michel Meyer Samama, Hôpital Hotel Dieu, Paris.

Clinical Events Adjudication Committee: Jean Luc Dubois Randé (Chairperson), Hôpital Henri Mondor; Michel Slama, Hôpital Antoine Béclère, Clamart; and Kamel Boughalem, Hôpital Broussais, Paris.

Angiographic Core Laboratory: Isaac Azancot (Chairperson), Victor Stratiev, Hôpital Lariboisière, Paris.

ADMIRAL trial investigators
The following institutions and investigators participated in the ADMIRAL study. Pitié Salpêtrière Hospital, Paris: G. Montalescot (Cardiology Division) and P. Ecollan (MICU); Des Franciscaines Clinic, Nîmes: O. Wittenberg (Cardiology Division) and J.E. De La Coussaye (University Hospital–MICU); Lagny-Marne-La-Vallée Hospital, Lagny sur Marne: S. Elhadad; Les Fleurs Clinic, Ollioules: P. Villain; Saint Joseph Clinic, Colmar: J.M. Boulenc; Institut Cardiovasculaire Paris Sud, Antony: M.C. Morice; Trousseau Hospital, Tours: L. Maillard; Henri Duffaut Hospital, Avignon: M. Pansieri (Cardiology Division) and J. Vaque (MICU); Les Alpilles Clinic, Marseille: P. Barragan; La Valette Clinic, Montpellier: X. De Boisgelin; Centre Hospitalier Intercommunal of Eaubonne-Montmorency, Montmorency: A. Akesbi; Pays d'Aix Hospital, Aix en Provence: C. Barnay; Essey-Les-Nancy Clinic, Essey Les Nancy: M. Amor and P.E. Bollaert (Hôpital Central, Nancy, MICU); René Dubos Hospital, Pontoise: F. Funck; Boucicaut Hospital, Paris: A. Lafont; CMCO, Schiltigheim: M. Zupan; Hôpital Nord, Marseille: F. Paganelli; Saint Joseph Hospital, Marseille: F. Dhoudain; Necker Hospital, Paris: J.P. Metzger; Rhone-Durance Clinic, Avignon: J. Sainsous; Haut Lévesque Hospital, Pessac: P. Coste; and La Cavale Blanche Hospital, Brest: J.P. Boschat.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 Appendix
 References
 

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