Glycoprotein IIb/IIIa inhibition and long-term benefit: the stuff of dreams?

Gilles Montalescot*

Institut de of Cardiologie, Hôpital Pitié-Salpêtrière, Paris, France

* Correspondence to: Professor Gilles Montalescot MD, PhD, Institut de of Cardiologie, Hôpital Pitié-Salpêtrière, Bureau 2-236, 47 Bl de l'Hôpital, 75013 Paris, France. Tel.: +33 1 4216 3006; fax: +33 1 4216 2931 (E-mail: gilles.montalescot{at}psl.ap-hop-paris.fr).

This editorial refers to "Five-year outcome of patients with acute myocardial infarction enrolled in a randomised trial assessing the value of abciximab during coronary artery stenting"{dagger} by G. Ndrepepa et al. on page 1635

Over the years, several controversies have surrounded the choices made before and during the reperfusion process of acute ST-elevation myocardial infarction (STEMI). Among many others, questions have been raised over the value of percutaneous coronary intervention (PCI) versus thrombolysis, of stenting versus balloon angioplasty, of filters or thrombectomy devices versus no distal protection, and of course, of glycoprotein (GP) IIb/IIIa inhibitors versus no GP IIb/IIIa inhibitors. Among the dozen of randomized trials evaluating these drugs in primary PCI of evolving STEMI, only five were big enough to look at clinical endpoints and were performed with abciximab. The pooled results of these five trials showed an overall significant 34% reduction in death or reinfarction at 30 days, confirming the overall short-term benefit of this drug after primary PCI.1 Although the initial clinical benefits of abciximab are recognized in primary PCI of STEMI, a few studies, performed in similar or different situations, have challenged these benefits on the long-term.2,3 The Intracoronary Stenting and Antithrombotic Regimen-2 (ISAR-2) is now one of these studies; the well-respected Munich group of investigators reports in this issue of the Journal a loss of the initial benefit at 5-year follow-up.4 Interestingly, in this study there was a significant 5.5% absolute risk reduction of the composite endpoint of death, reinfarction, and target lesion revascularization at 30 days with abciximab, but the identical 5.7% absolute risk reduction at 1 year was no longer statistically significant due to increased rates of late target-lesion revascularization in both groups.5 Obviously, the "catch-up phenomenon" had already started.

Long-term benefit is a difficult and rarely won challenge for drugs in general and brief treatments in particular. The incremental number of events in both groups ineluctably leads Kaplan–Meier curves to catch-up when follow-up is long enough. Unless the treatment can deeply and definitively alter the pathological process (like antibiotics in tuberculosis) or impact a major trigger of outcome (like dialysis in renal failure), incremental benefit and even preservation of the initial benefit is unlikely in the very long term. Are GP IIb/IIIa inhibitors and more specifically abciximab, the stuff of dreams which can impact long-term prognosis? The rationale relies on the pleiotropic effects of abciximab such as its well demonstrated anti-inflammatory properties which could deeply alter the pathological process and, on the prevention of distal embolisation and LV dysfunction, a well-known trigger of outcome in STEMI. The present ISAR-2 data, especially the absence of long-term mortality benefit, do not support these hypotheses. However, beyond the power issue of the study, this information is in contradiction with previously published long-term data obtained with abciximab and it may well generate one of these controversies we are used to have in the field of mechanical reperfusion. Indeed, the 5799 patients randomized to abciximab or placebo in the three large "EPI" studies had a significant 20% reduction of death after a similar 5-year follow-up.6 We may think that primary PCI differs from elective PCI in the long-term, but in a meta-analysis of eight trials including four primary PCI trials, a similar benefit was observed with abciximab over a 3-year follow-up period in 9290 randomized patients.7 This meta-analysis did not incorporate the latest data including the 1 year diverging survival curves of the Abciximab and Carbostent Evaluation (ACE) study with a significantly lower mortality with abciximab (RRR=–52%),8 the 3-year follow-up of the Abciximab before Direct angioplasty and stenting in Myocardial Infarction Regarding Acute and Long-term follow-up (ADMIRAL) study showing a preservation of the 30-day clinical benefit including for mortality (RRR=–25%)9 and the favourable trend in the low risk Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) population at 1-year follow-up (RRR=–14%).2 Positive results were also reported after long follow-up of patients enrolled in large registries with cost-effective survival advantage.10,11 Although always difficult to conduct, more long-term follow-up studies are needed before we really know what the outcome of these patients reperfused with or without GP IIb/IIIa inhibitors is. Finally, numerous primary PCI studies have identified the risk factors of poor survival in the long term (e.g., age, diabetes mellitus, heart failure) and, as the years slide by these permanent and self-aggravating factors certainly become stronger and stronger factors of outcome overriding the initial protection brought by 12 h abciximab infusion.

If we accept the certainly unproven idea of a significant clinical benefit limited to only the first couple of months following primary PCI, would that be enough to dismiss the use of GP IIb/IIIa inhibitors in primary angioplasty? We could reformulate the question more simply by saying: does it matter to die now or later? Most drugs and devices have only postponed recurrent ischaemic events and prolonged life only mildly. The bottom line question is, "How much benefit can drugs provide and at what cost?" The cost of GPIIb/IIIa inhibitors compares favourably with that of drug-eluting stents, distal protection devices and new long-term oral antiplatelet therapy all of which have yet to show survival benefit. How much benefit can we expect from a modern strategy of transferring STEMI patients on GPIIb/IIIa inhibitors for primary PCI in comparison with thrombolysis? Despite the attendant delay, the transfer for primary PCI reduces mortality by 19% compared with local thrombolysis.12 The absence or negligible use of Gp IIb/IIIa antagonists in the primary PCI arms of the studies of this meta-analysis may have reduced the magnitude of benefit observed with primary PCI. Indeed, abciximab reduces mortality by 26% at 30 days in comparison with no abciximab during primary PCI.1 However, in these five studies pooled together, less than 5% of patients received the drug early in the casualty department or in the ambulance, underestimating the effect of the study drug. When STEMI patients are treated with a GP IIb/IIIa inhibitor, pre-catheterization laboratory initiation of therapy is associated with a 28% reduction of mortality compared with in-catheterization laboratory initiation of the drug.13 The impact of such an early use of Gp IIb/IIIa inhibitors on outcome is no less cost-effective than a late administration and only a matter of organization of our healthcare systems including emergency room service and ambulance networks. All these analyses are limited by sample size but the benefits may well be additive and strongly encourage to the optimisation of care delivery to STEMI patients, considering the time issues not only for balloon inflation but also for GP IIb/IIIa inhibition.

Whether more aggressive pharmacological approaches using a full regimen of thrombolytics, or reduced dose of lytics combined with Gp IIb/IIIa inhibitors before PCI, can open more arteries with finally improved clinical outcomes is at present unknown and cannot therefore be recommended. All strategies that include thrombolysis significantly increase the risk of intracranial haemorrhage, which is approximately seven-times higher than with Gp IIb/IIIa blockers alone. Recent studies have also suggested little impact on infarct size and clinical outcomes of these new facilitating strategies which are now being tested in large scale trials such as the safety and efficacy of a new thrombolytic (ASSENT)-4 and Facilitated INtervention with Enhanced reperfusion Speed to Stop Events (FINESSE) trials.

The reperfusion dream may come in many options, but the dream that matters for most physicians is the one they have not yet seen. For those of us who work at primary PCI centres, optimising the chain of care upstream of the catheterization laboratory is critical to transform a slow process of transfer into the first step of effective drug reperfusion, management of potentially fatal complications and fast transition to mechanical reperfusion. Stepping up this "out of cath-lab phase" into an active process of treatment with current and future drugs could propel primary PCI further forward; then the dream of a palpable long-term benefit may come true.

Footnotes

{dagger} doi:10.1016/j.ehj.2004.04.031 Back

References

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Related articles in EHJ:

Five-year outcome of patients with acute myocardial infarction enrolled in a randomised trial assessing the value of abciximab during coronary artery stenting
Gjin Ndrepepa, Adnan Kastrati, Franz-Josef Neumann, Claus Schmitt, Julinda Mehilli, and Albert Schömig
EHJ 2004 25: 1635-1640. [Abstract] [Full Text]  




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