Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany
E-mail address: achim.buettner{at}herzzentrum.de
* Correspondence to: Prof. Dr. med. Franz-Josef Neumann, Herz-Zentrum Bad Krozingen, Südring 15, 79189 Bad Krozingen, Germany. Tel.: +49-7633-402-8201; fax: +49-7633-402-8204
E-mail address: franz-josef.neumann{at}herzzentrum.de
This editorial refers to "Facilitation of primary coronary angioplasty by early start of a glycoprotein 2b/3a inhibitor: results of the ongoing tirofiban in myocardial infarction evaluation (On-TIME) trial"1 by A.W.J. Van 't Hof et al. on page 837.
The primary goal of treatment in acute myocardial infarction is re-perfusion of ischaemic myocytes to salvage myocardium and thus improve the long-term clinical outcome. An indispensable pre-requisite for this goal is full patency (TIMI grade 3 flow) of the infarct-related artery. In 1993, the Zwolle group was among the first who published compelling data that this purpose is best served by percutaneous catheter intervention (PCI).1 Even in patients who need to be transported to the PCI center from another hospital, PCI is superior to fibrinolysis.2 A critical time limit for this benefit appears to be 90 min for the delay between the potential start of fibrinolysis and PCI.3 The On-TIME trial published in this issue once more demonstrates that this time limit can be kept over large distances and in a large number of patients and that the strategy of transporting patients with acute myocardial infarction to PCI results in an excellent clinical outcome with a 30-day and 1-year mortality of 2.2% and 4.1%, respectively.4 Together with the DANAMI-2 and PRAGUE-1&2 trials the On-TIME study presents a strong incentive to optimise the logistics of regional myocardial networks to provide state-of-the-art re-perfusion therapy to all patients with acute myocardial infarction.
Although PCI is established as the best re-perfusion therapy for acute myocardial infarction, there is still room for improvement. From a variety of studies, including the use of myocardial contrast echography, positron emission tomography, Doppler flow velocity measurements, and angiographic analyses of contrast-dye propagation and distribution, we have learnt that, even with TIMI grade 3 flow after PCI of the infarct-related artery there is large variation of microvascular perfusion that has a major impact on clinical outcome.
Mechanistic studies with abciximab have shown that peri-interventional glycoprotein (GP) IIb/IIIa receptor blockade is an option to improve microvascular perfusion after PCI for acute myocardial infarction.5 The clinical impact of this potential was tested in six randomised trials, with an overall total of 3755 patients. Comparing abciximab to placebo as an adjunct to PCI in acute myocardial infarction, each of these trials showed a significant reduction in the 30-day composite of death, re-infarction and target vessel re-vascularisation by abciximab.6 Furthermore, in the most recent trial, ACE, a significant survival benefit of abciximab was found at one year ().7 Secondary analyses of ADMIRAL showed that the subgroup of patients receiving abciximab in the ambulance or the emergency room benefited most.8 This observation, however, is based on small numbers and there is still uncertainty about the role of upstream administration of abciximab for primary PCI in acute myocardial infarction. At present, this concept is under further investigation by a large randomised trial.
Among the GP IIb/IIIa receptor blockers, small molecule compounds, such as tirofiban, are attractive alternatives to abciximab; offering better steerability of the anti-platelet effect at a lower cost. Thus far, however, we do not have the data from randomised placebo-controlled studies that support the use of small molecule GP IIb/IIIa receptor blockers as an adjunct to PCI in acute myocardial infarction. In the absence of these data, it may be tempting to assume a class effect. The TARGET study, however, warns us not to do so. In this study, the 30-day outcome of patients undergoing PCI with peri-interventional administration of tirofiban was significantly inferior to that of patients receiving abciximab, a difference that was particularly prominent in those with unstable coronary syndromes.9 Although non-specific integrin blockade by abciximab may have played a role, a more plausible explanation appears to be that the dose of tirofiban was insufficient to achieve optimal platelet inhibition at the time of intervention.
In this issue van 't Hof and co-workers4 report the results of On-TIME, which investigated the use of tirofiban for PCI in acute myocardial infarction. Despite the uncertainty about the effect of tirofiban in this setting, On-TIME compared upstream administration of tirofiban to administration in the catheterisation laboratory. Dosing of tirofiban was the same as in TARGET. On-TIME, thus, took two steps at a time: if there had been convincing evidence that early administration of tirofiban was superior to late administration, superiority to placebo would have been apparent. Unfortunately, the On-TIME study turned out to be negative; the primary endpoint, the proportion of infarct-related arteries with TIMI grade 3 flow before PCI, was not significantly different between early and late administration (19% versus 15%, odds ratio 1.35 [95%-confidence interval 0.842.18]; ). Therefore, the questions whether tirofiban was the correct agent, or was administered at the right dose, or whether timing of administration is relevant remain unanswered.
In the various secondary analyses of On-TIME, there was an advantage of early over late administration of tirofiban with respect to the proportion of infarct-related arteries with TIMI grade 2 or 3 flow that reached marginal statistical significance. Because the primary end-point was negative, any secondary analysis, and particularly those with marginal statistical significance, must be interpreted with extreme caution. Therefore, the findings on the composite of TIMI grade 2 and 3 before PCI cannot be taken as definite proof of effect, but only as an indication. These statistical considerations aside, the relevance of the surrogate of TIMI grade 2 and 3 before PCI is debatable. The investigators of On-TIME had good reason to choose TIMI grade 3 flow as their primary clinical endpoint: In the large retrospective analysis of all PAMI studies that served as the rationale for design of On-TIME, pre-PCI TIMI flow 3 (not
2) was an independent baseline determinant of late mortality.10 Notably, in On-TIME, the significantly higher proportion of patients with TIMI grade 2 and 3 before PCI in the early administration arm, compared with the late administration arm, was not associated with a better clinical outcome, either at 30-day or at 1-year follow-up.
Based on these findings, the On-TIME investigators raise the question, `Is an open infarct-related artery before PCI that important?' Indeed, the observation that spontaneous patency of the infarct related-artery before PCI identifies a patient sub-group with favourable prognosis, does not necessarily imply clinical benefit of therapeutic interventions to improve pre-PCI patency of infarct-related arteries. Currently, there is no sound evidence that these interventions improve outcome. In PACT, the higher patency of the infarct-related artery in the thrombolysis group did not translate into a higher convalascent ejection fraction as compared with the control group.11 Similarly, in BRAVE, myocardial salvage did not demonstrate any significant benefit to the group pre-treated with abciximab plus half a dose of fibrinolytic compared with the abciximab-alone group, despite a higher patency of the infarct-related artery in patients of the fibrinolytic arm.12 In fact, the point estimate for myocardial salvage in this arm was even lower than in the abciximab-alone arm. As the On-TIME investigators point out, neither the PACT, BRAVE, LIMI, or PRAGUE-1 trials, nor the PCI analysis of SPEED have found that the significantly higher pre-PCI patency rates, induced by the respective fibrinolytic intervention, afforded any appreciable improvement in clinical outcome. It is an important observation of On-TIME that this paradigm does not appear to be altered if pre-PCI patency is induced by GP IIb/IIIa blockade.
What are the practical consequences of On-TIME? Does On-TIME support the use of tirofiban in acute myocardial infarction or facilitation of infarct PCI by upstream GP IIb/IIIa receptor blockade? We think the answer to both of these questions is no. On the other hand, On-TIME by no means excludes that tirofiban, if adequately dosed, is a powerful drug to improve the outcome of PCI in acute myocardial infarction. This, however, awaits to be tested in an adequately designed randomized trial, preferably with abciximab as active control.
Footnotes
References
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