CORRESPONDENCE: LETTER TO THE EDITOR
Clinical Implications of the PROTECT–TIMI-30 Trial
Marco Valgimigli, MD, PhD*,
Giuseppe G.L. Biondi-Zoccai, MD and
Pierfrancesco Agostoni, MD
* Institute of Cardiology, University of Ferrara and Cardiovascular Research Centre, Salvatore Maugeri Foundation, IRCCS Gussago (BS), Italy (Email: vlgmrc{at}unife.it).
We would like to congratulate Gibson et al. (1) for the completion of the recently reported PROTECT–TIMI-30 (Randomized Trial to Evaluate the Relative PROTECTion against Post-PCI Microvascular Dysfunction and Post-PCI Ischemia among Anti-Platelet and Anti-Thrombotic Agents–Thrombolysis In Myocardial Infarction-30) trial, in which patients with moderate to high-risk acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) were randomly allocated to receive eptifibatide with either unfractionated heparin or enoxaparin versus bivalirudin monotherapy. Although this study adds insightful information to the ongoing debate on the comparison of direct thrombin inhibitor alone versus the association of glycoprotein (GP) IIb/IIIa inhibitors and indirect antithrombin agents as adjunctive treatment during PCI, it also puzzles the reader with the contrasting data on efficacy provided by the primary and secondary end points.
The post-PCI coronary flow reserve (CFR), quantified through the corrected Thrombolysis In Myocardial Infarction (TIMI) frame count, has to the best of our knowledge never been shown to correlate with outcomes in patients with non–ST-segment elevation ACS. Moreover, its agreement with Doppler-derived CRF in this setting has been questioned (2). In contrast, the 25% relative risk reduction in the composite of death or myocardial infarction (MI) at 48 h and the significant 35% relative decrease in the rate of patients showing post-PCI creatine kinase-myocardial band (CK-MB) elevation among subjects (n = 624; 73%) CK-MB–negative at baseline in the group allocated to eptifibatide seem to support the additive value of complete platelet inhibition in such a setting (3). We believe that some methodological issues beyond those discussed by Gibson et al. (1) may help explain the paradoxical results of the primary end point when put into the context of the results reported for the secondary outcomes. Coronary flow reserve after the procedure could not be analyzed according to the intention-to-treat principle in the study because patients who sustained abrupt vessel closure, emergent coronary bypass graft surgery, or thrombotic closure with bailout to eptifibatide had to be excluded (n = 103; 12% of the enrolled population). It thus remains possible that patients at relatively lower risk have been selected for the primary end point assessment in whom no or minor benefit from GP IIb/IIIa inhibitors on microcirculation may be expected. It would be of utmost interest to know the rate of major adverse events in this excluded fraction of patients, stratified according to the randomization scheme and as compared to the patient group in whom primary end point analysis could be accomplished. This may help to reconcile the apparently contrasting data between the primary end point (based on 88% of the enrolled population) and secondary outcome (based on the whole population) results in the study.
Finally, the investigators comment in the discussion section that the risk of death or MI was significantly reduced among eptifibatide patients who were pretreated for <6 h with clopidogrel before PCI, but they fail to report throughout the study the actual figures for the observed event rates in this subset of patients despite the fact that this was a prespecified secondary analysis and that randomization was stratified according to prior use of thienopyridines. We believe that this information may help to put PROTECT–TIMI-30 findings in perspective, especially considering that <40% of ACS patients may undergo PCI after upfront blockade of the P2Y12 receptor in current clinical practice (4).
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References
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- Gibson CM, Morrow DA, Murphy SA, et al. A randomized trial to evaluate the relative protection against post-percutaneous coronary intervention microvascular dysfunction, ischemia, and inflammation among antiplatelet and antithrombotic agents: the PROTECT–TIMI-30 trial J Am Coll Cardiol 2006;47:2364-2373.[Abstract/Free Full Text]
- Chugh SK, Koppel J, Scott M, et al. Coronary flow velocity reserve does not correlate with TIMI frame count in patients undergoing non-emergency percutaneous coronary intervention J Am Coll Cardiol 2004;44:778-782.[Abstract/Free Full Text]
- Cavallini C, Rugolotto M, Savonitto S. Prognostic significance of creatine kinase release after percutaneous coronary intervention Ital Heart J 2005;6:522-529.[Medline]
- Savonitto S, Ambrosini V, Marzocchi A, et al. Drug therapy during percutaneous coronary interventions in stable and unstable coronary artery disease: the Italian Drug Evaluation in Angioplasty (IDEA) study Ital Heart J 2005;6:106-118.[Medline]
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J. Am. Coll. Cardiol. 2007 49: 730-731.
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