Measuring the Right Compound at the Right Time is Not Always Easy
- Volume 22 - Issue 1 - January, 2010
- Posted on: 1/7/10
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The introduction of intravenous glycoprotein IIb/IIIa inhibitors (GPI) nearly two decades ago has revolutionized the care of patients undergoing percutaneous coronary intervention (PCI). Enrollment in GPI trials was the fastest ever reported in interventional cardiology and the amount of data amassed in a short time enabled us to characterize and refine the role of these compounds. While inhibiting platelet aggregation, it was demonstrated that these agents can also decrease the amount of the inflammation promoting CD40 shed from platelets and thus further decrease platelet activation and aggregation.1 The level of CD40 ligand even predicted clinical events in patients with acute coronary syndromes (ACS).2 Subsequently, other inflammatory substances and markers of plaque destabilization were found to predict events in ACS patients.3,4 After the initial studies performed with the chimeric, non-specific antibody abciximab, two specific antagonists of the GP IIb/IIIa were developed — a cyclic heptapeptide — eptifibatide and a non-peptide tyrosine derivative — tirofiban. Both these “small molecules” are specific for sequences of the GP IIb/IIIa receptor (KGD and RGD, respectively) and exhibit reversible inhibition of the receptor with a half life of approximately 2 hours. Their introduction engendered a great debate as to whether differences in outcome between the different drugs are related to extent of platelet inhibition only, or to non-specific effects, such as inhibition of inflammation, smooth muscle cell migration and proliferation or thrombosis. Candidate receptors such as vitronectin and MAC-1 were found to be inhibited by abciximab, but not by the other GPI.5,6 It is important to note that the timing of these interactions and their role in vascular healing and restenosis are very different from that related to immediate prevention of thrombosis, mediated through platelet inhibition.7 Inflammation occurs in the first 12–24 hours after PCI (not in the first few minutes), proliferation of smooth muscle cell proliferation ensues in days 1–14 and matrix production and deposition starts on day 7 and peaks around day 60.
In this issue,8 Dr. Saltzman and colleagues visit this issue in a mechanistic pilot study comparing the platelet inhibition afforded by standard doses of abciximab or tirofiban in patients undergoing PCI. They measured platelet aggregation inhibition at baseline and every 10–15 minutes during the procedure using the rapid function platelet assay Ultegra (Accumetrics, San Diego, California). At the same time points, hs-CRP was measured using a commercially available Dade-Behring kit. They found that among the 95 patients randomized to abciximab (n = 44) or tirofiban (n = 51), the level of platelet inhibition was very high (> 80%) and similar at all time points. Only a small, and similar, proportion of patients in each group (10–20%) had > 95% inhibition of platelet aggregation at any time point. This level of platelet inhibition has been associated with best PCI outcomes in an earlier abciximab study.9 In a prespecified subset of diabetic patients, the inhibition of aggregation afforded by tirofiban was slightly higher, particularly at the earliest measurement after the bolus. Consistent with platelet biology in diabetics, fewer patients in each group had inhibition > 95%, and virtually none did so 30 minutes after the bolus. The hs-CRP levels exhibited large variations in both groups, without significant differences between the groups. Even though the data were not presented, by my calculations, the change in hs-CRP from baseline appeared different in the two groups, with an increase of 1.89 mg/L in the abciximab group and a decrease of 5.11 mg/L in the tirofiban group (p = 0.006). Of course, we are not told how long the procedures lasted in each group, thus the results may be representing two very different time points. If one uses the 45-minute time point, the results are completely different, with a marked increase in the tirofiban group and essentially no change in the abciximab group. Thus, the hs-CRP results are quite unreliable and, as the authors recognize, it is not clear what the relationship between intraprocedural variations in CRP and sustained inflammation after PCI is.
Clinical events were extremely rare, as expected from a relatively low-acuity population, and thus we cannot index the level of platelet inhibition or inflammation suppression to a substantial modification of clinical outcome.
While these findings are interesting, it is what we are not told that could be more relevant. The relation of vascular inflammation to clinical outcome after PCI has preoccupied clinicians and scientists for more than a decade. The timing of the inflammatory response and its suppression are as critical as the intensity of the inflammation. We do know that many medications influence inflammation, but we do not know whether and when they were administered in this study. Aspirin, thienopyridines, GPI, statins, fibrates, to name a few, decrease the levels of one or more markers of inflammation.10 Even the type of stent implanted can affect the magnitude of the inflammatory response.11 In the most ambitious attempt so far, chronic administration of clopidogrel, in addition to aspirin, to patients with vascular disease has not resulted in a substantial reduction in clinical events. More importantly, the change in inflammatory markers did not correlate with the suppression of major adverse cardiac events.12
In the only direct comparison of the two GPI (in the doses used in this study) in a large clinical trial, patients undergoing PCI derived a significant benefit at 30 days when treated with abciximab (6.0% vs. 7.6%; p = 0.04), but not at 6 months (15.1% vs. 17.6%; p = 0.06). There was no difference in the diabetic subset of these patients.13
In the end, we are left wondering whether the findings of this manuscript reflect a failure of understanding the principles of vascular inflammation and its role as a translator of the effects of platelet inhibition on clinical events following PCI, or whether they re-emphasize that doing the right thing at the wrong time is as ineffective as doing the wrong thing altogether. I suspect it is the latter.
From New York Methodist Hospital, Brooklyn, New York.
The author reports no conflicts of interest regarding the content herein.
Address for correspondence: Sorin J. Brener, MD, Director, Cardiac Catheterization Laboratory, New York Methodist Hospital, 506 6th Street, Brooklyn, New York 11215. E-mail: [email protected]