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- ↵⁎Reprint requests and correspondence:
Dr. Antonio Colombo, EMO Centro Cuore Columbus, Via M. Buonarroti 48, 20145 Milan, Italy.
For a drug to be defined a medication and not a placebo it is important that the medication proves more effective in preventing or treating a pathologic condition. This goal is always achieved by paying two prices: the higher cost of the drug compared to the placebo and the higher risk of side effects. The value of selectivity and the identification of the specific patients who may benefit the most from the administration of a drug is very important.
It should be borne in mind that patients undergoing percutaneous coronary intervention (PCI) in the midst of an acute coronary event or with multiple complex lesions may require a different level of anticoagulation and platelet inhibition than low-risk patients undergoing elective PCI for stable angina pectoris with simple lesions. Similarly, generalizing antithrombotic regimen safety data to a wide spectrum of catheter-based therapeutic devices should be avoided.
These are the main reasons why we consider the subanalysis of the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial by Puma et al. (1) reported in this issue of the Journalto be an important useful contribution toward improving the care of our patients undergoing PCI.
Use of IIb/IIIa inhibitors during PCI has demonstrated an absolute reduction of 1.5% to 6.5% in the 30-day risk of death, myocardial infarction, or repeat urgent revascularization, with some variability in treatment effect among the agents tested (abciximab, eptifibatide, and tirofiban) (2).
The ESPRIT trial is the first step in evaluating the clinical value in PCI of another IIb/IIIa inhibitor in addition to abciximab with an already proven efficacy (3–6). This trial demonstrated that eptifibatide, when used with appropriate dosing to guarantee over 80% effective platelet inhibition, can significantly lower complications after PCI (7).
Puma et al. (1) used a simple and straightforward classification to define a high-risk patient: age >75 years, presence of diabetes mellitus (including diet-controlled diabetes), elevated creatine kinase (CK)-MB or troponin at admission, ST-segment elevation myocardial infarction (STEMI) within 7 days of admission, and unstable angina within 48 h from admission. It is necessary to point out that the ESPRIT trial enrolled only patients undergoing elective stenting. This subanalysis categorizes a high-risk population from a larger group of patients apparently at low risk.
The ESPRIT trial enrolled 2,064 patients and 1,018 of them had at least one adverse baseline characteristic as defined by Puma et al. (1).
Death and myocardial infarction defined as CK-MB elevation more than three times the normal value at 30 days and at 12 months were the end points evaluated. This end point is different from the primary composite endpoint of the ESPRIT trial, which included death, myocardial infarction, urgent target vessel revascularization, and thrombotic bailout glycoprotein IIb/IIIa inhibitor therapy within 48 h after randomization. In addition, the investigators of the ESPRIT trial separately evaluated the occurrence of large versus small myocardial infarctions.
A concern arises with the decision to use the cut-off value of three times elevation of CK-MB rather that eight times as suggested by others (8) and not having available for the reader the incidence of non–Q-wave myocardial infarction according to this last definition.
The important findings of this study are that the incidence of the prespecified end point at 30 days in the high-risk group decreased from 12.38% in the placebo group to 6.19% in the eptifibatide group (p < 0.001). The incidence of corresponding events in the low-risk groups were minimally different, 8.03% and 6.51%, respectively, and without statistical significance. A clear and significant advantage in the high-risk group persisted at 12 months: 15.89% in the placebo group versus 7.99% in the eptifibatide group (p < 0.001). When we calculate that 14 patients need to be treated to prevent one adverse event at one year we find a robust recommendation.
The authors report that bleeding complications were higher in the eptifibatide group, but this difference was not statistically significant. However it would have been interesting to see the incidence of severe and minor bleeding complications in the high- and low-risk groups. In the ESPRIT trial there was a trend toward increased rates of bleeding with eptifibatide (9). Another particular group of patients that always generates concern regarding possible bleeding complications are the ones older than 75 years, and specific information in this subgroup would have been of interest.
It is important to consider that the characteristics used by Puma et al. (1) to define high-risk patients were only clinical without any specific evaluation of the complexity of the lesions.
Currently, PCI with drug-eluting stents is performed on complex lesions in addition to complex patients. It will be of interest to see how some lesion and procedural characteristics, such as bifurcations, use of multiple long stents, or overlapping stents may further help to better define high-risk subgroups where enhanced platelet inhibition may be of advantage. A previously reported subanalysis of the ESPRIT trial showed that patients treated with eptifibatide had trends toward fewer angiographic complications: 10% versus 12% (p = 0.13). In addition patients who sustained angiographic complications and received eptifibatide had fewer subsequent CK-MB elevations (43% vs. 50%; p = 0.31) (10). These types of angiographic complications may become more frequent with use of long stents to treat long lesions and diffuse disease. It is therefore reasonable to assume that patients with complex lesions may further benefit from an intense antiplatelelet therapy.
In the ESPRIT trial, 97% of the patients received clopidogrel with a 300-mg loading dose when needed. Despite eptifibatide treatment, high-risk patients had an incidence of death and myocardial infarction of 6.19% at 30 days, which means that there is room for further improvement. There are recent data regarding the benefit of a loading dose of 600 mg of clopidogrel and statin pretreatment (11–14). In addition new antithrombotic agents such as bivalirudin are routinely used during PCI in some centers (15).
New therapies and recommendations become continuously available to the clinician. It is therefore important to remember the concept highlighted at the beginning: An astute clinical scientist needs to better tailor potent and expensive therapies to the patient who will benefit the most. Today this decision is performed by obtaining a complete history and evaluating the clinical conditions and coronary anatomy of the patient; it may be possible that in the future genetic mapping may further refine this task.
↵⁎ Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
- American College of Cardiology Foundation
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