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Via multidetector computed tomography (MDCT) with retrospective electrographic gating, we sought to evaluate whether plaque distribution differs between Responders and Low Responders to clopidogrel treatment. Low response was defined as a post-treatment aggregation of 35% to 70%.
In this observational study, we enrolled 62 patients (mean age, 64.8 ± 8.9 yr; 51 men). In addition to determining coronary calcium scores, we performed noninvasive coronary angiography with MDCT before stent implantation. Plaques were visually classified as calcified, mixed, or completely noncalcified. Mean density was measured. Residual platelet aggregation (RPA) was evaluated by aggregometry 6 hr after administration of a 600-mg loading dose of clopidogrel. Patients with an RPA of less than 35% were defined as Responders.
The median calcium score was 736 Agatston score equivalent (ASE) (range, 0–5,772) and mean platelet inhibition was 35% ± 19% (range, 0–70%). A total of 494 coronary plaques were detected (Responders: calcified, 197; mixed, 47, noncalcified, 5; and Low Responders: calcified, 177; mixed, 65; noncalcified, 3). Responders (n=35) had significantly lower ASEs and fewer mixed but more calcified plaques than did Low Responders. In mean plaque density (measured within the noncalcified part of the plaques), no statistically significant difference existed between the 2 patient groups. By use of MDCT, we showed that ASE and plaque distribution were associated with RPA after clopidogrel treatment. Patients with a low coronary plaque burden and a small proportion of mixed plaques were more likely to have low RPA after administration of clopidogrel.
Coronary atherosclerosis is still one of the major causes of morbidity and death worldwide: almost 17 million persons die as a consequence of coronary artery disease annually.1 In patients with acute myocardial ischemia, and in other symptomatic patients as well, percutaneous coronary intervention with consecutive stent placement is the method of choice to reduce morbidity and death.2 However, stent thrombosis rivals the acute sequelae of dissection and rupture as a dreaded possible consequence of stent placement.
Although several factors are known to raise the risk of stent thrombosis, the underlying mechanisms are incompletely understood. As recently shown,3 residual platelet aggregation (RPA) after the administration of clopidogrel is an important determinant of stent thrombosis, and patients with acute coronary syndromes (ACSs) are more likely to have a low response to clopidogrel treatment. Other data show that plaque distribution differs between patients with stable angina pectoris and patients with ACS.4,5 Multidetector computed tomography (MDCT) scanning, the current state-of-the-art imaging technique, enables the noninvasive visualization and classification of coronary plaques.6,7 We sought to determine whether residual platelet aggregation is associated with plaque distribution in patients with stable coronary artery disease.
Between December 2005 and May 2007, we enrolled 62 consecutive patients in this observational study (mean age, 64.8 ± 8.9 yr; 51 men). All patients displayed typical angina pectoris and, due to the presence of significant coronary stenosis (>75% luminal narrowing) or proven ischemia, were scheduled for coronary angioplasty with stent placement during the same procedure. The patients' characteristics are summarized in Table I.
All computed tomographic (CT) scans were performed 24 to 168 hours before invasive angiography. The study protocol was approved by our local ethics committee. All patients gave informed consent before inclusion in the study. All coronary angiography was performed by an experienced cardiologist, who used the standard Judkins technique.
Blood Sampling and Platelet Aggregation. The patients' blood was collected when maximum platelet inhibition was achieved, at least 6 hr after the 1st administration of 600 mg of clopidogrel by mouth.8 Blood samples were collected in citrate plasma (3.8% solution) and centrifuged at 1,000 rpm for 10 min to obtain platelet-rich plasma, and then for an additional 10 min at 3,500 rpm to recover platelet-poor plasma. The platelet concentration of platelet-rich plasma was adjusted to 2 × 105/μL by adding homologous platelet-poor plasma. The percentage of platelet aggregation after stimulation with 20 μmol/L adenosine diphosphate was determined by the turbidimetric method, using a Chrono-log Lumi-Aggregometer with Aggro/Link software (Chrono-log Corporation; Havertown, Pa). Low response to clopidogrel was defined as a post-treatment aggregation of 35% to 70% and adequate response as an aggregation of <35%.9
Coronary Calcium Scoring. Coronary calcium scoring was determined by means of MDCT. Nineteen patients were examined with a 64-slice CT scanner (SOMATOM Sensation 64™, Siemens Medical Solutions USA, Inc.; Malvern, Pa) with a collimation of 64 × 1.2 mm, a gantry rotation time of 330 ms, a pitch of 0.23, tube voltage of 120 kV, and a maximum tube current-time product of 100 mAs. In 43 patients, coronary calcium scoring was performed with a dual-source CT scanner (SOMATOM Definition™, Siemens AG; Erlangen, Germany) with a collimation of 2 × 64 × 1.2 mm, a gantry rotation time of 330 ms, a tube voltage of 120 kV, and a maximum tube current-time product of 2 × 100 mAs. Automated dose modulation (via Care Dose 4D™) was used with both scanners. The quantification of coronary calcifications was performed on native scans by means of dedicated post-processing software (syngo® MultiModality Workplace, Siemens). Calcium scores were expressed as Agatston score equivalents (ASEs).
Contrast-Enhanced Scans. Vessel opacification for CT angiography was achieved by automated injection (CT2™, MEDTRON AG; Saarbrücken, Germany) of 70 mL (dual-source CT) or 80 mL (64-slice CT) iomeprol (Imeron® 400, ALTANA Pharma AG, part of Nycomed International Management GmbH; Zürich, Switzerland) at a flow rate of 5 mL/s, followed by a 60-mL chaser bolus. Individual circulation time was estimated by means of the test-bolus technique, using a 20-mL bolus and dynamic evaluation software (DynEva™, syngo®, Siemens; Forchheim, Germany).
For CT angiography, the collimation was 32 × 0.6 mm, the slice acquisition was 64 × 0.6 mm using the z-flying focal spot technique, the gantry rotation time was 330 ms, the pitch was 0.20 to 0.43 adapted to heart rate, the tube voltage was 120 kV, and the maximum tube current was 400 mAs per rotation. For dose reduction, prospective tube-current modulation was applied.
A test series—obtained in a transverse plane at the level of segment 2 and displaying reconstruction window offsets by 5% of the entire cardiac cycle—formed the basis for the initial reconstruction window. When motion artifacts appeared in the initial reconstruction, further reconstructions were obtained in 5% increments of the cardiac cycle, until all individual arteries could be visualized at optimal image quality.
Effective slice thickness was 0.75 mm, with a reconstruction increment of 0.4 mm. Data sets were filtered with a medium-soft convolution kernel (B26f). All CT angiographic data sets were evaluated for the presence of coronary plaques. Plaques were visually classified as noncalcified, mixed, or completely calcified plaque (Fig. 1). Depending on the plaque area, the Hounsfield unit (HU) was determined within the noncalcified part of the plaque by placing a region of interest into the dedicated area. The reader of the CT dataset was unaware of the platelet-aggregation results.
Statistical Analysis. Continuous variables were described as mean ± SD. Categorical data were presented with absolute frequencies and percentages. Unpaired t tests were performed to evaluate differences between patients with high RPA and low RPA after clopidogrel treatment. The Kruskal-Wallis test or the 1-way analysis of variance test was performed to evaluate differences between subgroups. Values of P <0.05 were considered to be statistically significant. All statistical analyses were performed using GraphPad Prism® 4.0 (GraphPad Software, Inc.; San Diego, Calif).
All CT scans were of diagnostic quality and were performed without adverse sequelae.
Mean Platelet Inhibition. Mean platelet inhibition was 35% ± 19% (range, 0–70%). Responders had significantly lower calcium scores than did Low Responders: 719 ± 786 vs 1,366 ± 1,393; P <0.05 (Fig. 2).
Plaque Distribution. A total of 494 coronary plaques were detected. In the group of Responders, 197 plaques were completely calcified, 47 were mixed, and 5 were noncalcified. In the group of Low Responders, 177 plaques were completely calcified, 65 were mixed, and 3 were noncalcified. The Responders had significantly lower Agatston score equivalents than did Low Responders (median, 417 vs 912; P <0.05) (Table I) and a significantly lower number of mixed plaques (19% vs 27%; P <0.05) (Table II). However, the Responders had a significantly higher number of completely calcified plaques than did Low Responders (79% vs 72%, P <0.05).
Mean Plaque Density. To characterize mixed plaques more precisely, mean contrast attenuation of the noncalcified part of the mixed plaque was measured. There was no statistically significant difference between the 2 patient groups (220 ± 85 HU vs 220 ± 89 HU; P = 0.3386) (Fig. 3).
This is, to the best of our knowledge, the 1st report on the association between coronary plaque distribution and RPA after the administration of clopidogrel in patients with stable angina pectoris. We found a significant correlation between RPA and coronary calcification. Patients with a high RPA had significantly higher Agatston score equivalents (which finding reflects total coronary plaque burden) than did patients with low RPA.
Moreover, plaque distribution seems to be associated with RPA. In our study, patients with a low coronary plaque burden and a small proportion of mixed plaque were more likely to have low RPA after the administration of clopidogrel.
Coronary Calcium Scoring and Noncalcified Plaques. With the exception of patients in advanced renal failure, calcifications occur solely within the context of atherosclerotic lesions,10–12 and coronary calcium deposits are indicative of the amount of coronary atherosclerotic plaque.10,11
The possibility of detecting and classifying coronary plaques noninvasively by the use of cardiac CT was reported in 2001.13,14 Even noncalcified plaque can be detected in approximately 10% of all patients without coronary calcifications.15 In our cohort, 5 patients (8%) had a negative coronary calcium scan even in the presence of a high-grade stenosis.
Plaque Distribution and Residual Platelet Aggregation after Clopidogrel Treatment. The association between plaque distribution and ACS was first described in 2003 by Leber and associates.4 Patients with ACS had significantly more noncalcified plaques than did matched patients with stable angina pectoris, although the total plaque burden was comparable. These results were confirmed by Schuijf and colleagues in 2007.5
The association between ACS and RPA after clopidogrel treatment was discovered by Geisler and coworkers in 2008.3 In addition to some clinical variables like age, left ventricular function, diabetes mellitus, and renal function, ACS significantly influenced the response to clopidogrel treatment in a cohort of more than 1,000 patients. Moreover, there are data that RPA is influenced by co-medication with proton-pump inhibitors.16 However, we observed no significant difference between Responders and Low Responders in terms of proton-pump-inhibitor medication. In addition, we found no significant difference in the clinical characteristics of patients with high and low RPA. Therefore, plaque distribution might be an independent predictor for RPA after clopidogrel administration.
Our results might be interpreted as a link between the observations of Leber4 and those of Geisler3 and their respective colleagues. Although the total number of coronary plaques was not different between patients with high or low RPA, RPA was significantly higher in patients with larger proportions of mixed plaques than in patients with predominantly calcified plaques. These results seem to be inconsistent with the observation that patients with higher calcium scores have higher RPA, because the amount of coronary calcification is known to reflect total plaque burden. However, our unexpected result might be explained by the fact that we distinguished plaque types qualitatively and not quantitatively; therefore, mixed plaques with a large calcified fraction added markedly to the Agatston score equivalents. This assumption could be verified by measuring the total plaque burden, were it not for the fact that the spatial resolution of cardiac CT does not yet enable reliable quantification of total plaque burden, especially within small side branches.
Another curiosity was the large overlap in Agatston scores between Responders and Low Responders: that is, patients without coronary calcification (ASE, 0) and patients with severe coronary calcification (ASE, >1,000) were present in both groups. Apparently, the extent of coronary calcification is only 1 factor that might influence the response to antiplatelet therapy. Another such factor could be the presence of vulnerable plaque (leading to local platelet activation and a high RPA)—but the imaging of “vulnerable plaque” is still not possible with CT technology. Certainly the multiplicity of factors that might influence response to antiplatelet therapy merits discussion.
Measurements of contrast attenuation within the noncalcified parts of the plaques did not reveal any significant difference between patients with high and low RPA. Consequently, the “quality” of the mixed plaque in the 2 groups seems to be quite similar.
The pathophysiologic mechanism behind our results remains open to speculation. Because coronary calcification is indicative of the total amount of coronary plaque burden and, when present in large quantity, is associated with increased “inflammation,” calcification and clopidogrel metabolism can be causally entwined. In addition, mixed plaques might be interpreted as the result of enlargement of an atherosclerotic lesion; larger trials are necessary to elucidate this cause-and-effect relationship.
We are aware that our study is limited by several factors. The sample size was not large enough to enable multivariate analysis, and the study was observational in nature. Moreover, no patient in our cohort had a post-treatment platelet aggregation of >70%, nor did we measure aggregation at baseline. Because we performed calcium scoring and contrast-enhanced CT of the coronary arteries before the invasive procedure, we were obliged to exclude patients with acute conditions, such as unstable angina and myocardial infarction.
Although some data indicate that plaque characterization might be performed by means of cardiac CT,17 the potential to accurately evaluate plaque composition is limited even when the latest types of scanners are used. Finally, because we performed no follow-up, it remains unclear whether our observed data might be associated with a higher cardiovascular event rate.
Through the use of MDCT, we could show that the amount of coronary calcification and the distribution of plaque are associated with RPA after clopidogrel treatment. Patients with a low coronary plaque burden and a small proportion of mixed plaque are more likely to have low RPA after the administration of clopidogrel. Contrast-enhanced CT might be helpful in predicting the response to clopidogrel, independently of known variables, in patients with stable angina pectoris.
Address for reprints: Christof Burgstahler, MD, Department of Internal Medicine–Sports Medicine, University of Tübingen, Silcherstrasse 5, D-72076 Tübingen, Germany