Abstract
Background
Platelets play an important role in inflammation. Inhibitors of the P2Y12 receptor, which is involved in platelet activation, may have a direct effect on carotid atherosclerotic plaque inflammation.
Hypothesis
We compared the effects of clopidogrel and ticagrelor therapy for carotid atherosclerotic plaque inflammation using 18F‐fluorodeoxyglucose (18FDG) positron emission tomography (PET) imaging.
Methods
Fifty patients with acute coronary syndrome and ≥1 18FDG uptake in the carotid artery (target‐to‐background ratio [TBR] ≥1.6) were randomized to either clopidogrel or ticagrelor groups. Of these, 46 completed PET examinations at baseline and at 6 months. The primary endpoint was the percent change in TBR of the index vessel at the most diseased segment (MDS).
Results
Baseline characteristics were similar between the 2 groups. At 6‐month follow‐up, low‐density lipoprotein cholesterol and C‐reactive protein significantly decreased in both groups (P < 0.001). The TBR of the index vessel and aorta significantly decreased in both groups (P < 0.01). The percent change in the MDS TBR of the index vessel was numerically but not significantly lower in the clopidogrel group than in the ticagrelor group (−9.5 ± 14.6% vs −13.5 ± 19.3%; P = 0.427). Likewise, the percent change in the whole‐vessel TBR of the index vessel was not different between the 2 groups (P = 0.166). Similar findings were observed for changes in the MDS TBR (P = 0.412) or whole‐vessel TBR of the aorta (P = 0.363).
Conclusions
Carotid atherosclerotic plaque inflammation significantly decreases to a similar degree following 6 months of either clopidogrel or ticagrelor treatment.
Keywords: plaque inflammation, P2Y12 inhibitors, Imaging, positron emission tomography, ticagrelor, clopidogrel
1. INTRODUCTION
Platelet activation and thrombus formation at the site of plaque rupture are the underlying mechanisms responsible for acute coronary syndrome (ACS).1, 2 The P2Y12 receptor plays a key role in platelet activation,3, 4 and clopidogrel, a P2Y12 receptor blocker, is superior to aspirin for the prevention of vascular events.5 However, variable responses to clopidogrel have led to the development of new P2Y12 receptor blockers with superior efficacy.6, 7, 8 The P2Y12 receptor is expressed in vascular cells as well as platelets.9, 10 P2Y12 receptor blockers reduce the levels of vascular inflammation markers and improve endothelial function, suggesting pleiotropic effects coupled with P2Y12 receptor antagonism.11, 12, 13, 14, 15, 16 We therefore speculated that P2Y12 receptor blockers may have a direct effect on atherosclerotic plaque inflammation and that ticagrelor may be superior in efficacy to clopidogrel.
In our present study, we compared the effects of clopidogrel and ticagrelor therapy to carotid atherosclerotic plaque inflammation using serial 18F‐fluorodeoxyglucose (18FDG) positron emission tomography–computed tomography (PET/CT) imaging (http://www.ClinicalTrials.gov NCT01905566). This technique allows for noninvasive efficacy assessment of therapeutic interventions.17, 18, 19, 20 Uptake of arterial 18FDG was assessed as target‐to‐background ratio (TBR): (1) as a mean of standardized uptake values (SUV) of all slices of the vessel, and (2) within most diseased segment (MDS) of all vessels.18, 19, 20
2. METHODS
2.1. Study Design
This was a prospective, single center, open‐label, randomized comparison trial conducted between September 2013 and August 2015. Patients were eligible if they presented with their first ACS requiring dual antiplatelet therapy, asymptomatic carotid artery disease (diameter stenosis 20%–50%) by duplex ultrasound scanning, and ≥1 18FDG uptake lesion in the carotid artery (target‐to‐background ratio [TBR] ≥1.6) by 18FDG PET/CT imaging. Exclusion criteria included thrombocytopenia (platelet count <100 000/μL), P2Y12 inhibitor therapy in the previous 4 weeks, cardiogenic shock, heart failure, chronic liver disease, chronic renal failure, concomitant inflammatory conditions (such as active infection, inflammatory arthritis, or connective tissue disease), type 1 diabetes mellitus, malignancies, or a contraindication to clopidogrel or ticagrelor.
Patients received a 600‐mg loading dose of clopidogrel (or 180 mg ticagrelor) at the emergency room, followed by 75 mg clopidogrel once daily (or 90 mg ticagrelor twice daily) before randomization. Baseline 18FDG PET/CT was performed within 2 days of coronary angiography or percutaneous coronary intervention (3–5 days after admission). Patients meeting our inclusion criteria, and none of the exclusion criteria, were randomized at a ratio of 1:1 to clopidogrel (75 mg once a day for 12 months) or ticagrelor (90 mg twice a day for 12 months) groups. All patients were treated with standard medications including aspirin and statins. A follow‐up 18FDG PET/CT examination at 6 months was requested for all patients. Biochemical laboratory tests were performed at admission and at the 6‐month follow‐up. The study protocol was approved by our institutional review committee. All patients provided written informed consent.
2.2. 18F‐fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Examination
Vascular 18FDG PET/CT imaging was performed in accordance with standard methods.17, 18, 19, 21 In brief, after ≥8 hours of fasting, patients received an intravenous administration of 18FDG (5.2 MBq [0.14 mCi]/kg body weight) through the antecubital vein. Patients with diabetes mellitus were instructed to adhere to their regular schedules of glucose‐controlling drugs. Serum glucose levels were routinely measured and were maintained <130 mg/dL in all patients. Two hours after the 18FDG injection, a 3‐dimensional PET/CT scan was initiated. Computed tomography was performed first without the administration of contrast medium to correct photon attenuation and scattering using a continuous spiral 64‐slice technique with a voltage of 140 kV, a pitch of 0.98 (39.4 mm/rotation), a slice thickness of 2.5 mm, a current of 200 mA, and a rotation speed of 0.4 s/revolution.
Positron emission tomography was performed immediately afterward, using a full‐ring dedicated scanner with an axial field of view of 15.7 cm and an image reconstruction matrix of 256 × 256. All examinations were performed using the time of flight–capable Discovery 690 PET/CT scanner (GE Healthcare, Waukesha, WI). Patients were imaged in the supine position using a head fixation device, which holds the patient's neck firmly with respect to the shoulders, and features an extension. Images were acquired for 10 minutes in each bed position during normal tidal breathing, with overlapping scans from the skull base to the upper chest obtained using 2 or 3 bed positions. Images were reconstructed after CT‐based attenuation correction and scattering correction using the 3‐dimensional ordered subsets expectation maximization reconstruction algorithm (4 iterations, 18 subsets) with time of flight reconstruction. The PET data were routinely recalculated to display images of SUVs based on the lean body mass.
2.3. Image Analysis
Image analysis was performed on a dedicated workstation. 18FDG PET was quantified after identification of the common carotid arteries and ascending aorta of the aortic arch. The PET images were subsequently visually evaluated for the presence of focal 18FDG uptake by the carotid arteries and ascending aorta. Arterial 18FDG uptake was determined by drawing a simple circular region of interest (ROI) around the artery on every slice of the co‐registered transaxial PET/CT images. On each image slice, the maximal SUVs of 18FDG in the ROI (containing the arterial wall and the lumen) were calculated as the maximal pixel activity, respectively. The SUV was the decay‐corrected tissue concentration of 18FDG (in kBq/g), adjusted for the injected 18FDG dose and lean body mass. By averaging the SUVs of all artery slices within an arterial territory, maximal SUVs for each region were derived. The SUVs were normalized to blood 18FDG activity by dividing them by the average blood ROI (calculated from ≥6 venous ROI measurements) estimated from the superior vena cava, which yielded an arterial TBR.
The MDS TBR was calculated by centering on the slice of the artery that demonstrated the highest 18FDG uptake, then averaging 5 contiguous segments (about 1.5 cm extent), combined with the immediate inferior and superior neighbors. The whole‐vessel TBR was defined as the average of the maximal TBR activity for all of the axial segments. Whole‐vessel 18FDG uptake (TBR) was measured in the 3 target arteries (right and left carotid and aorta) and used to indicate 18FDG‐defined atherosclerotic inflammation activity. Cardiac catheterization may have variable impact on 18FDG uptake of the ascending aorta because of catheter‐induced aorta injury, and the carotid artery with the highest 18FDG uptake at baseline was chosen as the index vessel.19, 22
2.4. Study Endpoints
The primary endpoint was the percent change in MDS TBR of the index vessel, defined as (MDS TBR at 6 months − MDS TBR at baseline)/(MDS TBR at baseline) × 100. Secondary endpoints included changes in whole‐vessel TBR within the index vessel, MDS TBR, and whole‐vessel TBR of the aorta.
2.5. Statistical Analysis
A sample size of approximately 22 patients per treatment group was needed to yield 90% power (assuming a SD of 15% in the clopidogrel group and 15% in the ticagrelor group) for detecting a difference of 15% with a significance level of 0.05, using a 2‐sided test. At an anticipated dropout rate of 10%, a final sample size of 25 patients per treatment group (total, 50 patients) was specified to provide an adequate number of evaluable patients. Continuous variables were expressed as mean ± SD or median (interquartile range), whereas categorical variables were expressed as frequencies. Continuous variables were compared using the paired t test or Wilcoxon rank‐sum test for changes in each group, and unpaired t test or the Mann–Whitney U test for differences between groups. Statistical significance was defined as a 2‐sided P value <0.05.
3. RESULTS
A total of 137 patients with ACS were initially screened in our current study. Of these patients, 87 did not fulfill the criteria for randomization, and the remaining 50 patients were randomly assigned to receive either clopidogrel or ticagrelor. Exclusion was due to absence of carotid atherosclerosis (n = 69), enrollment of other studies (n = 11), and patient refusal (n = 7; Figure 1). Four patients did not receive PET/CT follow‐up because of refusal (n = 2) or adverse events (n = 2). The remaining 46 patients (92%) completed PET/CT examination at the 6‐month follow‐up.
Figure 1.
Flowchart of patient enrollment. Abbreviations: CT, computed tomography; PET, positron emission tomography.
3.1. Baseline Characteristics
The baseline characteristics were similar between the 2 groups (Table 1). The median age of the patients was 61.0 years (interquartile range, 61–70 years), and 82.4% were men. Clinical presentations at the time of admission included ST‐segment elevation myocardial infarction in 39.2% of the patients and non–ST‐segment elevation acute coronary syndrome in 60.8% of the patients. Most patients (91.8%) were treated with percutaneous coronary intervention, with 4 cases (8.2%) receiving medications.
Table 1.
Baseline Clinical Characteristics
| Characteristics | Clopidogrel, n = 25 | Ticagrelor, n = 25 | P Value |
|---|---|---|---|
| Age, y | 62.4 ± 11.0 | 60.6 ± 8.8 | 0.535 |
| Male sex | 20 (80) | 21 (84) | 0.713 |
| Current smoker | 9 (36) | 5 (20) | 0.208 |
| DM | 5 (20) | 7 (28) | 0.508 |
| HTN | 12 (48) | 13 (52) | 0.777 |
| Diagnosis | 0.826 | ||
| STEMI | 11 (44) | 9 (36) | |
| NSTE‐ACS | 14 (56) | 16 (64) | |
| Culprit artery of ACS | 0.743 | ||
| LAD | 11 (44) | 12 (48) | |
| LCX | 3 (12) | 3 (12) | |
| RCA | 11 (44) | 9 (36) | |
| Ramus intermedius | 0 (0) | 1 (4) | |
| Culprit lesion PCI | 48 (91.7) | 48 (91.7) | 1.0 |
| LVEF, % | 56.2 ± 7.8 | 59.2 ± 5.9 | 0.141 |
| Medications at time of follow‐up | |||
| ASA | 25 (100) | 25 (100) | 1.0 |
| Statins | 25 (100) | 25 (100) | 1.0 |
| ACEI/ARBs | 6 (24) | 6 (24) | 1.0 |
| β‐Blockers | 21 (84) | 22 (88) | 0.684 |
| Calcium channel antagonists | 6 (24) | 5 (20) | 0.733 |
Abbreviations: ACEI, angiotensin‐converting‐enzyme inhibitor; ACS, acute coronary syndrome; ARB, angiotensin receptor blocker; ASA, aspirin; DM, diabetes mellitus; HTN, hypertension; LAD, left anterior descending coronary artery; LCX, left circumflex coronary artery; LVEF, left ventricular ejection fraction; NSTE‐ACS, non–ST‐segment elevation acute coronary syndrome; PCI, percutaneous coronary intervention; RCA, right coronary artery; SD, standard deviation; STEMI, ST‐segment elevation myocardial infarction.
Data are presented as n (%) or mean ± SD.
3.2. Laboratory Findings
Lipid and high‐sensitivity C‐reactive protein (hs‐CRP) levels at baseline were similar between the 2 groups (Table 2). At the 6‐month follow‐up, total cholesterol, low‐density lipoprotein cholesterol (LDL‐C), and hs‐CRP levels significantly decreased in both groups (P < 0.001), whereas high‐density lipoprotein cholesterol levels significantly increased in both groups (P < 0.01).
Table 2.
Laboratory Findings
| Characteristics | Clopidogrel, n = 23 | Ticagrelor, n = 23 | P Value |
|---|---|---|---|
| Total cholesterol, mg/dL | |||
| Baseline | 183.4 ± 42.8 | 180.5 ± 31.7 | 0.839 |
| 6 months | 135.3 ± 32.2 | 136.8 ± 21.7 | 0.860 |
| LDL‐C, mg/dL | |||
| Baseline | 114.7 ± 26.4 | 116.8 ± 30.3 | 0.902 |
| 6 months | 83.9 ± 24.8 | 86.2 ± 19.4 | 0.723 |
| HDL‐C, mg/dL | |||
| Baseline | 40.8 ± 10.5 | 40.4 ± 10.0 | 0.909 |
| 6 months | 43.9 ± 8.1 | 45.6 ± 10.9 | 0.563 |
| Hs‐CRP, mg/L | |||
| Baseline | 3.2 ± 1.9 | 3.2 ± 2.8 | 0.995 |
| 6 months | 1.4 ± 1.9 | 1.5 ± 2.5 | 0.801 |
Abbreviations: HDL‐C, high‐density lipoprotein cholesterol; hs‐CRP, high‐sensitivity C‐reactive protein; LDL‐C, low‐density lipoprotein cholesterol; SD, standard deviation.
Data are presented as mean ± SD.
3.3. Positron Emission Tomography/Computed Tomography Findings
Representative images of improved 18FDG uptake in the carotid plaque after ticagrelor therapy are shown in Figure 2, and 18FDG PET/CT data are summarized in Table 3. Baseline measurements were similar between the 2 groups. At the 6‐month follow‐up, MDS TBR and TBR of the index vessel significantly decreased in both groups (P <0.01). The percent change in MDS TBR of the index vessel (primary endpoint) was numerically but not significantly less in the clopidogrel group than in the ticagrelor group (−9.5 ± 14.6% vs −13.5 ± 19.3%, respectively; P = 0.427). Likewise, the percent change in whole‐vessel TBR of the index vessel was not different between the 2 groups. Compared with baseline, however, the maximal SUV of the index vessel at the 6‐month follow‐up significantly decreased in the ticagrelor group (2.21 ± 0.53 vs 1.89 ± 0.36, respectively; P = 0.004), but not in the clopidogrel group (2.0 ± 0.23 vs 1.89 ± 0.29, respectively; P = 0.055). Similar findings were observed for changes in the MDS TBR or whole‐vessel TBR of the aorta. There were no significant correlations between lipid levels and percent changes in MDS TBR of the index vessel. Likewise, the hs‐CRP levels did not correlate with the percent change in the MDS TBR of the index vessel.
Figure 2.
18FDG uptakes of the index vessel in a patient treated with ticagrelor (arrowheads). Representative CT (left), 18FDG‐PET (middle), 18FDG‐PET/CT (right) images at baseline (top) and at 6‐month follow‐up (bottom) are shown. 18FDG uptakes markedly decreased at 6‐month follow‐up. Abbreviations: 18FDG‐PET, 18F‐fluorodeoxyglucose positron emission tomography; CT, computed tomography.
Table 3.
Changes in Arterial Inflammation Activity
| Characteristics | Clopidogrel, n = 23 | Ticagrelor, n = 23 | P Value Between Groups |
|---|---|---|---|
| MDS TBR of index carotid artery | |||
| Baseline | 2.24 ± 0.29 | 2.37 ± 0.65 | 0.379 |
| Follow‐up | 1.99 ± 0.28 | 2.0 ± 0.29 | 0.90 |
| Nominal change | −0.23 ± 0.32 | −0.43 ± 0.68 | 0.206 |
| P value compared with baseline | 0.002 | <0.001 | |
| % changea | −9.5 ± 14.6 | −13.5 ± 19.3 | 0.427 |
| Whole‐vessel TBR of index carotid artery | |||
| Baseline | 1.98 ± 0.32 | 2.11 ± 0.50 | 0.292 |
| Follow‐up | 1.79 ± 0.23 | 1.75 ± 1.88 | 0.462 |
| Nominal change | −0.19 ± 0.31 | −0.40 ± 0.55 | 0.109 |
| P value compared with baseline | 0.009 | 0.002 | |
| % changea | −7.9 ± 16.2 | −15.1 ± 18.4 | 0.166 |
| MDS TBR of aorta | |||
| Baseline | 2.65 ± 0.56 | 2.76 ± 0.58 | 0.491 |
| Follow‐up | 2.27 ± 0.34 | 2.32 ± 0.26 | 0.603 |
| Nominal change | −0.34 ± 0.45 | −0.50 ± 0.59 | 0.30 |
| P value compared with baseline | 0.001 | 0.006 | |
| % changea | −11.2 ± 17.3 | −15.3±16.5 | 0.412 |
| Whole‐vessel TBR of aorta | |||
| Baseline | 2.56 ± 0.52 | 2.67 ± 0.56 | 0.499 |
| Follow‐up | 2.24 ± 0.34 | 2.27 ± 0.24 | 0.737 |
| Nominal change | −0.28 ± 0.42 | −0.45 ± 0.58 | 0.243 |
| P value compared with baseline | 0.004 | 0.001 | |
| % changea | −9.5 ± 17.2 | −14.1 ± 16.7 | 0.363 |
Abbreviations: MDS, most diseased segment; SD, standard deviation; TBR, target‐to‐background ratio.
Data are presented as mean ± SD.
Primary endpoint.
4. DISCUSSION
In our present study, the MDS and whole‐vessel TBR of the index vessel at the 6‐month follow‐up significantly decreased in both clopidogrel‐ and ticagrelor‐treated patients, and a similar degree of improvement was observed in these 2 treatment groups. Despite moderate levels of LDL‐C at the 6‐month follow‐up, both of these antiplatelet drugs resulted in a significant reduction in 18FDG uptake in the carotid artery and aorta. These findings suggest that P2Y12 inhibitors may reduce atherosclerotic plaque inflammation if they are used in addition to standard medical therapy.
In addition to their role in hemostasis and thrombosis, platelets regulate a variety of inflammatory responses.23 In our present study, LDL‐C levels modestly decreased at the 6‐month follow‐up, and no correlation between LDL‐C levels and changes of MDS TBR was observed. However, atherosclerotic plaque inflammation significantly improved in both clopidogrel‐ and ticagrelor‐treated patients, suggesting that P2Y12 receptor blockers may have a direct effect on atherosclerotic plaque inflammation. In addition, the hs‐CRP levels did not correlate with the MDS or whole‐vessel TBR of the index vessel, showing poor correlations with local and systemic inflammatory markers.
In the previous Platelet Inhibition and Patient Outcomes (PLATO) trial, the cardiovascular benefits of ticagrelor outweighed those of clopidogrel, despite more spontaneous bleeds.24, 25, 26 These benefits may not be fully explained by platelet inhibition alone. The P2Y12 receptor is present in human atherosclerotic plaques, and its level of expression is higher in patients with ACS compared with those with stable angina.27 The short half‐life of the clopidogrel active metabolite may prevent the drug from penetrating the vascular wall, whereas ticagrelor may be continuously available to interact with the vascular P2Y12 receptor.10, 28 In our present study, the MDS TBR values of the index vessel were not statistically different between the 2 treatment groups. However, changes in the MDS and whole‐vessel TBR of the index vessels and aorta exhibited similar trends in favor of ticagrelor. In addition, the maximal SUV of the index vessel, which may be representative of the most active spot of atherosclerotic inflammation of a specific artery,29, 30, 31 significantly improved after ticagrelor therapy, but not after clopidogrel therapy.
In recent years, the majority of studies prefer to use MDS TBR to evaluate the anti‐inflammatory effects of specific therapies on the vessels.17, 19, 21 Compared with whole‐vessel TBR, MDS TBR may be superior for investigating the effects of interventions on atherosclerotic plaque inflammation because the former assesses both diseased and healthy segments.32 However, it remains controversial as to whether MDS‐based analysis is the best method for intervention studies.31, 32, 33, 34, 35, 36 In some reports, the maximal SUV has been used because it is less affected by blood pool activity.31, 37, 38, 39 In our current study, the hottest spot of inflamed atherosclerotic plaques showed significant improvements in ticagrelor‐treated patients, but not in clopidogrel‐treated patients. Taken together, both clopidogrel and ticagrelor therapy decreased 18FDG uptake of carotid atherosclerotic plaques in our study patients, with a greater reduction of maximal SUV found following ticagrelor therapy. Considering that the maximal SUV in patients with a recent stroke is the key predictor of early stroke recurrence,38, 40 our present findings may increase our understanding of the superior outcomes in patients treated with ticagrelor vs those treated by clopidogrel in the PLATO trial.
4.1. Study Limitations
Several potential limitations of our current analyses need to be addressed. First, the sample size was small, which may have underpowered the detection of small differences in the MDS TBR of the index vessel. Second, our study had an open‐label design, which was subject to inherent limitations. We attempted to minimize these limitations by using blind 18FDG PET/CT measurements. Third, there was no placebo arm because of ethical considerations.
5. CONCLUSION
Our study shows that the MDS and whole‐vessel TBR of the index vessel at the 6‐month follow‐up significantly decreased in both clopidogrel‐ and ticagrelor‐treated patients, and a similar degree of improvement was observed in these 2 treatment groups. These findings suggest that P2Y12 inhibitors may reduce atherosclerotic plaque inflammation if they are used in addition to standard medical therapy.
Oh M, Lee CW, Lee HS, Chang M, Ahn JW, Park DW, Kang SJ, Lee SH, Kim YH, Moon DH, Park SW, Park SJ. Similar Impact of Clopidogrel or Ticagrelor on Carotid Atherosclerotic Plaque Inflammation, Clin Cardiol 2016;39(11):646–652.
This study was supported by a research grant from AstraZeneca Korea and a grant from the Asan Institute for Life Sciences, Seoul, Korea (no. 2014–217).
The authors have no other funding, financial relationships, or conflicts of interest to disclose.
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