Early revascularization therapy such as percutaneous coronary intervention (PCI) is associated with an improved clinical outcome in patients with acute coronary syndrome (ACS) 1,2. Patients with ACS who undergo primary PCI are recommended to be treated with dual antiplatelet therapy (aspirin and P2Y12 receptor inhibitor) to prevent stent thrombosis and recurrence of ischemic events. Clopidogrel has been widely used as a P2Y12 receptor inhibitor. However, its efficacy is limited by a modest and variable platelet inhibition and a slow metabolism 3. As a consequence, some period of inadequate platelet inhibition after stent implantation may be present even if a loading dose of clopidogrel is administered before primary PCI in patients with ST-segment elevation myocardial infarction (STEMI).
Prasugrel is a relatively new P2Y12 receptor inhibitor that has faster and more effective platelet inhibition than clopidogrel 4. Prasugrel allows efficient conversion to its active metabolite with less dependence on the hepatic cytochrome P-450 enzymes than clopidogrel 5. Two randomized control trials demonstrated that prasugrel is more effective than clopidogrel for prevention of ischemic events in patients with ACS undergoing PCI 6,7. Reduced thrombus burden (TB) during PCI procedure by increased platelet inhibition of prasugrel may partly contribute to favorable outcomes. Intracoronary optical coherence tomography (OCT) is an emerging diagnostic modality that enables us to assess the morphologic characteristics of both native and stented lesions in the various clinical settings 8–11. Abtahian et al. 12 compared the efficacy of antiplatelet drugs on residual in-stent TB between patients with ACS treated with ticagrelor and clopidogrel using OCT. A loading dose of ticagrelor before PCI resulted in a trend toward smaller in-stent thrombus volume compared with that of clopidogrel before PCI 12.
It remains unclear whether the in-stent TB after stenting is more reduced in patients with STEMI treated with prasugrel compared with clopidogrel. The aim of this study was to compare the efficacy of prasugrel and clopidogrel on residual TB after stent implantation using OCT in patients with STEMI undergoing primary PCI.
Patients and methods
This study was a retrospective analysis. The study group consists of patients admitted to the Hirosaki University Hospital (Hirosaki, Japan) with STEMI between April 2014 and June 2015. STEMI was defined as typical chest pain lasting greater than 20 min; electrocardiogram showing new ST-segment elevation greater than or equal to 0.2 mV in at least two contiguous precordial leads, greater than or equal to 0.1 mV in at least two contiguous limb leads, or new left bundle branch block; and cardiac markers (creatine kinase-MB fraction or cardiac troponin T) elevated above the upper reference limit. All patients treated with a loading dose of prasugrel (20 mg), approved in Japan, or clopidogrel (300 mg), had a successful PCI with stenting within 12 h after the symptom onset, and underwent OCT immediately after stenting. The loading dose of 20-mg prasugrel in this study is less than that used in a previous clinical trial 6. All patients were treated with bare metal stent. The decisions of whether to use clopidogrel or prasugrel were left to the operator’s discretion. All patients provided written informed consent for the primary interventional procedure. The study was approved by the ethics committee of our institution.
Primary PCI and prestent OCT imaging
Heparin 100 IU/kg was administered before the procedure. None of the patients were pretreated with a thrombolytic agent and a glycoprotein IIb/IIIa inhibitor. The primary PCI was performed using a 7-Fr or 6-Fr guiding catheter. The decision to perform thrombus aspiration was left to the operator’s discretion. Aspiration thrombectomy using Rebirth (Goodman Co Ltd, Nagoya, Japan) or Eliminate 3 (Terumo, Tokyo, Japan) was performed to restore antegrade coronary flow. For an initial evaluation by OCT, predilation with balloon angioplasty was not allowed before OCT imaging.
Coronary angiograms before intervention and at the end of the procedure were analyzed. We evaluated baseline and final antegrade coronary flow according to theThrombolysis In Myocardial Infarction (TIMI) criteria 13 and final myocardial blush grades 14. Off-line quantitative coronary angiographic analysis was performed using a validated edge-detection system (CAAS 5.10.1; Pie Medical Imaging BV, Maastricht, the Netherlands). End-diastolic frames were selected for the analysis, and the tip of the catheter was used for calibration. Reference diameter, minimum lumen diameter, percentage of diameter stenosis, and lesion length were measured before and after primary PCI.
OCT image acquisition and analysis
OCT image acquisition was performed using a frequency-domain OCT system (ILUMIEN OCT Intravascular Imaging System; St. Jude Medical, St. Paul, Minnesota, USA). A 2.7-Fr OCT catheter (Dragonfly; St. Jude Medical) was advanced distally to the coronary culprit lesion or stented segment, and an automated pullback was initiated at a speed of 20 mm/s in concordance with blood clearance by dextran. Offline analysis was performed using semiautomated contour-detection software (St. Jude Medical).
Plaques were categorized into plaque rupture, plaque erosion, calcified nodule, and others . Plaque rupture was identified by fibrous cap disruption and a cavity formation within the lipid plaque. Erosion was identified by the presence of attached thrombus overlying an intact plaque. Calcified nodule was identified by fibrous cap disruption detected over a calcified plaque characterized by protruding superficial calcification. Culprit lesions that did not satisfy these criteria were classified as others and included tight stenosis, spontaneous coronary artery dissection, and coronary spasm 11,15. Prestent thrombus was semiquantitatively calculated by summing the number of involved quadrants in each 1-mm interval cross-section 16. For the in-stent thrombus measurement, OCT images were analyzed at 0.2-mm intervals for the entire stented segment by two independent investigators blinded to clinical and angiographic data.
Thrombus was defined as an irregular mass with diameter greater than or equal to 250 µm attached to the stent strut or floating within the lumen. When irregular protrusion could not be completely differentiated from thrombus, we categorized it as thrombus 10. Thrombus area was measured by planimetry in each frame, and thrombus volume was calculated by multiplying the sum of thrombus areas in each frame and 0.2 mm. Stent area was measured by planimetry in each frame, and stent volume was calculated by multiplying the sum of stent areas in each frame and 0.2 mm. Stent and thrombus areas were traced as previously described 16,17. A semi-quantitative thrombus score was derived by summing the number of involved quadrants in each frame along the stent length 16,18. TB was defined as the mean thrombus volume (TV) divided by the mean stent area (SV), [TB (%)=TV (mm3)/SV (mm3)×100] 19.
Categorical outcomes were presented as counts and percentages, and Fisher exact test or χ 2-test was used as appropriate. The distributions of continuous variables were tested for normality with the Kolgormonov–Smirnov test. The mean±SD was reported when data were normally distributed, and the median (25th–75th percentiles) was reported when data were not normally distributed. Continuous variables were assessed using Student’s t-test or the Mann–Whitney U-test, as appropriate. A P value less than 0.05 was considered statistically significant. Intraobserver and interobserver reliabilities of in-stent thrombus volume were assessed by intraclass correlation, and a value of greater than 0.9 was defined as excellent correlation. Statistical analysis was performed using JMP pro 11 software (SAS, Cary, North Carolina, USA).
During the study period, 121 patients with STEMI underwent primary PCI within 12 h after the symptom onset. Patients treated with antiplatelet therapy before the onset of STEMI (n=19), those who did not undergo OCT after stenting (n=20), and those treated with balloon angioplasty without stenting (n=12) were excluded from the study (six patients had two of the above exclusion criteria). Finally, 76 patients (34 pretreated with prasugrel and 42 pretreated with clopidogrel) were studied. Baseline patient characteristics are shown in Table 1. There were no significant differences in age, sex, risk factors, medications before admission, and laboratory findings between the two groups.
Angiographic characteristics and PCI procedure
Angiographic characteristics and PCI procedural findings are summarized in Table 2. There were no differences in lesion location, baseline quantitative coronary angiographic findings, final TIMI flow grade, and final myocardial blush grade between the two groups. Stent length, stent diameter, and maximal balloon inflation pressure were similar between the two groups. The median P2Y12 receptor inhibitor loading-to-OCT time was 98 (81–126) in the prasugrel group and 94 (79–109) minutes in the clopidogrel group (P=0.32). Taken together, all of angiographic characteristics and PCI procedural findings shown in Table 2 did not differ between the two groups.
OCT findings before and after PCI are shown in Table 3 and Fig. 1. The thrombus score before PCI and the prevalence of plaque rupture, erosion, and calcified nodule were not different between the two groups. Five (7%) lesions were not evaluated because of an inability to advance an OCT catheter to the culprit lesion. The thrombus score immediately after PCI was significantly lower in the prasugrel group than in the clopidogrel group [2 (1–5) vs. 4 (2–8), P=0.04]. Although stent volume [169 (134–214) vs. 166 (128–210) mm3, P=0.83], mean stent area [8.00 (6.64–9.09) vs. 7.36 (6.32–9.06) mm2, P=0.73], and minimum stent area [6.10 (5.26–7.17) vs. 5.71 (4.96–7.29) mm2, P=0.61] immediately after PCI were not different between the two groups, in-stent thrombus volume [0.59 (0.16–1.09) vs. 1.08 (0.32–2.30) mm3, P=0.03], mean in-stent thrombus area [0.03 (0.01–0.05) vs. 0.05 (0.01–0.10) mm2, P=0.04], and maximum in-stent thrombus area [0.45 (0.27–0.75) vs. 0.77 (0.34–1.23) mm2, P=0.03] were significantly smaller in the prasugrel group than in the clopidogrel group (Fig. 1). TB was smaller in the prasugrel group than in the clopidogrel group with close to significance [0.35 (0.10–0.62) vs. 0.60 (0.17–1.32) %, P=0.05]. Representative OCT images of TB in the two groups were shown in the Fig. 2. Intraobserver and interobserver reliabilities were high for in-stent thrombus volume (interobserver: 0.95, intraobserver: 0.95).
The mean area and maximum area of in-stent thrombus were also significantly smaller in prasugrel than in clopidogrel group [0.03 (0.01–0.05) vs. 0.05 (0.01–0.10) mm2, P=0.04, and 0.45 (0.27–0.75) vs. 0.77 (0.34–1.23) mm2, P=0.03, respectively].
In the present study, we investigated the efficacy of prasugrel on in-stent TB as compared with clopidogrel in patients with STEMI treated with primary PCI. We found that patients with STEMI with prasugrel had a significantly reduced in-stent thrombus volume compared with those with clopidogrel. Our findings indicate that prasugrel may rapidly and effectively reduce in-stent TB after primary PCI in patients with STEMI.
In-stent thrombus burden after stenting
Large TB is shown to be an independent predictor for major adverse cardiac events and stent thrombosis in patients with STEMI with drug-eluting stent 20. Decreased intracoronary TB may contribute to a reduced risk of distal embolization and procedure-related myocardial infarction 21. Our recent OCT study showed that patients with STEMI with a large amount of TB even after aspiration thrombectomy had a higher risk of no-reflow and greater myocardial damage after stenting 22. Furthermore, large TB can interfere with adequate stent expansion, resulting in stent malapposition 23 and increased residual stenosis at the culprit site 18. These findings strongly suggest that a more thorough removal of thrombus may have a benefit in patients with STEMI with large TB. The clinical benefit of effective pretreatment with P2Y12 receptor inhibitor may be potentially related in part to reduction of intracoronary TB before and immediately after PCI. Actually, pretreatment with clopidogrel plus aspirin in patients with STEMI improves infarct-related artery patency, and more importantly reduces the risk of myocardial infarction and cardiovascular death compared with aspirin alone 24. In this context, our finding showing that prasugrel is more effective than clopidogrel in reduction of intracoronary in-stent TB in patients with STEMI implies a therapeutic benefit of prasugrel in patients with STEMI with large TB.
Efficacy of prasugrel in patients with STEMI
Faster and more potent inhibition of platelet aggregation is desirable for primary PCI in patients with STEMI. Prasugrel is a new thienopyridine which shows much more rapid and consistent inhibitory effects on platelet aggregation than clopidogrel. The active metabolite of prasugrel appears in circulating blood within 15 min after administration, which reaches maximal plasma concentration at within 30 min 25. The TRITON-TIMI 38 study randomly assigned patients with ACS to receive prasugrel (60 mg loading dose and 10 mg maintenance dose) or clopidogrel (300 mg loading dose and 75 mg maintenance dose). Prasugrel reduced primary combined end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke compared with clopidogrel. However, prasugrel was associated with an increase in the incidence of TIMI major bleeding and fatal bleeding 6. The PRASFIT-ACS Study conducted in Japanese patients with ACS undergoing PCI demonstrated that prasugrel treatment (20 mg loading dose and 3.75 mg maintenance dose) was associated with a low incidence of ischemic events and was similar in clinically relevant bleeding compared with clopidogrel treatment (300 mg loading dose and 75 mg maintenance dose) . Furthermore, it has been reported that the rate of stent thrombosis tended to be lower in prasugrel than in clopidogrel 26. Our results also support the clinical efficacy of low-dose prasugrel in Japanese patients with STEMI as suggested in the aforementioned studies.
Recently, Kubo et al. 27 reported that pretreatment with prasugrel was associated with significantly reduced in-stent thrombus/plaque protrusion immediately after PCI for ACS (included unstable angina and non-STEMI) compared with that with clopidogrel 27. In their study, the mean thienopyridine-to-balloon time was over 24 h. On the contrary, the mean P2Y12 receptor inhibitor loading-to-OCT time in our study was around 90 min. Our study demonstrated that favorable results of prasugrel can be achieved even after a shorter loading time in patients with STEMI undergoing primary PCI.
The present study has several limitations. First, this was a single-center study, and analysis was done retrospectively. Nonrandomized comparison might also reduce the applicability and interpretation of the results. Second, the number of eligible subjects in this study was small. Third, the number of thrombus aspiration was not counted in this study. It might affect the thrombus volume in the two group. Fourth, irregular protrusion could not be completely differentiated from thrombus by OCT. It might affect the results. Fifth, the loading dose of 20 mg prasugrel in this study is less than that used in a previous clinical trial 6. This dose was approved based on phase 1–3 clinical trial data in Japan. Prasugrel at the relatively low loading dose of 20 mg showed a platelet aggregation inhibition of approximately 80% in the light transmission aggregometry assay in Japanese healthy subjects 28. It was reported that in Western healthy subjects, prasugrel at the loading dose of 60 mg showed ∼80% platelet aggregation inhibition, which was almost identical with that in Japanese healthy subjects receiving prasugrel at the loading dose of 20 mg 29. Finally, it is reported that the median time to reach more than 20% platelet aggregation inhibition was 30 min for prasugrel and 1.5 h for clopidogrel (P<0.001) in healthy subjects 29. Therefore, the relatively long time from drug loading to OCT (median time 94 or 98 min) might affect the results by limiting the advantage of prasugrel.
Prasugrel more effectively reduced residual TB after stent implantation, suggesting a rapid and potent platelet inhibitory effect of prasugrel compared with clopidogrel in patients with STEMI. Further large-scale multicenter studies are needed to validate the efficacy of prasugrel on in-stent TB in patients with STEMI.
Conflicts of interest
Dr Yokota is an associate professor and Dr Tomita is a concurrent professor in the endowed department (the Advanced Cardiovascular Therapeutics) by Abbott Vascular Japan. Dr Tomita received research funding and Speakers’ Bureau/Honorarium from Daiichi-Sankyo. Dr Okumura received Speakers’ Bureau/Honorarium from Daiichi-Sankyo. For the remaining authors there are no conflicts of interest.
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