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A high loading dose of clopidogrel reduces myocardial infarct size in patients undergoing primary percutaneous coronary intervention: A magnetic resonance imaging study
Imaging and Diagnostic Testing
A high loading dose of clopidogrel reduces myocardial infarct size in patients undergoing primary percutaneous coronary intervention: A magnetic resonance imaging study Young Bin Song, MD, a Joo-Yong Hahn, MD, a Hyeon-Cheol Gwon, MD, a Sung-A Chang, MD, a,b Sang-Chol Lee, MD, a,b Yeon Hyeon Choe, MD, b,c Seung-Hyuk Choi, MD, a Jin-Ho Choi, MD, a Sang Hoon Lee, MD, a and Jae K. Oh, MD b Seoul, Republic of Korea
Background We sought to determine whether a 600-mg loading dose of clopidogrel reduces myocardial infarct size compared with a 300-mg dose using contrast-enhanced magnetic resonance imaging in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). Methods In 198 patients undergoing primary PCI for STEMI, contrast-enhanced magnetic resonance imaging was performed a median of 7 days after the index event. Infarct size was measured on delayed-enhancement imaging, and area at risk (AAR) was quantified on T2-weighted images. Results
Baseline characteristics were not significantly different between the 600-mg clopidogrel loading group (n = 117) and the 300-mg group (n = 81). The median infarct size was significantly smaller in the 600-mg group than in the 300-mg group (17.3% [8.9%-26.2%] vs 21.7% [12.9%-30.0%], P = .03). Myocardial salvage index ([AAR − infarct size] × 100/AAR) was greater in the 600-mg group than in the 300-mg group (47.7 [33.7-60.9] vs 32.0 [23.6-51.5], P b .01). Patients in the 600-mg group also had a significantly lower extent of microvascular obstruction and smaller number of segments with N75% of infarct transmurality than did those in the 300-mg group. After propensity score matching, the 600-mg group had smaller infarct size and greater myocardial salvage index compared with the 300-mg group. In multivariate analysis, the use of a 600-mg clopidogrel loading dose significantly reduced the risk of a large infarct (odds ratio 0.53, 95% CI 0.29-0.98, P = .04).
Conclusions In patients undergoing primary PCI for STEMI, a 600-mg loading dose of clopidogrel reduced myocardial infarct size and improved myocardial salvage compared with a 300-mg loading dose. (Am Heart J 2012;163:500-7.)
Dual antiplatelet therapy with aspirin and clopidogrel is critical in the prevention of adverse cardiac events in patients with acute coronary syndrome or those
From the aDivision of Cardiology, Department of Medicine, Seoul, Republic of Korea, b Cardiovascular Imaging Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, and cDepartment of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. This work was supported by a grant from the IN-SUNG Foundation for Medical Research, Republic of Korea (grant no. CA88331). Submitted June 5, 2011; accepted December 18, 2011. Reprint requests: Joo-Yong Hahn, MD, is to be contacted at Cardiac and Vascular Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Irwon-dong, Gangnam-gu, Seoul, 135-710, Republic of Korea. Yeon Hyeon Choe, MD, Department of Radiology, Cardiovascular Imaging Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. E-mails: [email protected], [email protected] 0002-8703/$ - see front matter © 2012, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2011.12.007
undergoing percutaneous coronary intervention (PCI). 1,2 A 300-mg loading dose of clopidogrel followed by a daily oral dose of 75 mg was the regimen used in several randomized trials that established clopidogrel's efficacy and safety. 2,3 However, several studies have demonstrated that the standard 300-mg loading dose of clopidogrel is inadequate to optimally inhibit platelet reactivity. 4,5 These studies also found that the inhibition of platelet aggregation is more intense and rapid with higher loading doses of clopidogrel. In addition, a higher loading dose may attenuate the variability in individual response to clopidogrel. 6 Recently, large randomized trials demonstrated that a 600-mg loading dose of clopidogrel reduced adverse ischemic events in patients undergoing primary PCI for ST-segment elevation myocardial infarction (STEMI). 7,8 However, the benefit of a 600-mg loading dose of clopidogrel in these trials was mainly driven by
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preventing stent thrombosis and reinfarction, and the effect of the loading dose on infarct size was not investigated. In the present study, we evaluated the impact of clopidogrel loading dose (600 mg vs 300 mg) on myocardial injury as measured by contrast-enhanced magnetic resonance imaging (CE-MRI) in patients undergoing primary PCI for STEMI.
Methods Study population From January 2006 to November 2009, a total of 349 STEMI patients presented to our hospital. Among them, 62 patients presented N12 hours after symptom onset, 17 patients underwent coronary artery bypass surgery because of extensive coronary artery disease, and 13 patients received only medical treatment including thrombolytics. Primary PCI was successfully performed in 257 patients with STEMI. All patients met the following criteria: presence of chest pain for N30 minutes and b12 hours after symptom onset and ST-segment elevation N1 mm in ≥2 contiguous leads or presumably a new-onset left bundle-branch block on electrocardiogram. Fifty patients did not undergo CE-MRI because of hemodynamic instability (n = 23), history of myocardial infarction (n = 10), requirement for multivessel intervention during the index procedure (n = 7), prior coronary artery bypass grafting (n = 6), and refusal to undergo CE-MRI (n = 4). Of 207 patients who underwent CEMRI, 9 patients were excluded from the present analysis, including 3 patients with evidence of previous myocardial infarction on CE-MRI, 1 patient with subacute stent thrombosis before CE-MRI, and 5 patients with unavailable clopidogrel loading dose data in the referring hospital. Finally, 198 patients were included in this study. Baseline characteristics, angiographic and procedural data, medication use, and outcome data were recorded prospectively by research coordinators of the dedicated registry. The local institutional review board approved this study, and all subjects gave their informed consent to participation.
Percutaneous coronary intervention All patients received dual oral antiplatelet therapy with 300 mg aspirin and either 300 mg or 600 mg clopidogrel before PCI. The physicians decided which loading dose of clopidogrel each patient received. Coronary angiography and stent implantation were performed using standard interventional techniques. 9,10 Intravenous administration of glycoprotein IIb/IIIa receptor antagonists was used at the operator's discretion. All baseline and procedural cine coronary angiograms were reviewed and analyzed quantitatively at the angiographic core laboratory of the Samsung Medical Centre (Seoul, Korea). Myocardial blush grade (MBG) was evaluated using the final angiogram, as described previously. 11
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field echo, steady state free precession) along the long and the short axes from the apex to the base of left ventricle. T2weighted MRI was performed in the cardiac short-axis direction using a dark-blood T2-weighted inversion-recovery fast-spin echo sequence. Next, a dose of 0.15 mmol/kg gadoliniumdiethylenetriamine pentaacetic acid (Magnevist; Bayer Schering Pharma, Berlin, Germany) was injected intravenously at a rate of 3 mL/s followed by saline flush. A first pass of the contrast agent through the myocardium after intravenous bolus injection was enabled with the T1-weighted dynamic sequence (turbo field echo with SENSE, repetition time/echo time, 2.6/1.3 milliseconds). The slice thickness was 6 mm with a field of view of 40 × 40 cm and an image matrix of 128 × 128 for the first-pass perfusion study, and images of 4 locations for every 2 heart beats were obtained for 40 phases. Delayed hyperenhancement and the extent of microvascular obstruction (MVO) were evaluated 5, 10, and 15 minutes after gadolinium-diethylenetriamine pentaacetic acid administration in contiguous 10 to 12 slices of 6 mm thickness with a 4-mm interslice gap by use of a multishot turbo field echo breath-hold sequence with a nonselective inversion (typical repetition time/time to echo 4.6/1.4 milliseconds). The field of view and image matrix were 35 × 35 cm and 256 × 256, respectively. The inversion delay time is varied in a range of 200 to 300 milliseconds. A LookLocker sequence was used to determine optimal inversion time. All measurements were performed at our MRI core laboratory. Infarct size by delayed enhanced images and area at risk (AAR) on T2-weighted images were analyzed with visual assessment by consensus of 2 experienced radiologists who were blinded to the clinical information of the patient. After the short-axis images were acquired at end-diastole and end-systole and the endocardial borders were traced, left ventricular end-diastolic volume, end-systolic volume, and ejection fraction were computed using Simpson algorithm. The infarct volume was calculated from the summation of the area with delayed hyperenhancement within each segment of the short-axis images, multiplied by the slice thickness to cover the entire left ventricle. The extent of MVO was calculated in the same manner. The endocardial and epicardial borders were planimetered to calculate myocardial area and summated in the same manner to calculate left ventricle myocardial volume. The percent infarct volume was expressed as percentages of the left ventricle myocardial volume. T2-weighted images were used to determine the presence of myocardial hemorrhage. 12 The AAR was quantified on T2-weighted images by using a similar algorithm as above and expressed as percentages of the left ventricle myocardial volume. Myocardial salvage index was computed as follows: myocardial salvage index = (AAR − infarct size) × 100/AAR. 13 The infarct transmurality for each segment was calculated by dividing the hyperenhanced area by the total area of the affected myocardium in each segment. The transmural extent of infarction was expressed as the sum of segments with N75% of infarct transmurality.
Magnetic resonance imaging protocol and analysis
End points
A 1.5-T magnetic scanner (Achieva, Philips Medical Systems, Best, Netherlands) with a SENSE cardiac coil was used. The MRI protocol consisted of cine, T2-weighted imaging, first-pass perfusion, and delayed enhancement imaging. Cine MRI images were obtained using a fast gradient echo sequence (balance fast
The primary objective was to compare myocardial infarct size as assessed by CE-MRI between the 600-mg group and the 300mg group. The secondary objectives included (1) myocardial salvage index, the extent of MVO, the number of segments with N75% of infarct transmurality, and the presence of myocardial
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Table I. Baseline characteristics of the study patients Total population Variable Age (y) Age ≥65 y Male Body mass index (kg/m 2) Current smoker Diabetes mellitus Hypertension Dyslipidemia Chronic renal failure Previous PCI Killip class ≥2 Anterior infarction LVEF b40% Systolic blood pressure at admission Heart rate at admission Door-to-drug time (min) Door-to-balloon time (min) Symptom-to-balloon time (min) Medication after PCI Aspirin Clopidogrel β-Blocker Statins ARB or ACEI
Propensity-matched population
300 mg (n = 81)
600 mg (n = 117)
55 (47-66) 22 (27.2) 75 (92.6) 24.3 ± 2.8 51 (63.0) 20 (24.7) 23 (28.4) 16 (19.8) 5 (6.2) 2 (2.5) 9 (11.1) 48 (59.3) 10 (12.3) 133 ± 27 75 ± 14 29 (20-48) 90 (67-128) 240 (160-372)
59 (51-68) 40 (34.2) 97 (82.9) 24.5 ± 2.9 67 (57.3) 26 (22.2) 41 (35.0) 30 (25.6) 6 (5.1) 5 (4.3) 8 (6.9) 64 (54.7) 14 (12.0) 132 ± 28 76 ± 16 26 (16-41) 85 (69-114) 290 (166-480)
81 (100) 80 (98.8) 68 (84.0) 74 (91.4) 51 (63.0)
116 (99.1) 111 (94.9) 103 (88.0) 111 (94.9) 76 (65.0)
P .02 .29 .05 .63 .42 .69 .33 .34 .75 .70 .72 .53 .94 .72 .60 .46 .90 .37 N .99 .24 .41 .33 .77
300 mg (n = 65)
600 mg (n = 65)
P
55 (47-67) 19 (29.2) 59 (90.8) 24.7 ± 2.9 41 (63.1) 15 (23.1) 21 (32.3) 15 (23.1) 3 (4.6) 2 (3.1) 4 (6.2) 37 (56.9) 7 (10.8) 133 ± 27 74 ± 14 27 (20-49) 88 (65-130) 240 (162-383)
57 (51-67) 20 (30.8) 59 (90.8) 24.1 ± 2.8 39 (60.0) 11 (16.9) 22 (33.8) 11 (16.9) 3 (4.6) 1 (1.5) 4 (6.2) 32 (49.2) 6 (9.2) 132 ± 25 74 ± 17 24 (15-40) 80 (68-105) 275 (166-463)
.08 .85 N.99 .28 .74 .39 .86 .37 N.99 .56 N.99 .40 .76 .80 .99 .31 .46 .77
65 (100) 65 (100) 54 (83.1) 59 (90.8) 41 (63.1)
64 61 57 60 42
(98.5) (93.8) (87.7) (92.3) (64.6)
N.99 .12 .46 .75 .86
Continuous variables are expressed as median (interquartile range) or mean ± SD; categorical variables, as n (%). LVEF, Left ventricular ejection fraction; ARB, angiotensin II receptor blocker; ACEI, angiotensin-converting enzyme inhibitor.
hemorrhage as assessed by T2-weighted images and CE-MRI; (2) enzymatic infarct size; and (3) the incidence of stent thrombosis and the composite of major adverse cardiovascular events including cardiac death, nonfatal reinfarction, and rehospitalization for congestive heart failure at the 6-month follow-up. Stent thrombosis was assessed based on the definitions of the Academic Research Consortium. 14 All deaths were considered cardiac unless a definite noncardiac cause could be established. Reinfarction was defined as elevated cardiac enzymes (troponin or MB fraction of creatine kinase, CK-MB) greater than the upper limit of the normal value with ischemic symptoms or electrocardiography findings indicative of ischemia that were not related to the index procedure. Rehospitalization for congestive heart failure was defined as hospitalization because of exacerbation of congestive heart failure occurring after discharge.
Statistical analysis Continuous variables were expressed as the mean ± SD or the median and interquartile range and were compared using the independent t test or Wilcoxon rank sum test. Categorical variables were compared with Pearson χ 2 or Fisher exact tests. Multivariate logistic regression analysis was performed with a stepwise, backward selection process to determine the independent predictors of large infarct (percent infarct volume Nmedian infarct size in the present study). The criterion for the entry and removal of variables were set at .05 and .10, respectively.
The propensity scores were estimated using multiple logistic regression analysis. A full nonparsimonious model was developed that included all variables listed in Table I and II except baseline and final thrombolysis in myocardial infarction (TIMI) flow, no-reflow, and final MBG, which were outcome variables rather than baseline ones. The discrimination and calibration ability of the propensity-score model were assessed using the cstatistic and the Hosmer-Lemeshow statistic. Continuous variables were compared using the paired t test or Wilcoxon signed rank test, and categorical variables were compared using the McNemar test or Symmetry test, as appropriate. Stratified linear regression analysis using pairs matched by a greedy algorithm and the nearest available pair-matching method among patients with an individual propensity score was also preformed. A value of P b .05 in the 2-tailed test was considered significant. The Statistical Analysis Software package (SAS version 9.1; SAS Institute, Cary, NC) was used for all analyses. This work was supported by a grant from the IN-SUNG Foundation for Medical Research, Republic of Korea (grant no. CA88331). The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents.
Results Patient characteristics The study population was composed of 198 patients, including 81 patients who received a 300-mg loading
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Table II. Angiographic and procedural findings Total population Variable Culprit vessel Left anterior descending artery Left circumflex artery Right coronary artery No. of diseased vessels 1 2 3 Baseline TIMI flow grade 0/1 2 3 Final TIMI flow grade 0/1 2 3 Angiographic no-reflow Final MBG 3 Thrombus aspiration Glycoprotein IIb/IIIa inhibitor Type of stents No stenting Bare-metal stents Drug-eluting stents Stent diameter (mm) Stent length (mm)
Propensity-matched population
300 mg (n = 81)
600 mg (n = 117)
48 (59.3) 8 (9.9) 25 (30.9)
64 (54.7) 15 (12.8) 38 (32.5)
45 (55.6) 23 (28.4) 13 (16.0)
66 (56.4) 35 (29.9) 16 (13.7)
67 (82.8) 4 (4.9) 10 (12.3)
93 (79.5) 11 (9.4) 13 (11.1)
2 (2.4) 3 (3.7) 76 (93.8) 10 (12.3) 26 (32.1) 28 (34.6) 17 (21.0)
1 (0.9) 5 (4.3) 111 (94.9) 11 (9.4) 55 (47.0) 34 (29.1) 21 (17.9)
4 (4.9) 11 (13.6) 66 (81.5) 3.3 ± 0.3 24.3 ± 5.9
9 (7.7) 11 (9.4) 97 (82.9) 3.2 ± 0.5 24.1 ± 6.2
P
300 mg (n = 65)
600 mg (n = 65)
37 (56.9) 7 (10.8) 21 (32.3)
32 (49.2) 9 (13.8) 24 (36.9)
35 (53.8) 18 (27.7) 12 (18.5)
36 (55.4) 18 (27.7) 11 (16.9)
53 (81.6) 3 (4.6) 9 (13.8)
54 (83.0) 7 (10.8) 4 (6.2)
2 (3.1) 1 (1.5) 62 (95.4) 8 (12.3) 20 (30.8) 24 (36.9) 12 (18.5)
1 2 62 5 31 28 14
2 (3.1) 8 (12.3) 55 (84.6) 3.3 ± 0.4 23.9 ± 5.6
3 (4.6) 5 (7.7) 57 (87.7) 3.2 ± 0.5 24.8 ± 6.1
.64
.67
.76
.97
.66
.26
.44
.51 .04 .41 .59 .52
.15 .80
P
.72 (1.5) (3.1) (95.4) (7.7) (47.7) (43.1) (21.5)
.38 .05 .47 .66 .63
.15 .36
TIMI, Thrombolysis in myocardial infarction; MBG, myocardial blush grade.
dose of clopidogrel and 117 patients who received a 600-mg loading dose of clopidogrel before coronary angiography. The clinical and demographic characteristics according to the clopidogrel loading dose are shown in Table I. Baseline clinical characteristics were not significantly different between the groups except age. Door-to-balloon time and symptom onset-to-balloon time were also similar in both groups. Clopidogrel loading was entirely done at the emergency department. Clopidogrel loading-to-balloon time was not significantly different between the groups (60 minutes [41-85 minutes] in the 300-mg group vs 56 minutes [38-78.5 minutes] in the 600-mg group, P = .47).
Angiographic and procedural data There were no significant differences in the angiographic or procedural characteristics between the groups (Table II). The achievement of final MBG 3 was greater in the 600-mg group than in the 300-mg group. The peak CK-MB was lesser in patients with 600-mg loading dose of clopidogrel compared with those with 300-mg loading dose of clopidogrel (187 ± 146 ng/mL vs 246 ± 230 ng/mL, P = .03).
Contrast-enhanced MRI analysis Results of MRI were available in all patients (Table III). Figure 1 shows a representative CE-MRI image of reperfused anterior STEMI. CE-MRI was performed a median of 7 days after the index event (interquartile range [IQR] 4-15 days). There was no difference in the intervals from procedure to CE-MRI between the groups (7 days [IQR 4-16 days] vs 8 days [IQR 4-15 days], P = .96). The median of infarct size was significantly smaller in the 600mg group compared with that of the 300-mg group. Although there was no statistically significant difference in AAR between the groups, myocardial salvage index was also greater in the 600-mg group than in the 300-mg group. Circumferential extent of AAR was almost the same as circumferential extent of infarction by delayed enhancement image in the 300-mg group (37.1 ± 19.4 mm and 35.9 ± 18.7 mm, r = 0.996, P b .001) as well as 600-mg group (31.3 ± 19.6 mm and 30.2 ± 19.3 mm, r = 0.997, P b .001) (Figure 2). The ratio of circumferential extent of infarction by delayed enhancement image to that of AAR was similar in both groups (0.96 ± 0.06 vs 0.96 ± 0.13, P = .97), which strongly suggests that improved salvage by a 600-mg loading of clopidogrel was attributable to decreased transmural extent rather than decreased
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Table III. Results of cine, T2-weighted, and CE-MRI Total population Variable LVEDV (mL) LVESV (mL) LV mass LV ejection fraction (%) Infarct size (% of LV) AAR (% of LV) Myocardial salvage index Hemorrhagic infarction, n (%) MVO area (% of LV) No. of segments with N75% of infarct transmurality
Propensity-matched population
300 mg (n = 81)
600 mg (n = 117)
P
300 mg (n = 65)
600 mg (n = 65)
P
131 (107-156) 68 (51-84) 128 (99-143) 49 (38-58) 21.7 (12.9-30.0) 33.1 (26.2-45.2) 32.0 (23.6-51.5) 51 (63.0) 1.5 (0-3.9) 4.8 ± 2.7
127 (105-151) 58 (44-81) 124 (106-147) 52 (43-60) 17.3 (8.9-26.2) 31.5 (22.6-46.0) 47.7 (33.7-60.9) 57 (48.7) 0.9 (0-2.2) 3.9 ± 2.7
.47 .07 .61 .07 .03 .51 b.01 .048 .049 .03
137 (113-159) 69 (51-84) 129 (106-143) 50 (39-59) 20.3 (12.6-29.4) 32.1 (26.2-40.5) 32.3 (24.2-51.2) 40 (61.5) 1.5 (0-3.6) 4.8 ± 2.6
134 (107-154) 60 (45-79) 133 (112-157) 52 (45-58) 16.7 (8.9-23.0) 31.5 (23.1-41.8) 49.0 (35.0-61.1) 35 (53.8) 0.9 (0-2.2) 3.8 ± 2.6
.68 .19 .34 .22 .03 .47 b.01 .38 .13 .04
LVEDV, Left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; MVO, microvascular obstruction. LV, left ventricular.
circumferential extent. The extent of MVO and the number of segments with N75% of infarct transmurality were significantly smaller in the 600-mg group than in the 300-mg group. In addition, myocardial hemorrhage was detected less frequently in the 600-mg group compared with that in the 300-mg group. Multivariate analysis showed that the independent predictors of a large infarct (percent infarct volume N18.5% of median infarct size) were anterior infarction and angiographic no-reflow (odds ratio [OR] 1.98, 95% CI 1.07-3.67, P = .03; OR 3.00, 95% CI 1.05-8.52, P = .04, respectively). The use of a 600-mg clopidogrel loading dose significantly reduced the risk of a large infarct (OR 0.53, 95% CI 0.29-0.98, P = .04).
Clinical outcomes At the 6-month follow-up, there had been 2 cardiac deaths (1.7%) in the 600-mg group and 1 (1.2%) in the 300-mg group (P = .79). Nonfatal reinfarction and rehospitalization for congestive heart failure occurred with similar frequency in the 600-mg and 300-mg groups (2.6% vs 3.7%, P = .69 and 3.4% vs 3.7%, P = .92, respectively). The composite major adverse cardiac event rates at the 6-month follow-up were 6.0% in the 600-mg loading dose group and 8.6% in the 300-mg loading dose group (P = .47). The incidences of definite or probable stent thrombosis were not significantly different between the 2 groups (0.9% in the 600-mg group vs 3.7% in the 300-mg group, P = .31). Propensity-matched population After performing propensity-score matching in the entire population, a total of 65 matched pairs of patients were created (Table I and II). The c-statistic for the propensity score model was 0.68. There were no significant differences in baseline clinical, angiographic, and procedural characteristics for the propensitymatched subjects. The median of infarct size was still
significantly smaller in the 600-mg group compared with that in the 300-mg group (Table III). Similarly, number of segments with N75% of infarct transmurality and myocardial salvage index were significantly different between the groups. In addition, the magnitude of difference in infarct size from the propensity-matched analysis was similar to that from crude analysis.
Discussion This is the first study to investigate the impact of 600mg versus 300-mg loading doses of clopidogrel in patients undergoing primary PCI for STEMI on myocardial infarct size as measured by CE-MRI. The major findings of the present study are that, in patients undergoing primary PCI for STEMI, a 600-mg loading dose of clopidogrel reduced myocardial infarct size and improved myocardial salvage as measured by CE-MRI compared with a 300-mg loading dose. In addition, infarct transmurality and the extent of MVO were lower in the 600-mg group compared with that of the 300-mg group. Clopidogrel is an inactive drug and needs to be metabolized by cytochrome P450 enzyme after oral administration, 15 which results in delayed onset of action. 16 To overcome this limitation, pretreatment with a 300-mg loading dose of clopidogrel has become the standard therapy for patients undergoing PCI. 1,2 However, even after a 300-mg loading of clopidogrel, at least 6 hours are required for sufficient platelet inhibition and reduction of adverse cardiac events. 2 This delay may be especially problematic in patients with STEMI because PCI should be performed as soon as possible. In addition, there is enhanced platelet activation and aggregation in this setting compared with stable coronary artery disease. 17 Several studies have shown that a 600-mg loading dose of clopidogrel results in greater and faster inhibition of platelet aggregation compared with those of a 300-mg dose. 4,5 Although a couple of studies demonstrated that a
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Figure 1
Short-axis slices of T2-weighted image (A) and the corresponding delayed enhancement image (B) in patient with anterior STEMI. In this case, the extent of AAR (C) and that of infarct size (D) was 47.0% and 35.1%, respectively, yielding myocardial salvage index of 25.3.
600-mg, compared with a 300-mg, clopidogrel loading dose reduced major adverse cardiovascular events in patients with non–ST-segment-elevation acute coronary syndrome undergoing elective PCI, 4 there has been paucity of data in patients with STEMI undergoing primary PCI. Recently, a 600-mg loading dose of clopidogrel was reported to reduce the rate of 30-day ischemic adverse events compared with a 300-mg loading in STEMI patients undergoing primary PCI. 7,8 In these trials, the benefit of 600-mg loading doses of clopidogrel was mainly because of reductions in stent thrombosis and reinfarction. Our results, on the other hand, show a reduction in myocardial infarct size and provide another mechanism to explain improved clinical outcomes after a 600-mg loading dose of clopidogrel. More potent and quicker platelet inhibition with a 600-mg clopidogrel loading dose would decrease distal embolization and protect
microcirculation during primary PCI, which, in turn, would reduce myocardial infarct size. Improved MBG in the 600-mg group supported this explanation. Enzymatic infarct size was also significantly smaller in the 600-mg group than in the 300-mg group, which strengthened our MRI data. CE-MRI can assess myocardial infarct size and the extent of MVO with high spatial resolution and excellent reproducibility, 18 providing high-resolution images of infarcted myocardium using delayed hyperenhancement. 19 Delayed hyperenhancement after contrast enables accurate delineation between the infracted and viable myocardium, allowing for the prediction of myocardial functional recovery. 20 Because our study was a nonrandomized observational study, we quantified AAR and calculated salvage index to reduce any possible imbalance in amount of jeopardized myocardium
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Figure 2
such as a 600-mg clopidogrel loading dose. Finally, the sample size was relatively small, which made it difficult to evaluate the superior efficacy of a 600-mg clopidogrel loading dose on clinical outcomes.
Conclusions The present study showed that a 600-mg loading dose of clopidogrel reduced myocardial infarct size and improved myocardial salvage as measured by CE-MRI compared with a 300-mg loading dose in patients undergoing primary PCI for STEMI. Our findings may explain the previously documented improved clinical outcomes after a 600-mg loading dose of clopidogrel in another way.
Disclosures Conflict of Interest: none declared. Circumferential extent of myocardial infarct by delayed hyperenhancement image and AAR by T2-weight image. Linear regression of circumferential extent showed good correlation, and the slope of line (regression coefficient) was b1.
between groups, which demonstrated that myocardial salvage was greater in the 600-mg group compared with the 300-mg group. Recent studies have shown that myocardial salvage assessed by T2-weighted and CE-MRI predicts the outcomes in patients undergoing primary PCI for STEMI. 13 Therefore, cardiovascular MRI is an excellent method for assessing myocardial infarct size, the extent of MVO, and myocardial salvage as surrogate end points for studies comparing different treatment strategies, and its higher accuracy allows for sample size reduction. 21 To the best of our knowledge, this is the first study to demonstrate the superior efficacy of a 600-mg clopidogrel loading dose compared with that of a 300-mg dose in terms of infarct size reduction, the extent of MVO, and myocardial salvage using cardiovascular MRI.
Study limitations Our study had several limitations. First, this was a nonrandomized, observational design, which may have significantly affected the results because of confounding factors. The selection of the clopidogrel loading dose was at the discretion of the physician. Although we performed various risk-adjusted and propensity score–matched analyses to adjust for these potential confounding factors, we were not able to correct for the unmeasured variables. However, we quantified AAR and calculated salvage index to reduce any possible imbalance in amount of jeopardized myocardium between groups. Second, we excluded patients with hemodynamic instability or a history of MI who might benefit from more potent platelet inhibition,
References 1. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527-33. 2. Steinhubl SR, Berger PB, Mann III JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288: 2411-20. 3. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502. 4. Cuisset T, Frere C, Quilici J, et al. Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non–ST-segment elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol 2006;48:1339-45. 5. Montalescot G, Sideris G, Meuleman C, et al. A randomized comparison of high clopidogrel loading doses in patients with non– ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol 2006;48:931-8. 6. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. High clopidogrel loading dose during coronary stenting: effects on drug response and interindividual variability. Eur Heart J 2004;25:1903-10. 7. Mehta SR, Tanguay JF, Eikelboom JW, et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 2010;376:1233-43. 8. Dangas G, Mehran R, Guagliumi G, et al. Role of clopidogrel loading dose in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty: results from the HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trial. J Am Coll Cardiol 2009;54:1438-46. 9. Hahn JY, Gwon HC, Choe YH, et al. Effects of balloon-based distal protection during primary percutaneous coronary intervention on early and late infarct size and left ventricular remodeling: a pilot study using serial contrast-enhanced magnetic resonance imaging. Am Heart J 2007;153:665.e1-8.
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10. Lee HY, Kim JH, Kim BO, et al. Effect of aspiration thrombectomy on microvascular dysfunction in ST-segment elevation myocardial infarction with an elevated neutrophil count. Korean Circ J 2011;41: 68-75. 11. van 't Hof AW, Liem A, Suryapranata H, et al. Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction: myocardial blush grade. Zwolle Myocardial Infarction Study Group. Circulation 1998;97: 2302-6. 12. Ganame J, Messalli G, Dymarkowski S, et al. Impact of myocardial haemorrhage on left ventricular function and remodelling in patients with reperfused acute myocardial infarction. Eur Heart J 2009;30: 1440-9. 13. Eitel I, Desch S, Fuernau G, et al. Prognostic significance and determinants of myocardial salvage assessed by cardiovascular magnetic resonance in acute reperfused myocardial infarction. J Am Coll Cardiol 2010;55:2470-9. 14. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344-51.
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15. Kim GB, Kim JK, Park S, et al. Effect of atorvastatin and clopidogrel co-administration after coronary stenting in korean patients with stable angina. Korean Circ J 2011;41:28-33. 16. Sharis PJ, Cannon CP, Loscalzo J. The antiplatelet effects of ticlopidine and clopidogrel. Ann Intern Med 1998;129:394-405. 17. Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007;357:2482-94. 18. Thiele H, Kappl MJ, Conradi S, et al. Reproducibility of chronic and acute infarct size measurement by delayed enhancement-magnetic resonance imaging. J Am Coll Cardiol 2006;47:1641-5. 19. Kim RJ, Fieno DS, Parrish TB, et al. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation 1999;100:1992-2002. 20. Beek AM, Kuhl HP, Bondarenko O, et al. Delayed contrast-enhanced magnetic resonance imaging for the prediction of regional functional improvement after acute myocardial infarction. J Am Coll Cardiol 2003;42:895-901. 21. Mahrholdt H, Wagner A, Holly TA, et al. Reproducibility of chronic infarct size measurement by contrast-enhanced magnetic resonance imaging. Circulation 2002;106:2322-7.
A high loading dose of clopidogrel reduces myocardial infarct size in patients undergoing primary percutaneous coronary intervention: A magnetic resonance imaging study Young Bin Song, MD, a Joo-Yong Hahn, MD, a Hyeon-Cheol Gwon, MD, a Sung-A Chang, MD, a,b Sang-Chol Lee, MD, a,b Yeon Hyeon Choe, MD, b,c Seung-Hyuk Choi, MD, a Jin-Ho Choi, MD, a Sang Hoon Lee, MD, a and Jae K. Oh, MD b Seoul, Republic of Korea
Background We sought to determine whether a 600-mg loading dose of clopidogrel reduces myocardial infarct size compared with a 300-mg dose using contrast-enhanced magnetic resonance imaging in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). Methods In 198 patients undergoing primary PCI for STEMI, contrast-enhanced magnetic resonance imaging was performed a median of 7 days after the index event. Infarct size was measured on delayed-enhancement imaging, and area at risk (AAR) was quantified on T2-weighted images. Results
Baseline characteristics were not significantly different between the 600-mg clopidogrel loading group (n = 117) and the 300-mg group (n = 81). The median infarct size was significantly smaller in the 600-mg group than in the 300-mg group (17.3% [8.9%-26.2%] vs 21.7% [12.9%-30.0%], P = .03). Myocardial salvage index ([AAR − infarct size] × 100/AAR) was greater in the 600-mg group than in the 300-mg group (47.7 [33.7-60.9] vs 32.0 [23.6-51.5], P b .01). Patients in the 600-mg group also had a significantly lower extent of microvascular obstruction and smaller number of segments with N75% of infarct transmurality than did those in the 300-mg group. After propensity score matching, the 600-mg group had smaller infarct size and greater myocardial salvage index compared with the 300-mg group. In multivariate analysis, the use of a 600-mg clopidogrel loading dose significantly reduced the risk of a large infarct (odds ratio 0.53, 95% CI 0.29-0.98, P = .04).
Conclusions In patients undergoing primary PCI for STEMI, a 600-mg loading dose of clopidogrel reduced myocardial infarct size and improved myocardial salvage compared with a 300-mg loading dose. (Am Heart J 2012;163:500-7.)
Dual antiplatelet therapy with aspirin and clopidogrel is critical in the prevention of adverse cardiac events in patients with acute coronary syndrome or those
From the aDivision of Cardiology, Department of Medicine, Seoul, Republic of Korea, b Cardiovascular Imaging Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, and cDepartment of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. This work was supported by a grant from the IN-SUNG Foundation for Medical Research, Republic of Korea (grant no. CA88331). Submitted June 5, 2011; accepted December 18, 2011. Reprint requests: Joo-Yong Hahn, MD, is to be contacted at Cardiac and Vascular Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Irwon-dong, Gangnam-gu, Seoul, 135-710, Republic of Korea. Yeon Hyeon Choe, MD, Department of Radiology, Cardiovascular Imaging Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. E-mails: [email protected], [email protected] 0002-8703/$ - see front matter © 2012, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2011.12.007
undergoing percutaneous coronary intervention (PCI). 1,2 A 300-mg loading dose of clopidogrel followed by a daily oral dose of 75 mg was the regimen used in several randomized trials that established clopidogrel's efficacy and safety. 2,3 However, several studies have demonstrated that the standard 300-mg loading dose of clopidogrel is inadequate to optimally inhibit platelet reactivity. 4,5 These studies also found that the inhibition of platelet aggregation is more intense and rapid with higher loading doses of clopidogrel. In addition, a higher loading dose may attenuate the variability in individual response to clopidogrel. 6 Recently, large randomized trials demonstrated that a 600-mg loading dose of clopidogrel reduced adverse ischemic events in patients undergoing primary PCI for ST-segment elevation myocardial infarction (STEMI). 7,8 However, the benefit of a 600-mg loading dose of clopidogrel in these trials was mainly driven by
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preventing stent thrombosis and reinfarction, and the effect of the loading dose on infarct size was not investigated. In the present study, we evaluated the impact of clopidogrel loading dose (600 mg vs 300 mg) on myocardial injury as measured by contrast-enhanced magnetic resonance imaging (CE-MRI) in patients undergoing primary PCI for STEMI.
Methods Study population From January 2006 to November 2009, a total of 349 STEMI patients presented to our hospital. Among them, 62 patients presented N12 hours after symptom onset, 17 patients underwent coronary artery bypass surgery because of extensive coronary artery disease, and 13 patients received only medical treatment including thrombolytics. Primary PCI was successfully performed in 257 patients with STEMI. All patients met the following criteria: presence of chest pain for N30 minutes and b12 hours after symptom onset and ST-segment elevation N1 mm in ≥2 contiguous leads or presumably a new-onset left bundle-branch block on electrocardiogram. Fifty patients did not undergo CE-MRI because of hemodynamic instability (n = 23), history of myocardial infarction (n = 10), requirement for multivessel intervention during the index procedure (n = 7), prior coronary artery bypass grafting (n = 6), and refusal to undergo CE-MRI (n = 4). Of 207 patients who underwent CEMRI, 9 patients were excluded from the present analysis, including 3 patients with evidence of previous myocardial infarction on CE-MRI, 1 patient with subacute stent thrombosis before CE-MRI, and 5 patients with unavailable clopidogrel loading dose data in the referring hospital. Finally, 198 patients were included in this study. Baseline characteristics, angiographic and procedural data, medication use, and outcome data were recorded prospectively by research coordinators of the dedicated registry. The local institutional review board approved this study, and all subjects gave their informed consent to participation.
Percutaneous coronary intervention All patients received dual oral antiplatelet therapy with 300 mg aspirin and either 300 mg or 600 mg clopidogrel before PCI. The physicians decided which loading dose of clopidogrel each patient received. Coronary angiography and stent implantation were performed using standard interventional techniques. 9,10 Intravenous administration of glycoprotein IIb/IIIa receptor antagonists was used at the operator's discretion. All baseline and procedural cine coronary angiograms were reviewed and analyzed quantitatively at the angiographic core laboratory of the Samsung Medical Centre (Seoul, Korea). Myocardial blush grade (MBG) was evaluated using the final angiogram, as described previously. 11
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field echo, steady state free precession) along the long and the short axes from the apex to the base of left ventricle. T2weighted MRI was performed in the cardiac short-axis direction using a dark-blood T2-weighted inversion-recovery fast-spin echo sequence. Next, a dose of 0.15 mmol/kg gadoliniumdiethylenetriamine pentaacetic acid (Magnevist; Bayer Schering Pharma, Berlin, Germany) was injected intravenously at a rate of 3 mL/s followed by saline flush. A first pass of the contrast agent through the myocardium after intravenous bolus injection was enabled with the T1-weighted dynamic sequence (turbo field echo with SENSE, repetition time/echo time, 2.6/1.3 milliseconds). The slice thickness was 6 mm with a field of view of 40 × 40 cm and an image matrix of 128 × 128 for the first-pass perfusion study, and images of 4 locations for every 2 heart beats were obtained for 40 phases. Delayed hyperenhancement and the extent of microvascular obstruction (MVO) were evaluated 5, 10, and 15 minutes after gadolinium-diethylenetriamine pentaacetic acid administration in contiguous 10 to 12 slices of 6 mm thickness with a 4-mm interslice gap by use of a multishot turbo field echo breath-hold sequence with a nonselective inversion (typical repetition time/time to echo 4.6/1.4 milliseconds). The field of view and image matrix were 35 × 35 cm and 256 × 256, respectively. The inversion delay time is varied in a range of 200 to 300 milliseconds. A LookLocker sequence was used to determine optimal inversion time. All measurements were performed at our MRI core laboratory. Infarct size by delayed enhanced images and area at risk (AAR) on T2-weighted images were analyzed with visual assessment by consensus of 2 experienced radiologists who were blinded to the clinical information of the patient. After the short-axis images were acquired at end-diastole and end-systole and the endocardial borders were traced, left ventricular end-diastolic volume, end-systolic volume, and ejection fraction were computed using Simpson algorithm. The infarct volume was calculated from the summation of the area with delayed hyperenhancement within each segment of the short-axis images, multiplied by the slice thickness to cover the entire left ventricle. The extent of MVO was calculated in the same manner. The endocardial and epicardial borders were planimetered to calculate myocardial area and summated in the same manner to calculate left ventricle myocardial volume. The percent infarct volume was expressed as percentages of the left ventricle myocardial volume. T2-weighted images were used to determine the presence of myocardial hemorrhage. 12 The AAR was quantified on T2-weighted images by using a similar algorithm as above and expressed as percentages of the left ventricle myocardial volume. Myocardial salvage index was computed as follows: myocardial salvage index = (AAR − infarct size) × 100/AAR. 13 The infarct transmurality for each segment was calculated by dividing the hyperenhanced area by the total area of the affected myocardium in each segment. The transmural extent of infarction was expressed as the sum of segments with N75% of infarct transmurality.
Magnetic resonance imaging protocol and analysis
End points
A 1.5-T magnetic scanner (Achieva, Philips Medical Systems, Best, Netherlands) with a SENSE cardiac coil was used. The MRI protocol consisted of cine, T2-weighted imaging, first-pass perfusion, and delayed enhancement imaging. Cine MRI images were obtained using a fast gradient echo sequence (balance fast
The primary objective was to compare myocardial infarct size as assessed by CE-MRI between the 600-mg group and the 300mg group. The secondary objectives included (1) myocardial salvage index, the extent of MVO, the number of segments with N75% of infarct transmurality, and the presence of myocardial
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Table I. Baseline characteristics of the study patients Total population Variable Age (y) Age ≥65 y Male Body mass index (kg/m 2) Current smoker Diabetes mellitus Hypertension Dyslipidemia Chronic renal failure Previous PCI Killip class ≥2 Anterior infarction LVEF b40% Systolic blood pressure at admission Heart rate at admission Door-to-drug time (min) Door-to-balloon time (min) Symptom-to-balloon time (min) Medication after PCI Aspirin Clopidogrel β-Blocker Statins ARB or ACEI
Propensity-matched population
300 mg (n = 81)
600 mg (n = 117)
55 (47-66) 22 (27.2) 75 (92.6) 24.3 ± 2.8 51 (63.0) 20 (24.7) 23 (28.4) 16 (19.8) 5 (6.2) 2 (2.5) 9 (11.1) 48 (59.3) 10 (12.3) 133 ± 27 75 ± 14 29 (20-48) 90 (67-128) 240 (160-372)
59 (51-68) 40 (34.2) 97 (82.9) 24.5 ± 2.9 67 (57.3) 26 (22.2) 41 (35.0) 30 (25.6) 6 (5.1) 5 (4.3) 8 (6.9) 64 (54.7) 14 (12.0) 132 ± 28 76 ± 16 26 (16-41) 85 (69-114) 290 (166-480)
81 (100) 80 (98.8) 68 (84.0) 74 (91.4) 51 (63.0)
116 (99.1) 111 (94.9) 103 (88.0) 111 (94.9) 76 (65.0)
P .02 .29 .05 .63 .42 .69 .33 .34 .75 .70 .72 .53 .94 .72 .60 .46 .90 .37 N .99 .24 .41 .33 .77
300 mg (n = 65)
600 mg (n = 65)
P
55 (47-67) 19 (29.2) 59 (90.8) 24.7 ± 2.9 41 (63.1) 15 (23.1) 21 (32.3) 15 (23.1) 3 (4.6) 2 (3.1) 4 (6.2) 37 (56.9) 7 (10.8) 133 ± 27 74 ± 14 27 (20-49) 88 (65-130) 240 (162-383)
57 (51-67) 20 (30.8) 59 (90.8) 24.1 ± 2.8 39 (60.0) 11 (16.9) 22 (33.8) 11 (16.9) 3 (4.6) 1 (1.5) 4 (6.2) 32 (49.2) 6 (9.2) 132 ± 25 74 ± 17 24 (15-40) 80 (68-105) 275 (166-463)
.08 .85 N.99 .28 .74 .39 .86 .37 N.99 .56 N.99 .40 .76 .80 .99 .31 .46 .77
65 (100) 65 (100) 54 (83.1) 59 (90.8) 41 (63.1)
64 61 57 60 42
(98.5) (93.8) (87.7) (92.3) (64.6)
N.99 .12 .46 .75 .86
Continuous variables are expressed as median (interquartile range) or mean ± SD; categorical variables, as n (%). LVEF, Left ventricular ejection fraction; ARB, angiotensin II receptor blocker; ACEI, angiotensin-converting enzyme inhibitor.
hemorrhage as assessed by T2-weighted images and CE-MRI; (2) enzymatic infarct size; and (3) the incidence of stent thrombosis and the composite of major adverse cardiovascular events including cardiac death, nonfatal reinfarction, and rehospitalization for congestive heart failure at the 6-month follow-up. Stent thrombosis was assessed based on the definitions of the Academic Research Consortium. 14 All deaths were considered cardiac unless a definite noncardiac cause could be established. Reinfarction was defined as elevated cardiac enzymes (troponin or MB fraction of creatine kinase, CK-MB) greater than the upper limit of the normal value with ischemic symptoms or electrocardiography findings indicative of ischemia that were not related to the index procedure. Rehospitalization for congestive heart failure was defined as hospitalization because of exacerbation of congestive heart failure occurring after discharge.
Statistical analysis Continuous variables were expressed as the mean ± SD or the median and interquartile range and were compared using the independent t test or Wilcoxon rank sum test. Categorical variables were compared with Pearson χ 2 or Fisher exact tests. Multivariate logistic regression analysis was performed with a stepwise, backward selection process to determine the independent predictors of large infarct (percent infarct volume Nmedian infarct size in the present study). The criterion for the entry and removal of variables were set at .05 and .10, respectively.
The propensity scores were estimated using multiple logistic regression analysis. A full nonparsimonious model was developed that included all variables listed in Table I and II except baseline and final thrombolysis in myocardial infarction (TIMI) flow, no-reflow, and final MBG, which were outcome variables rather than baseline ones. The discrimination and calibration ability of the propensity-score model were assessed using the cstatistic and the Hosmer-Lemeshow statistic. Continuous variables were compared using the paired t test or Wilcoxon signed rank test, and categorical variables were compared using the McNemar test or Symmetry test, as appropriate. Stratified linear regression analysis using pairs matched by a greedy algorithm and the nearest available pair-matching method among patients with an individual propensity score was also preformed. A value of P b .05 in the 2-tailed test was considered significant. The Statistical Analysis Software package (SAS version 9.1; SAS Institute, Cary, NC) was used for all analyses. This work was supported by a grant from the IN-SUNG Foundation for Medical Research, Republic of Korea (grant no. CA88331). The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents.
Results Patient characteristics The study population was composed of 198 patients, including 81 patients who received a 300-mg loading
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Table II. Angiographic and procedural findings Total population Variable Culprit vessel Left anterior descending artery Left circumflex artery Right coronary artery No. of diseased vessels 1 2 3 Baseline TIMI flow grade 0/1 2 3 Final TIMI flow grade 0/1 2 3 Angiographic no-reflow Final MBG 3 Thrombus aspiration Glycoprotein IIb/IIIa inhibitor Type of stents No stenting Bare-metal stents Drug-eluting stents Stent diameter (mm) Stent length (mm)
Propensity-matched population
300 mg (n = 81)
600 mg (n = 117)
48 (59.3) 8 (9.9) 25 (30.9)
64 (54.7) 15 (12.8) 38 (32.5)
45 (55.6) 23 (28.4) 13 (16.0)
66 (56.4) 35 (29.9) 16 (13.7)
67 (82.8) 4 (4.9) 10 (12.3)
93 (79.5) 11 (9.4) 13 (11.1)
2 (2.4) 3 (3.7) 76 (93.8) 10 (12.3) 26 (32.1) 28 (34.6) 17 (21.0)
1 (0.9) 5 (4.3) 111 (94.9) 11 (9.4) 55 (47.0) 34 (29.1) 21 (17.9)
4 (4.9) 11 (13.6) 66 (81.5) 3.3 ± 0.3 24.3 ± 5.9
9 (7.7) 11 (9.4) 97 (82.9) 3.2 ± 0.5 24.1 ± 6.2
P
300 mg (n = 65)
600 mg (n = 65)
37 (56.9) 7 (10.8) 21 (32.3)
32 (49.2) 9 (13.8) 24 (36.9)
35 (53.8) 18 (27.7) 12 (18.5)
36 (55.4) 18 (27.7) 11 (16.9)
53 (81.6) 3 (4.6) 9 (13.8)
54 (83.0) 7 (10.8) 4 (6.2)
2 (3.1) 1 (1.5) 62 (95.4) 8 (12.3) 20 (30.8) 24 (36.9) 12 (18.5)
1 2 62 5 31 28 14
2 (3.1) 8 (12.3) 55 (84.6) 3.3 ± 0.4 23.9 ± 5.6
3 (4.6) 5 (7.7) 57 (87.7) 3.2 ± 0.5 24.8 ± 6.1
.64
.67
.76
.97
.66
.26
.44
.51 .04 .41 .59 .52
.15 .80
P
.72 (1.5) (3.1) (95.4) (7.7) (47.7) (43.1) (21.5)
.38 .05 .47 .66 .63
.15 .36
TIMI, Thrombolysis in myocardial infarction; MBG, myocardial blush grade.
dose of clopidogrel and 117 patients who received a 600-mg loading dose of clopidogrel before coronary angiography. The clinical and demographic characteristics according to the clopidogrel loading dose are shown in Table I. Baseline clinical characteristics were not significantly different between the groups except age. Door-to-balloon time and symptom onset-to-balloon time were also similar in both groups. Clopidogrel loading was entirely done at the emergency department. Clopidogrel loading-to-balloon time was not significantly different between the groups (60 minutes [41-85 minutes] in the 300-mg group vs 56 minutes [38-78.5 minutes] in the 600-mg group, P = .47).
Angiographic and procedural data There were no significant differences in the angiographic or procedural characteristics between the groups (Table II). The achievement of final MBG 3 was greater in the 600-mg group than in the 300-mg group. The peak CK-MB was lesser in patients with 600-mg loading dose of clopidogrel compared with those with 300-mg loading dose of clopidogrel (187 ± 146 ng/mL vs 246 ± 230 ng/mL, P = .03).
Contrast-enhanced MRI analysis Results of MRI were available in all patients (Table III). Figure 1 shows a representative CE-MRI image of reperfused anterior STEMI. CE-MRI was performed a median of 7 days after the index event (interquartile range [IQR] 4-15 days). There was no difference in the intervals from procedure to CE-MRI between the groups (7 days [IQR 4-16 days] vs 8 days [IQR 4-15 days], P = .96). The median of infarct size was significantly smaller in the 600mg group compared with that of the 300-mg group. Although there was no statistically significant difference in AAR between the groups, myocardial salvage index was also greater in the 600-mg group than in the 300-mg group. Circumferential extent of AAR was almost the same as circumferential extent of infarction by delayed enhancement image in the 300-mg group (37.1 ± 19.4 mm and 35.9 ± 18.7 mm, r = 0.996, P b .001) as well as 600-mg group (31.3 ± 19.6 mm and 30.2 ± 19.3 mm, r = 0.997, P b .001) (Figure 2). The ratio of circumferential extent of infarction by delayed enhancement image to that of AAR was similar in both groups (0.96 ± 0.06 vs 0.96 ± 0.13, P = .97), which strongly suggests that improved salvage by a 600-mg loading of clopidogrel was attributable to decreased transmural extent rather than decreased
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Table III. Results of cine, T2-weighted, and CE-MRI Total population Variable LVEDV (mL) LVESV (mL) LV mass LV ejection fraction (%) Infarct size (% of LV) AAR (% of LV) Myocardial salvage index Hemorrhagic infarction, n (%) MVO area (% of LV) No. of segments with N75% of infarct transmurality
Propensity-matched population
300 mg (n = 81)
600 mg (n = 117)
P
300 mg (n = 65)
600 mg (n = 65)
P
131 (107-156) 68 (51-84) 128 (99-143) 49 (38-58) 21.7 (12.9-30.0) 33.1 (26.2-45.2) 32.0 (23.6-51.5) 51 (63.0) 1.5 (0-3.9) 4.8 ± 2.7
127 (105-151) 58 (44-81) 124 (106-147) 52 (43-60) 17.3 (8.9-26.2) 31.5 (22.6-46.0) 47.7 (33.7-60.9) 57 (48.7) 0.9 (0-2.2) 3.9 ± 2.7
.47 .07 .61 .07 .03 .51 b.01 .048 .049 .03
137 (113-159) 69 (51-84) 129 (106-143) 50 (39-59) 20.3 (12.6-29.4) 32.1 (26.2-40.5) 32.3 (24.2-51.2) 40 (61.5) 1.5 (0-3.6) 4.8 ± 2.6
134 (107-154) 60 (45-79) 133 (112-157) 52 (45-58) 16.7 (8.9-23.0) 31.5 (23.1-41.8) 49.0 (35.0-61.1) 35 (53.8) 0.9 (0-2.2) 3.8 ± 2.6
.68 .19 .34 .22 .03 .47 b.01 .38 .13 .04
LVEDV, Left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; MVO, microvascular obstruction. LV, left ventricular.
circumferential extent. The extent of MVO and the number of segments with N75% of infarct transmurality were significantly smaller in the 600-mg group than in the 300-mg group. In addition, myocardial hemorrhage was detected less frequently in the 600-mg group compared with that in the 300-mg group. Multivariate analysis showed that the independent predictors of a large infarct (percent infarct volume N18.5% of median infarct size) were anterior infarction and angiographic no-reflow (odds ratio [OR] 1.98, 95% CI 1.07-3.67, P = .03; OR 3.00, 95% CI 1.05-8.52, P = .04, respectively). The use of a 600-mg clopidogrel loading dose significantly reduced the risk of a large infarct (OR 0.53, 95% CI 0.29-0.98, P = .04).
Clinical outcomes At the 6-month follow-up, there had been 2 cardiac deaths (1.7%) in the 600-mg group and 1 (1.2%) in the 300-mg group (P = .79). Nonfatal reinfarction and rehospitalization for congestive heart failure occurred with similar frequency in the 600-mg and 300-mg groups (2.6% vs 3.7%, P = .69 and 3.4% vs 3.7%, P = .92, respectively). The composite major adverse cardiac event rates at the 6-month follow-up were 6.0% in the 600-mg loading dose group and 8.6% in the 300-mg loading dose group (P = .47). The incidences of definite or probable stent thrombosis were not significantly different between the 2 groups (0.9% in the 600-mg group vs 3.7% in the 300-mg group, P = .31). Propensity-matched population After performing propensity-score matching in the entire population, a total of 65 matched pairs of patients were created (Table I and II). The c-statistic for the propensity score model was 0.68. There were no significant differences in baseline clinical, angiographic, and procedural characteristics for the propensitymatched subjects. The median of infarct size was still
significantly smaller in the 600-mg group compared with that in the 300-mg group (Table III). Similarly, number of segments with N75% of infarct transmurality and myocardial salvage index were significantly different between the groups. In addition, the magnitude of difference in infarct size from the propensity-matched analysis was similar to that from crude analysis.
Discussion This is the first study to investigate the impact of 600mg versus 300-mg loading doses of clopidogrel in patients undergoing primary PCI for STEMI on myocardial infarct size as measured by CE-MRI. The major findings of the present study are that, in patients undergoing primary PCI for STEMI, a 600-mg loading dose of clopidogrel reduced myocardial infarct size and improved myocardial salvage as measured by CE-MRI compared with a 300-mg loading dose. In addition, infarct transmurality and the extent of MVO were lower in the 600-mg group compared with that of the 300-mg group. Clopidogrel is an inactive drug and needs to be metabolized by cytochrome P450 enzyme after oral administration, 15 which results in delayed onset of action. 16 To overcome this limitation, pretreatment with a 300-mg loading dose of clopidogrel has become the standard therapy for patients undergoing PCI. 1,2 However, even after a 300-mg loading of clopidogrel, at least 6 hours are required for sufficient platelet inhibition and reduction of adverse cardiac events. 2 This delay may be especially problematic in patients with STEMI because PCI should be performed as soon as possible. In addition, there is enhanced platelet activation and aggregation in this setting compared with stable coronary artery disease. 17 Several studies have shown that a 600-mg loading dose of clopidogrel results in greater and faster inhibition of platelet aggregation compared with those of a 300-mg dose. 4,5 Although a couple of studies demonstrated that a
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Figure 1
Short-axis slices of T2-weighted image (A) and the corresponding delayed enhancement image (B) in patient with anterior STEMI. In this case, the extent of AAR (C) and that of infarct size (D) was 47.0% and 35.1%, respectively, yielding myocardial salvage index of 25.3.
600-mg, compared with a 300-mg, clopidogrel loading dose reduced major adverse cardiovascular events in patients with non–ST-segment-elevation acute coronary syndrome undergoing elective PCI, 4 there has been paucity of data in patients with STEMI undergoing primary PCI. Recently, a 600-mg loading dose of clopidogrel was reported to reduce the rate of 30-day ischemic adverse events compared with a 300-mg loading in STEMI patients undergoing primary PCI. 7,8 In these trials, the benefit of 600-mg loading doses of clopidogrel was mainly because of reductions in stent thrombosis and reinfarction. Our results, on the other hand, show a reduction in myocardial infarct size and provide another mechanism to explain improved clinical outcomes after a 600-mg loading dose of clopidogrel. More potent and quicker platelet inhibition with a 600-mg clopidogrel loading dose would decrease distal embolization and protect
microcirculation during primary PCI, which, in turn, would reduce myocardial infarct size. Improved MBG in the 600-mg group supported this explanation. Enzymatic infarct size was also significantly smaller in the 600-mg group than in the 300-mg group, which strengthened our MRI data. CE-MRI can assess myocardial infarct size and the extent of MVO with high spatial resolution and excellent reproducibility, 18 providing high-resolution images of infarcted myocardium using delayed hyperenhancement. 19 Delayed hyperenhancement after contrast enables accurate delineation between the infracted and viable myocardium, allowing for the prediction of myocardial functional recovery. 20 Because our study was a nonrandomized observational study, we quantified AAR and calculated salvage index to reduce any possible imbalance in amount of jeopardized myocardium
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Figure 2
such as a 600-mg clopidogrel loading dose. Finally, the sample size was relatively small, which made it difficult to evaluate the superior efficacy of a 600-mg clopidogrel loading dose on clinical outcomes.
Conclusions The present study showed that a 600-mg loading dose of clopidogrel reduced myocardial infarct size and improved myocardial salvage as measured by CE-MRI compared with a 300-mg loading dose in patients undergoing primary PCI for STEMI. Our findings may explain the previously documented improved clinical outcomes after a 600-mg loading dose of clopidogrel in another way.
Disclosures Conflict of Interest: none declared. Circumferential extent of myocardial infarct by delayed hyperenhancement image and AAR by T2-weight image. Linear regression of circumferential extent showed good correlation, and the slope of line (regression coefficient) was b1.
between groups, which demonstrated that myocardial salvage was greater in the 600-mg group compared with the 300-mg group. Recent studies have shown that myocardial salvage assessed by T2-weighted and CE-MRI predicts the outcomes in patients undergoing primary PCI for STEMI. 13 Therefore, cardiovascular MRI is an excellent method for assessing myocardial infarct size, the extent of MVO, and myocardial salvage as surrogate end points for studies comparing different treatment strategies, and its higher accuracy allows for sample size reduction. 21 To the best of our knowledge, this is the first study to demonstrate the superior efficacy of a 600-mg clopidogrel loading dose compared with that of a 300-mg dose in terms of infarct size reduction, the extent of MVO, and myocardial salvage using cardiovascular MRI.
Study limitations Our study had several limitations. First, this was a nonrandomized, observational design, which may have significantly affected the results because of confounding factors. The selection of the clopidogrel loading dose was at the discretion of the physician. Although we performed various risk-adjusted and propensity score–matched analyses to adjust for these potential confounding factors, we were not able to correct for the unmeasured variables. However, we quantified AAR and calculated salvage index to reduce any possible imbalance in amount of jeopardized myocardium between groups. Second, we excluded patients with hemodynamic instability or a history of MI who might benefit from more potent platelet inhibition,
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