Abstract
Background:
The effect of prior use of aspirin (ASA) on the onset of acute coronary syndrome (ACS) has not been clarified. This study used optical coherence tomography (OCT) to investigate the morphological features of culprit lesions of ACS in patients with prior ASA use.
Methods and Results:
In total, 442 patients with their first ACS episode undergoing OCT for the culprit lesions were investigated. Clinical characteristics, OCT findings, and adverse events at 30 days were compared between patients with prior ASA use and ASA-naïve patients (non-ASA). 67 patients (15.2%) had received ASA at presentation. The ASA group was older, had higher frequency of dyslipidemia and hypertension, and lower renal function than the non-ASA group. Non-ST-elevation ACS was more prevalent in the ASA than in the non-ASA group (79.1 vs. 53.6%, P<0.001). Propensity score matching yielded 49 patients in both groups. OCT revealed less frequent thrombi in the ASA than in the non-ASA group in both the entire (37.3 vs. 75.2%, P<0.001) and score-matched cohorts (38.8 vs. 75.5%, P<0.001), whereas no significant difference was observed in plaque characteristics. Rate of adverse events did not differ between the ASA and the non-ASA groups in the matched cohort.
Conclusions:
With a first ACS presentation, patients with prior ASA use were more likely to present with non-ST-elevation ACS with less frequent intraluminal thrombi, but no significant difference in underlying plaque characteristics or clinical course.
Based on substantial evidence, acetylsalicylic acid (ASA), also known as aspirin, has for decades been accepted as the first-line antithrombotic agent for the treatment of acute coronary syndrome (ACS) and for secondary prevention in patients with cardiovascular disease.1–3
Despite its protective actions against coronary thrombi and its proven effectiveness in ACS patients, the prior use of ASA in advance of a presentation of non-ST-elevation ACS is reported as a high-risk feature for subsequent adverse events.4,5
However, there remains controversy whether prior ASA use is an independent risk for worse outcomes or only a marker of different high-risk features.6
Moreover, in contrast to secondary prevention, the benefit of ASA for primary prevention has been controversial.2
Although previous reports suggested the efficacy of ASA for primary prevention in high-risk subjects with diabetes, recent studies cast doubt on this finding.7,8
Thus, despite clinical data and reasonable pharmacological action against thromboembolism, the effects of ASA on the presentation of first ACS continue to be debated. Of note, the effect of prior ASA use on the local pathogenesis of culprit lesions in ACS has not been elucidated. Optical coherence tomography (OCT) is an unprecedented imaging modality, which enables in vivo assessment of coronary plaque and intracoronary thrombus with near-pathology resolution.9
Therefore, we conducted a retrospective analysis to investigate the morphological differences of culprit lesions of ACS between patients with and without prior ASA use at their first presentation of ACS.
Methods
Study Population
From a total of 1,150 patients with ACS treated with percutaneous coronary intervention (PCI) at Tsuchiura Kyodo General Hospital between October 2008 and December 2015, we identified 511 patients with their first presentation of ACS who underwent OCT examinations of the de novo culprit lesion at the time of PCI. The exclusion criteria for OCT imaging were patients with cardiogenic shock, congestive heart failure, significant left main disease, and suboptimal results after thrombectomy with Thrombolysis in Myocardial Infarction (TIMI) 0–2 flow. We further excluded from the analysis lesions in which balloon angioplasty was required before OCT imaging or those with insufficient image quality. Therefore, the final dataset included 442 patients with 442 culprit lesions.
Definitions
Myocardial infarction (MI) was diagnosed based on the 3rd universal definition of MI.10
Briefly, MI was defined as having symptoms of ischemia, ECG change or imaging evidence of a new regional wall motion abnormality accompanied by a rise and/or fall of cardiac troponin-I or creatine kinase MB (CK-MB) with at least 1 value >99 th percentile of the upper reference. ST-elevation MI (STEMI) was defined as MI associated with ST-segment elevation >1 mm in ≥2 contiguous leads or newly developed left bundle branch block. Non-STEMI (NSTEMI) was defined as MI without significant ST-segment elevation or new left bundle branch block. The diagnosis of unstable angina pectoris (UAP) was dependent on the physician’s diagnosis and based on the definition of having chest pain associated with significant coronary lesions and ECG change without the rise/fall of cardiac markers. Prior ASA use was defined as taking ASA on a regular basis during the week preceding the ACS presentation as defined in previous studies.6,11,12
History of ASA prescription was obtained from the primary physician; otherwise, over-the-counter low-dose ASA for daily use is not available in Japan.
The patients were divided into 2 groups according to prior ASA use (ASA group and non-ASA group, respectively), and their characteristics and OCT findings were compared. The 30-day clinical events were defined as major adverse cardiac events (MACE), including cardiac death, target vessel revascularization, or a new onset of MI, or documented complications, including cardiogenic shock, sustained ventricular arrhythmia, and congestive heart failure after PCI procedure within 30 days from onset. Bleeding was defined as having type 3 or 5 bleeding according to the Bleeding Academic Research Consortium (BARC) definition.13
Type 3 bleeding was defined as clinically overt hemorrhage or bleeding resulting in a hemoglobin drop >3 g/dL or requiring transfusion. Type 5 bleeding was defined as fatal bleeding. The presence of clinical and bleeding events was determined from the clinical records by an independent cardiologist who was blinded to the OCT and angiographic findings.
OCT Image Acquisition and Interpretation
The OCT images were acquired before balloon angioplasty or thrombectomy for lesions showing TIMI 3 flow without suspected angiographic thrombi; otherwise, thrombectomy was performed with an aspiration catheter (Eliminate, Terumo, Tokyo, Japan or Export Advance, Medtronic, Minneapolis, MN) to obtain TIMI 3 flow before the OCT imaging. Either the time-domain (M2/M3 Cardiology Imaging System, LightLab Imaging, Inc., Westford, MA, USA) or the frequency-domain OCT system (C8-XRTM
OCT Intravascular Imaging System, St. Jude Medical, St. Paul, MN, USA or LUNAWAVETM
OFDI System, Terumo, Tokyo, Japan) was used in the present study. The technique of intracoronary OCT imaging is described elsewhere.9,14,15
The OCT analysis included either the presence or absence of intraluminal thrombus, lipid-rich plaque and ruptured plaque, thin-capped fibroatheroma, calcification, and macrophage infiltration according to consensus documents.9,16,17
Intraluminal thrombus was defined as a mass attached to the lumen or floating within the lumen. In the present study, floating thrombus was defined as not having contact with the vessel wall along more than half of the thrombus’ length. Red thrombus was characterized by high backscattering with high attenuation. White thrombus was characterized by less backscattering with low-attenuated signal and a homogeneous appearance (Figure 1). The presence or absence of red and white thrombi was analyzed separately, and the presence of OCT-defined thrombus was defined as having red, white or both types of thrombus within the culprit lesion. Respective intra- and inter-observer variabilities were κ=0.93 and 0.91 for OCT-defined thrombus, κ=0.88 and 0.74 for red thrombus, κ=0.86 and κ=0.75 for white thrombus. In cases of discordance, a consensus reading was obtained. In addition, thrombus length, maximal arc of the thrombus, and thrombus volume were measured according to previous studies.18,19
In brief, for the measurements of thrombus, OCT images were analyzed at 0.2-mm intervals. Thrombus area was traced by planimetry in frames with clear visualization of the vessel contours >270 degrees; otherwise thrombus area was calculated by subtracting residual lumen area from the vessel contour area extrapolated from the nearest visible frames. Thrombus length was calculated by the number of frames with OCT thrombus multiplied by frame interval (0.2 mm). Thrombus arc was measured from the center of the residual lumen, and the maximum value was obtained as the maximum thrombus arc. The lipid core on OCT was characterized by diffusely bordered, signal-poor regions with an overlaying signal-rich band that represented the fibrous cap. The arc of the lipid and the fibrous cap thickness were measured, and plaque with a lipid arc >90 degrees circumference was defined as fibroatheroma in the present study. A ruptured plaque was defined as a plaque showing disruption of the fibrous cap with or without cavity formation. Thin-capped fibroatheroma was defined as a fibroatheroma with a fibrous cap thickness <65 µm. Calcification was identified by a signal-poor region with a sharply delineated border. Lipid core length was defined as the longitudinal length of contiguous cross-sections that fulfilled the definition of fibroatheroma.
Baseline coronary angiograms obtained before the interventional procedures were analyzed off-line (QAngio XA 7.3, Medis, Leiden, The Netherlands). Reference diameter, minimum lumen diameter, diameter stenosis and lesion length were determined at the culprit lesion. The TIMI flow grade was assessed for the culprit vessel. Angiographic lesion morphology was classified according to the American Heart Association (AHA)/American College of Cardiology lesion classification.20
Statistical Analysis
Categorical values are presented as counts and proportions, and comparisons between groups were performed using the chi-square test or Fisher’s exact test depending on the data. Continuous values showing a normal distribution are expressed as the mean value±standard deviation, and Student’s t-test was performed to compare groups. Non-normally distributed, continuous values are expressed as the median value (25–75 th percentile), and the Mann-Whitney U test was used to compare groups. Because of significant differences in the baseline characteristics of patients with and without prior ASA use, we used propensity score matching to adjust for possible confounders. We derived propensity scores for each patient based on age, sex, history of hypertension, diabetes mellitus, and dyslipidemia, low-density lipoprotein cholesterol (LDL-C) levels, and prior statin use, including the variables that showed significant associations with prior ASA use. Propensity score matching was then performed with a 1:1 algorithm using nearest neighbor matching with a caliper width of ±0.03 and no replacement. All the analyses were performed with SPSS 17 (SPSS Inc., Chicago, IL, USA), except for the calculation of the propensity score and propensity score matching, which were analyzed using R statistics version 3.2.3 (The R foundations for Statistical Computing, Vienna, Austria).
Results
Clinical Characteristics of the Entire Cohort
Of the 442 patients experiencing their first ACS episode who underwent OCT imaging for the culprit lesion, 67 (15.2%) were taking ASA at the time of ACS presentation. Of these 67 patients with prior ASA use, 11 were taking 81 mg daily, 37 were taking 100 mg, 1 was taking 162 mg, and 18 were on 200 mg. The clinical characteristics of the patients with (ASA group) and without (non-ASA group) prior ASA use are shown in
Table 1. In the entire cohort, the mean age was significantly higher in the ASA group than in the non-ASA group, and the prevalence of both dyslipidemia and hypertension was also significantly higher in the ASA group. The ASA group also tended to be prescribed statin more frequently than the non-ASA group, and the total cholesterol and LDL-C levels were significantly lower in the ASA group. Renal function, as indicated by serum creatinine levels and the estimated glomerular filtration rate, was significantly worse in the ASA group. As the clinical presentation, STEMI was significantly less frequent in the ASA group than in the non-ASA group, demonstrating that the ASA group tended to present with non-ST-elevation ACS, including NSTEMI and UAP. Cardiac markers on admission did not differ between the 2 groups, but peak CK and peak CK-MB levels were significantly lower in the ASA group than in the non-ASA group.
Table 1.
Characteristics of the ACS Patient With and Without Prior ASA Use
| |
Entire cohort (n=442) |
Matched cohort (n=98) |
| Total |
ASA
group |
Non-ASA
group |
P value |
Total |
ASA
group |
Non-ASA
group |
P value |
| n |
442 |
67 |
375 |
|
98 |
49 |
49 |
|
| Age (years) |
65.4±12.0 |
69.8±9.4 |
64.6±12.3 |
0.001 |
69.5±10.2 |
69.4±9.3 |
69.7±11.1 |
0.883 |
| Male (%) |
355 (80.3) |
56 (83.6) |
299 (79.7) |
0.510 |
78 (79.6) |
39 (79.6) |
39 (79.6) |
1.000 |
| DL (%) |
205 (46.4) |
39 (58.2) |
166 (44.3) |
0.046 |
47 (48.0) |
24 (49.0) |
23 (46.9) |
1.000 |
| HT (%) |
279 (63.1) |
54 (80.6) |
225 (60.0) |
0.001 |
73 (74.5) |
39 (79.6) |
34 (69.4) |
0.354 |
| DM (%) |
137 (31.0) |
22 (32.8) |
115 (30.7) |
0.775 |
31 (31.6) |
17 (34.7) |
14 (28.6) |
0.664 |
| Culprit vessel (%) |
| RCA |
160 (36.2) |
21 (31.3) |
139 (37.1) |
0.645 |
35 (35.7) |
14 (28.6) |
21 (42.9) |
0.327 |
| LAD |
204 (46.2) |
34 (50.7) |
170 (45.3) |
44 (44.9) |
24 (49.0) |
20 (40.8) |
| LCX |
79 (17.9) |
12 (17.9) |
67 (17.9) |
19 (19.4) |
11 (22.4) |
8 (16.3) |
| Clinical presentation (%) |
| STEMI |
188 (42.5) |
14 (20.9) |
174 (46.4) |
<0.001 |
31 (31.6) |
8 (16.3) |
23 (46.9) |
0.005 |
| NSTEMI |
190 (43.0) |
37 (55.2) |
153 (40.8) |
51 (52.0) |
31 (63.3) |
20 (40.8) |
| UAP |
64 (14.5) |
16 (23.9) |
48 (12.8) |
16 (16.3) |
10 (20.4) |
6 (12.2) |
| Prior CABG (%) |
3 (0.7) |
3 (4.5) |
0 (0.0) |
0.003 |
2 (2.0) |
2 (4.1) |
0 (0.0) |
0.495 |
| Prior PCI (%) |
19 (4.3) |
18 (26.9) |
1 (0.3) |
<0.001 |
13 (13.3) |
13 (26.5) |
0 (0.0) |
<0.001 |
| Prior statin (%) |
88 (19.9) |
31 (46.3) |
57 (15.2) |
<0.001 |
32 (32.7) |
17 (34.7) |
15 (30.6) |
0.830 |
| Creatinine (mg/dL) |
0.78
(0.65–0.90) |
0.84
(0.64–1.08) |
0.77
(0.65–0.90) |
0.031 |
0.80
(0.64–1.05) |
0.82
(0.62–1.07) |
0.80
(0.65–1.00) |
0.511 |
| eGFR |
73.0±25.2 |
66.5±29.1 |
74.1±24.6 |
0.023 |
69.0±26.2 |
65.6±30.7 |
70.9±22.8 |
0.424 |
| Glucose (mg/dL) |
132
(110–174) |
131
(111–169) |
133
(110–175) |
0.767 |
132
(113–168) |
132
(119–171) |
132
(112–157) |
0.697 |
Total cholesterol
(mg/dL) |
190
(166–220) |
169
(144–200) |
193
(170–221) |
<0.001 |
175
(155–201) |
179
(150–209) |
175
(159–193) |
0.826 |
| LDL-C (mg/dL) |
121
(98–144) |
99
(82–129) |
123
(103–147) |
<0.001 |
108
(89–128) |
112
(88–136) |
105
(90–121) |
0.439 |
| HDL-C (mg/dL) |
45
(38–53) |
44
(37–50) |
45
(39–53) |
0.152 |
45
(37–52) |
43
(37–50) |
46
(39–54) |
0.200 |
Triglycerides
(mg/dL) |
108
(70–161) |
89
(63–133) |
110
(72–164) |
0.066 |
101
(67–144) |
99
(72–141) |
104
(65–142) |
0.829 |
| WBC (count/μL) |
8,505
(6,550–10,700) |
7,080
(6,120–8,745) |
8,730
(6,755–10,950) |
<0.001 |
7,730
(6,158–9,885) |
7,100
(6,140–8,750) |
8,580
(6,510–11,000) |
0.059 |
| CRP (mg/dL) |
0.15
(0.00–0.51) |
0.18
(0.07–0.50) |
0.14
(0.00–0.51) |
0.272 |
0.17
(0.06–0.50) |
0.23
(0.08–0.51) |
0.11
(0.00–0.34) |
0.109 |
TnI on arrival
(ng/mL) |
0.37
(0.07–2.24) |
0.59
(0.05–1.56) |
0.36
(0.07–2.28) |
0.883 |
0.42
(0.07–1.57) |
0.59
(0.08–1.58) |
0.23
(0.07–1.19) |
0.464 |
CK on arrival
(IU/L) |
149
(91–304) |
158
(71–293) |
148
(95–302) |
0.470 |
141
(81–299) |
159
(70–261) |
129
(85–292) |
0.804 |
CK-MB on arrival
(IU/L) |
16 (11–28) |
17 (12–26) |
16 (11–29) |
0.839 |
15 (11–24) |
15 (11–23) |
14 (11–29) |
0.873 |
| Peak CK (IU/L) |
666
(200–2,179) |
350
(166–1,125) |
825
(232–2,246) |
0.003 |
459
(163–1,928) |
339
(168–899) |
727
(161–2,245) |
0.070 |
| Peak CK-MB (IU/L) |
59 (19–210) |
24 (15–124) |
71 (22–220) |
0.003 |
48 (15–171) |
27 (15–124) |
85 (16–182) |
0.094 |
| LVEF (%) |
61 (53–65) |
61 (53–65) |
61 (54–65) |
0.861 |
62 (54–67) |
62 (58–65) |
62 (52–67) |
0.875 |
Data are expressed as n (%) for categorical values, mean±standard deviation for normally distributed variables, or median (interquartile range) for non-normally distributed variables. ACS, acute coronary syndrome; ASA, aspirin; CABG, coronary artery bypass grafting; CK, creatine kinase; CRP, C reactive protein; DL, dyslipidemia; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; HT, hypertension; LAD, left anterior descending artery; LCX, left circumflex artery; LDL-C, low-density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; NSTEMI, non-ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; RCA, right coronary artery; STEMI, ST-elevation myocardial infarction; TnI, troponin-I; UAP, unstable angina; WBC, white blood cell.
The angiographic data are shown in
Table 2. In the entire cohort, there were no significant differences between the 2 groups in the quantitative coronary angiography (QCA) parameters. There was no significant difference in the prevalence of complex lesions and multivessel disease.
Table 2.
Angiographic Data of the ACS Patient With and Without Prior ASA Use
| |
Entire cohort (n=442) |
Matched cohort (n=98) |
Total
(n=442) |
ASA group
(n=67) |
Non-ASA
group (n=375) |
P value |
Total
(n=98) |
ASA group
(n=49) |
Non-ASA
group (n=49) |
P value |
| MLD (mm) |
0.62
(0.35–0.88) |
0.68
(0.42–0.94) |
0.64
(0.37–0.88) |
0.394 |
0.63
(0.25–0.84) |
0.61
(0.37–0.91) |
0.68
(0.06–0.83) |
0.994 |
| RD (mm) |
2.76
(2.39–3.21) |
2.80
(2.42–3.29) |
2.77
(2.43–3.21) |
0.508 |
2.75
(2.32–3.09) |
2.77
(2.40–3.10) |
2.75
(2.38–3.05) |
0.809 |
| DS (%) |
78.5
(68.8–89.1) |
76.2
(65.5–85.4) |
78.3
(69.1–88.8) |
0.191 |
78.3
(68.6–92.1) |
80.6
(67.3–85.8) |
74.8
(69.0–97.5) |
0.864 |
| Lesion length (mm) |
12.8
(10.1–16.5) |
13.9
(10.2–17.2) |
12.7
(10.3–16.5) |
0.316 |
12.8
(10.1–16.5) |
14.1
(11.4–18.1) |
11.8
(9.9–15.1) |
0.028 |
AHA lesion classification
type B2/C (n [%]) |
202 (45.7) |
27 (40.3) |
175 (46.7) |
0.336 |
48 (49.0) |
20 (40.8) |
28 (57.1) |
0.108 |
| TIMI flow grade om initial angiogram |
| 0 |
83 (18.8) |
6 (9.0) |
77 (20.5) |
0.138 |
17 (17.3) |
5 (10.2) |
12 (24.5) |
0.313 |
| 1 |
27 (6.1) |
4 (6.0) |
23 (6.1) |
5 (5.1) |
3 (6.1) |
2 (4.1) |
| 2 |
152 (34.4) |
24 (35.8) |
128 (34.1) |
30 (30.6) |
16 (32.7) |
14 (28.6) |
| 3 |
180 (40.7) |
33 (49.3) |
147 (39.2) |
46 (46.9) |
25 (51.0) |
21 (42.9) |
| MVD (n [%]) |
160 (36.2) |
28 (41.8) |
132 (35.2) |
0.302 |
43 (43.9) |
23 (46.9) |
20 (40.8) |
0.544 |
Data are expressed as n [%] for categorical values, mean±standard deviation for normally distributed variables, or median (interquartile range) for non-normally distributed variables. DS, diameter stenosis; MLD, minimal lumen diameter; MVD, multivessel disease; RD, reference diameter; TIMI, Thrombolysis in Myocardial Infarction. Other abbreviations as in Table 1.
OCT-defined thrombi were observed in 307 lesions (69.5%) in the entire cohort, which included 91 lesions (20.6%) demonstrating both red and white thrombus. OCT-defined thrombus, red thrombus, and white thrombus were significantly less frequently observed in the ASA group than in the non-ASA group of the entire cohort (Table 3). In addition, the measurements of the thrombus revealed significantly smaller volume, length, and maximum arc of the thrombus in the ASA group than in the non-ASA group. However, there was no significant difference in the morphological characteristics of plaques, including the presence of fibroatheroma, calcified plaque, thin-capped fibroatheroma, ruptured plaque, fibrous cap thickness, and lipid arc, between the 2 groups. Furthermore, the OCT findings were compared between the ASA and non-ASA groups in a subset of patients with MI from which patients with UAP were excluded, to focus on the patients with MI (Tables S1,S2). OCT-defined thrombus was observed in 290 of 378 patients with MI (76.7%). In line with the results for the entire cohort including patients with UAP, the ASA group showed less frequent OCT-defined thrombi (45.1% and 81.7%, P<0.001) and smaller thrombus volume [0.0 (0.0–0.5) mm3
and 0.85 (0.16–2.71) mm3, P<0.001] in the MI cohort (Table S2). Representative OCT images from the ASA and non-ASA groups are shown in
Figures 2
and
3, respectively.
Table 3.
OCT Findings of the ACS Patient With and Without Prior ASA Use
| |
Entire cohort (n=442) |
Matched cohort (n=98) |
| Total |
ASA
group |
Non-ASA
group |
P value |
Total |
ASA
group |
Non-ASA
group |
P value |
| n |
442 |
67 |
375 |
|
98 |
49 |
49 |
|
| Fibroatheroma (%) |
404 (91.4) |
60 (89.6) |
344 (91.7) |
0.635 |
89 (90.8) |
44 (89.8) |
45 (91.8) |
1.000 |
| Calcified plaque (%) |
49 (11.1) |
11 (16.4) |
38 (10.1) |
0.140 |
13 (13.3) |
8 (16.3) |
5 (10.2) |
0.553 |
| OCT-defined thrombus (%) |
307 (69.5) |
25 (37.3) |
282 (75.2) |
<0.001 |
56 (57.1) |
19 (38.8) |
37 (75.5) |
<0.001 |
| Red thrombus |
178 (40.3) |
16 (23.9) |
162 (43.2) |
0.003 |
29 (29.6) |
11 (22.4) |
18 (36.7) |
0.184 |
| White thrombus |
220 (49.8) |
16 (23.9) |
204 (54.4) |
<0.001 |
35 (35.7) |
11 (22.4) |
24 (49.0) |
0.011 |
| Floating thrombus (%) |
36 (8.1) |
3 (4.5) |
33 (8.8) |
0.332 |
3 (5.1) |
3 (6.1) |
2 (4.1) |
1.000 |
| Thrombus volume (mm3) |
0.4
(0.0–1.9) |
0.0
(0.0–0.4) |
0.6
(0.0–2.3) |
<0.001 |
0.1
(0.0–0.7) |
0.0
(0.0–0.4) |
0.3
(0–1.16) |
0.020 |
| Thrombus length (mm) |
2.2 (0.0–4.7) |
0.0 (0.0–2.4) |
2.6 (0–4.8) |
<0.001 |
0.4 (0.0–2.9) |
0.0 (0.0–2.5) |
1.8 (0.0–4.0) |
0.027 |
Maximum thrombus arc
(degrees) |
87 (0–128) |
0 (0–104) |
97 (0–131) |
<0.001 |
41 (0–120) |
0 (0–107) |
71 (0–122) |
0.024 |
| Ruptured plaque (%) |
177 (40.0) |
24 (35.8) |
153 (40.8) |
0.500 |
35 (35.7) |
16 (32.7) |
19 (38.8) |
0.674 |
| TCFA (%) |
218 (49.3) |
26 (38.8) |
192 (51.2) |
0.065 |
44 (44.9) |
20 (40.8) |
24 (49.0) |
0.543 |
| Fibrous cap thickness (μm) |
63 (57–93) |
80 (60–120) |
60 (60–90) |
0.255 |
70 (55–102) |
80 (50–130) |
60 (60–90) |
0.918 |
| Lipid length (mm) |
7.0
(5.0–11.0) |
8.5
(5.5–11.9) |
7.0
(5.0–10.5) |
0.391 |
8.5
(6.0–12.5) |
8.5
(5.5–12.0) |
8.0
(6.4–12.6) |
0.673 |
| Lipid quadrants |
3 (2–4) |
3 (2–4) |
3 (2–4) |
0.599 |
3 (2–4) |
3 (2–4) |
3 (2–4) |
0.918 |
| Maximum lipid arc (degrees) |
222
(174–275) |
221
(174–288) |
223
(183–272) |
0.873 |
219
(168–295) |
217
(173–268) |
238
(160–297) |
0.893 |
Data are expressed as n (%) for categorical values, mean±standard deviation for normally distributed variables, or median (interquartile range) for non-normally distributed variables. OCT, optical coherence tomography; TCFA, thin-capped fibroatheroma. Other abbreviations as in Table 1.
We performed propensity score matching to adjust for the significant differences between groups, and 49 patients in each group were matched. The patients’ characteristics, angiographic findings, and OCT findings for the matched cohort are shown in
Tables 1–3, respectively. In the matched cohort, there were no significant differences between the groups for the patients’ characteristics except for more frequent NSTE-ACS presentation and a history of prior PCI in the ASA group (Table 1). The angiographic data showed a significantly longer lesion length in the ASA group than in the non-ASA group, whereas no significant differences were observed for the other QCA parameters (Table 2). In the OCT analysis, the ASA group in the matched cohort showed less frequent intraluminal thrombi, specifically white thrombi, than the non-ASA group. However, the ASA and non-ASA groups did not differ in the presence of red thrombi. For plaque characteristics, there were no significant differences in the frequency of fibroatheroma, calcified plaque, ruptured plaque, and thin-capped fibroatheroma, or in the lipid component characterized by fibrous cap thickness, lipid length, and lipid arc, which was consistent with findings for the entire cohort (Table 3).
Clinical Outcomes
In the entire cohort, 30-day clinical events, including adverse complications and MACE, occurred in 86 patients (19.4%) (Table 4). The overall event rate was higher in the ASA group than in the non-ASA group and was mainly driven by congestive heart failure. In the matched cohort, the 30-day clinical event rate was not different for either adverse complications or MACE. As for bleeding, BARC type 3 bleeding was observed in 29 (6.6%) patients. There was no significant difference between the 2 groups in either the entire or matched cohorts. One patient in the non-ASA group died from fatal gastrointestinal bleeding.
Table 4.
Clinical Events Within 30 Days in the ACS Patient With and Without Prior ASA Use
| |
Entire cohort |
Matched cohort |
Total
(n=442) |
ASA group
(n=67) |
Non-ASA
group (n=375) |
P value |
Total
(n=98) |
ASA group
(n=49) |
Non-ASA
group (n=49) |
P value |
| Overall events (n [%]) |
86 (19.5) |
19 (28.4) |
67 (17.8) |
0.046 |
28 (28.6) |
12 (24.5) |
16 (32.7) |
0.374 |
| Cardiogenic shock |
45 (10.2) |
8 (11.9) |
37 (9.9) |
0.660 |
13 (13.3) |
5 (10.2) |
8 (16.3) |
0.374 |
| VT/VF |
18 (4.1) |
2 (3.0) |
16 (4.3) |
1.000 |
7 (7.1) |
2 (4.1) |
5 (10.2) |
0.242 |
| CHF |
71 (16.1) |
17 (25.4) |
54 (14.4) |
0.024 |
21 (21.4) |
10 (20.4) |
11 (22.4) |
0.807 |
| Cardiovascular death |
2 (0.5) |
0 (0.0) |
2 (0.5) |
0.550 |
1 (1.0) |
0 (0.0) |
1 (2.0) |
1.000 |
| TLR |
0 (0.0) |
0 (0.0) |
0 (0.0) |
1.000 |
0 (0.0) |
0 (0.0) |
0 (0.0) |
1.000 |
| New onset of MI |
0 (0.0) |
0 (0.0) |
0 (0.0) |
1.000 |
0 (0.0) |
0 (0.0) |
0 (0.0) |
1.000 |
| Total bleeding (n [%]) |
29 (6.6) |
4 (6.0) |
25 (6.7) |
1.000 |
9 (9.2) |
4 (8.2) |
5 (10.2) |
1.000 |
| BARC type 3 |
28 (6.3) |
4 (6.0) |
24 (6.4) |
1.000 |
9 (9.2) |
4 (8.2) |
5 (10.2) |
1.000 |
| BARC type 5 |
1 (0.2) |
0 (0.0) |
1 (0.3) |
1.000 |
0 (0.0) |
0 (0.0) |
0 (0.0) |
1.000 |
Data are expressed as n [%]. BARC, Bleeding Academic Research Consortium; CHF, congestive heart failure; MI, myocardial infarction; TLR, target lesion revascularization; VF, ventricular fibrillation; VT, ventricular tachycardia. Other abbreviations as in Table 1.
Discussion
The major findings of the present study are as follows: (1) patients with prior ASA use at first presentation of ACS tended to have less frequent thrombi at the culprit lesion on OCT compared with those without ASA use, whereas no significant trend was observed in underlying plaque characteristics; (2) the presentation of STEMI was less frequent in patients with prior ASA use; and (3) adverse clinical events driven by congestive heart failure 30 days from presentation were significantly more frequent in the entire cohort of patients with prior ASA than in those without prior ASA use, but these rates did not differ after propensity score matching.
OCT Findings
The antiplatelet action of low-dose ASA is characterized by an irreversible inactivation of cyclooxygenase (COX) activity of prostaglandin H synthase 1, which consequently inhibits platelet aggregation.21
In addition, previous studies have indicated the protective effect of ASA on endothelial function and endothelial injury associated with oxidative stress.22–24
However, little has been demonstrated in vivo regarding the effect of preceding ASA use on local thrombosis and atherosclerosis within the coronary artery in the setting of ACS. In the entire cohort in the present study, any type of intraluminal thrombus was detected less frequently in the ASA group than in the non-ASA group (37.3% vs. 75.2%) and this difference remained after propensity score matching (38.8% vs. 75.5%) (Table 3). The frequency of intraluminal thrombus was lower in the present cohort as compared with previous histopathological and intracoronary imaging studies.25,26
This discrepancy may be potentially attributed to the higher prevalence of NSTEMI and UAP in the present cohort. These patients, if they do not have high-risk features, tended to receive conservative therapy with anti-angina and anticoagulation agents preceding invasive catheterization, which may have dissolved the intraluminal thrombus before OCT imaging. Other potential mechanisms of the lack of intraluminal thrombus on OCT may be tight stenosis or coronary spasm, which can cause myocardial ischemia or damage without thrombus formation. After propensity score matching, the frequency of red thrombi did not statistically differ between the 2 groups, whereas a significant difference was observed regarding white thrombi (Table 3). Coronary thrombosis is triggered by vascular injury, such as the rupture or endothelial erosion of atherosclerotic plaques, releasing multiple thrombogenic factors that initiate the substrates for the production of a platelet-rich thrombus, visually recognized as a white thrombus.1
Thereafter, activated platelets initiate coagulation cascades that lead to the production of a fibrin-rich thrombus, recognized as a red thrombus. Because ASA predominantly inhibits platelet aggregation and activation rather than downregulating the coagulation cascade, the effect of ASA on fibrin-rich thrombus is attenuated compared with platelet-rich thrombus. As for plaque characteristics, the present study did not detect any differences in OCT-derived plaque morphology, such as lipid arc, lipid length, fibrous cap thickness, and the presence of fibroatheroma or thin-cap fibroatheroma, in either the entire or propensity score-matched cohorts. The ASA group in the present study consisted of patients who failed primary prevention of ACS with ASA use; therefore, more severe and advanced plaque characteristics would be expected, but were not observed in our results. The OCT findings in the present study depicted the potential effect of ASA on the substrate of thrombus formation at the time of ACS onset, rather than modification of plaque characteristics through primary prevention.
Clinical Presentation
In the present study, patients with prior ASA use tended to present predominantly with NSTE-ACS rather than STEMI compared with those without prior ASA use, which is consistent with previous studies.6,27,28
In a retrospective analysis of an integrated database of TIMI trials, ACS patients with prior ASA use were older and had more coronary risk factors and a history of coronary interventions than non-ASA users, and notably, non-ST-elevation ACS was more frequent in ASA users.6
Despite promising data, a reasonable explanation and pathogenesis for the predominant NSTE-ACS presentation in ASA users has not been provided. Our study demonstrated potential inhibition of thrombus formation by prior ASA use as discussed, which may influence the clinical presentation. ACS occurrence is based on a systemic susceptibility to thrombosis accompanied by a focal manifestation within a coronary artery such as plaque rupture.29
It is possible that prior ASA use may not have a significant effect on the progression of atherosclerosis; however, it does have an effect on the final trigger of coronary thrombosis – the formation of a platelet-rich thrombus.
Clinical Outcomes
There is no controversy regarding the usefulness of ASA for the treatment of ACS patients. By contrast, worse clinical outcomes in prior ASA users have been controversial and recognized as a paradox of ASA. TIMI risk score for NSTE-ACS is a widely accepted measure for risk stratification in ACS patients, including prior ASA use as a predictor for MACE at 14 days. However, this score was derived from integrated data of large clinical trials conducted in the 1990 s when a conservative strategy was the mainstream treatment for NSTE-ACS.11
In fact, those studies analyzed the rate of death, Q-wave MI, and urgent revascularization as consequences of a non-invasive strategy after admission, which is not a common contemporary therapeutic strategy for NSTE-ACS. Conflicting data also show a lower mortality rate in those with prior ASA use,27,28
which is why this topic has been long debated. Brener et al12
reported the effect of prior ASA treatment on 3-year MACE using a modern strategy with intravascular ultrasound-guided PCI for ACS patients from the post-hoc analysis of the PROSPECT study. They reported that patients with prior ASA use had more coronary risk factors and a higher non-culprit revascularization rate at 3 years. However, for overall MACE, the unadjusted and propensity-score adjusted analyses showed no significant differences between the ASA pretreated and non-treated group. Consistent with that previous study, our entire cohort demonstrated more frequent congestive heart failure in the ASA group than in the non-ASA group at 30 days; however, the MACE rate was not different between the 2 groups. In the entire cohort, because of more high-risk features and older age, the ASA group had more frequent heart failure, but this did not lead to MACE. When we adjusted our results with propensity score matching by multiple confounders, no significant difference was observed in clinical outcomes, even for heart failure. Based on the results of the present study and previous study, we suggest that prior ASA use may represent an accumulation of high-risk features that are potentially relevant to non-fatal adverse outcomes after invasive strategies; however, prior ASA use itself does not independently affect the subsequent MACE rate, at least in the contemporary standard of care for ACS patients.
Study Limitations
This was a retrospective analysis at a single center, so a selection bias may exist. This study comprised patients who underwent OCT examination at the time of PCI of culprit lesions. Because of the exclusion criteria for OCT imaging, patients with potentially fatal conditions, such as cardiogenic shock, severe heart failure at the presentation, or left main disease, were excluded, which may also lead to selection bias. In the setting of ACS, intraluminal thrombus, specifically red thrombus, precludes visualization of underlying plaque morphology such as plaque rupture and thin-capped fibroatheroma. Therefore, some OCT findings may have been underestimated. In addition, thrombectomy preceded OCT imaging for lesions showing TIMI 0–2 flow grade on initial angiogram, which may have modified the underlying plaque morphology before OCT imaging. The present study did not consider ASA dosage, duration, or resistance, which may influence the results.
Conclusions
OCT detected less frequent thrombi at the culprit lesion in patients taking ASA before their first presentation with ACS than in those without prior ASA use, which may represent a potential modification of coronary thrombosis by prior use of ASA as a trigger for ACS. Although the clinical implications of ASA for primary prevention remain controversial, the present results provide additional understanding of the preventive effect of ASA in a specific spectrum of patients in whom the thrombotic risk exceeds the bleeding risk.
Supplementary Files
Supplementary File 1
Table S1.
Characteristics of the ACS patients in the myocardial infarction cohort
Table S2.
Optical coherence tomography findings in the myocardial infarction cohort of ACS patients
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-16-0957
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