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Dual versus Single Antiplatelet Therapy in Carotid Artery Endarterectomy: Direct Comparison of Complications Related to Antiplatelet Therapy
Journal Pre-proof Dual versus single Antiplatelet Therapy in Carotid Artery Endarterectomy: Direct Comparison of Complications Related to Antiplatelet Therapy Qun-long Jiang, M.D, Pei-jian Wang, M.D, Hui-xin Liu, M.D, Li-li Huang, M.D, Xiao-kui Kang, M.D PII:
S1878-8750(19)33099-2
DOI:
https://doi.org/10.1016/j.wneu.2019.12.070
Reference:
WNEU 13917
To appear in:
World Neurosurgery
Received Date: 25 September 2019 Revised Date:
11 December 2019
Accepted Date: 12 December 2019
Please cite this article as: Jiang Q-l, Wang P-j, Liu H-x, Huang L-l, Kang X-k, Dual versus single Antiplatelet Therapy in Carotid Artery Endarterectomy: Direct Comparison of Complications Related to Antiplatelet Therapy, World Neurosurgery (2020), doi: https://doi.org/10.1016/j.wneu.2019.12.070. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Title Page Dual versus single Antiplatelet Therapy in Carotid Artery Endarterectomy: Direct Comparison of Complications Related to Antiplatelet Therapy
Qun-long Jiang# M.D., Email: [email protected]; Department of Neurosurgery, Liaocheng people’s hospital, Liaocheng, Shandong, R.P. China, 252000. Pei-jian Wang# M.D., Email: [email protected]; Department of Neurosurgery, Liaocheng people’s hospital, Liaocheng, Shandong, R.P. China, 252000. Hui-xin Liu M.D., Email: [email protected]; Department of Medical Examination, Liaocheng people’s hospital, Liaocheng, Shandong, R.P. China, 252000. Li-li Huang M.D., Email: [email protected]; Department of Endocrinology, Liaocheng people’s hospital, Liaocheng, Shandong, R.P. China, 252000. corresponding author Xiao-kui Kang* M.D., Email: [email protected]; Tel:086-18963562676; Fax: 086 -02260362062, Department of Neurosurgery, Liaocheng people’s hospital, Liaocheng, Shandong, R.P. China, 252000. # These authors contributed equally to this work and should be considered co-first authors.
1
Dual versus Single Antiplatelet Therapy in Carotid Artery Endarterectomy:
2
Direct Comparison of Complications Related to Antiplatelet Therapy
3
Abstract
4
Background: Dual and single antiplatelet therapies are routinely used in carotid
5
artery endarterectomy (CEA). However, the efficacy and safety of these therapies are
6
controversial. The present study aimed to comprehensively compare the clinical
7
outcomes between dual and single antiplatelet therapies in CEA.
8
Method: This study retrieved available academic studies evaluating the complications
9
related to antiplatelet therapy between dual and single antiplatelet therapies in CEA
10
from the databases of ScienceDirect, the Cochrane Library, EMBASE, and PubMed.
11
References to previous reviews and related clinical trials were manually checked to
12
retrieve potential literature that was not included in our electronic search results.
13
Results: A total of ten articles (1 RCT, 9 non-RCT) were included in the study. The
14
overall number of patients in the dual antiplatelet group was 14280, whereas the
15
number of patients in the single antiplatelet group was 125850. The results revealed
16
that the single antiplatelet group had a lower incidence of thirty-day death (RD, 0.002;
17
95% CI, 0.000 to 0.003; P=0.014), neck haematoma (OR=2.120, 95% CI (1.431,
18
3.142), P<0.001), myocardial infarction (RD= 0.004, 95% CI (0.001, 0.007), P =
19
0.003), and major bleeding (RD=0.005, 95% CI (0.002, 0.008), P<0.001). Meanwhile,
20
the single antiplatelet group was associated with a shorter operation time
21
(WMD=4.000, 95% CI= 2.564 to 5.436, P<0.001). However, there was no significant
22
difference in the rate of postoperative transient ischaemic attack (P= 0.215), stroke
23
(P= 0.130), and length of stay (P= 0.563).
24
Conclusions: Based on current evidence, using single antiplatelet therapy in CEA
25
may reduce operation time and the incidences of thirty-day death, neck haematoma,
26
major bleeding, and myocardial infarction without increasing the risks of transient
27
ischaemic attack, stroke, and a longer operation time.
28 29 30
Keywords: Antiplatelet therapy; Carotid endarterectomy; Meta-analysis.
31
Introduction
32
Carotid stenosis (CS) has been recognized as the archcriminal of ischaemic strokes
33
and transient ischaemic attacks, accounting for approximately 20% of cases.[1]
34
Carotid endarterectomy (CEA) has been regarded as the standard treatment for CS [2,
35
3] After the first stroke, early adoption of antiplatelet therapy seems to be significantly
36
effective in reducing the occurrence rate, which is estimated at 5% within 48 hours
37
and 10% within 2 weeks.[4-8] However, there appears to be ongoing controversy
38
regarding the use of dual or single antiplatelet therapy. Although aspirin therapy has
39
been estimated to reduce thromboembolism risk by 20% to 25%,[9], Hayes et al.[10]
40
conducted a prospective trial involving 120 patients who underwent CEA and
41
illustrated that embolization was irrelevant to the ability of aspirin to inhibit platelet
42
aggregation. Furthermore, several studies have demonstrated an increased potential
43
for postoperative bleeding and transfusion requirements among clopidogrel-treated
44
patients.[11, 12] Recently, many researchers have shown that using dual antiplatelet
45
therapy in CEA is related to a lower incidence of restenosis[13], haemorrhagic
46
complications, and perioperative stroke.[14-16] Nevertheless, some scholars question
47
the merits of dual antiplatelet therapy, which has demonstrated increased mortality,
48
higher bleeding rates, prolonged surgical time or wound haematomas during CEA.[17,
49
18] The purpose of the present study was to conduct a comprehensive literature
50
review to assess the safety and efficiency between dual and single antiplatelet
51
therapies in patients undergoing CEA.
52 53
Materials and methods
54
Our study was performed according to the guidelines of the Preferred Reporting Items
55
for Systematic Reviews and Meta-Analyses (PRISMA).[19]
56 57
Data sources and searches
58
The online databases of the Cochrane Library, (1966-2019.6), ScienceDirect
59
(1985-2019.6), EMBASE (1980-2019.6), and PubMed (1966-2019.6) were searched
60
for all studies evaluating the complications related to antiplatelet therapy between
61
dual and single antiplatelet therapies in CEA. The following keyword search terms
62
were used in these databases: carotid endarterectomy OR CEA, antiplatelet OR
63
aspirin OR clopidogrel. Beyond that, all references to previous reviews and related
64
clinical trials were manually checked to find potential publications that were not
65
included in our electronic search results.
66 67
Inclusion and exclusion criteria
68
The studies were included in our meta-analysis if the literature met the following
69
criteria based on PICOS framework: (I) Population: limited to the participants
70
undergoing CEA; (II) Intervention: strictly used dual and single antiplatelet therapies;
71
(III) Comparison: evaluated the clinical outcomes about reducing complications
72
related to antiplatelet therapy; (IV) Outcome measures: eight outcomes including
73
death, neck haematoma, major bleeding, myocardial infarction, transient ischaemic
74
attack, stroke, length of stay, and operation time were compared in the present study;
75
and (V) an official published full-length article written in English.
76
The exclusion criteria of our study were as follows: (I) conference or commentary
77
literature, case reports, reviews, letters, and meta-analyses; (II) studies not associated
78
with humans, such as animal experiments; and (III) unclear or unavailable outcome
79
data.
80 81
Data extraction and outcome measures
82
Three authors independently extracted data by using a pre-planned, standardized data
83
extraction form, with disagreements resolved by consensus or by the third author
84
when there were different opinions. The following characteristics were extracted for
85
each included article: the first author’s name, publication year, recruitment period,
86
number of samples, study design, study outcomes and other relevant data. The
87
extracted data (range, median, mean difference and standard deviation) were inserted
88
into the data extraction form. The measurements of each outcome were thirty-day
89
death, neck haematoma, major bleeding, myocardial infarction, transient ischaemic
90
attack, stroke, length of stay, and operation time.
91 92
Statistical analysis
93
STATA version 11.0 (Stata Corporation, College Station, Texas, USA) was applied for
94
our statistical analyses. The weighted mean difference (WMD) with 95% confidence
95
intervals (CIs) for the continuous outcomes (operation duration and length of stay in
96
hospital) was calculated. For discontinuous outcomes (stroke, transient ischaemic
97
attack, myocardial infarction, major bleeding, neck haematoma, and thirty-day death),
98
the odds ratio (OR) or rate difference (RD) with 95% CIs was used for the evaluation.
99
The I2 test was performed to estimate heterogeneity. Heterogeneity was considered
100
obvious when I2>50%, and we conducted our meta-analysis using the random-effects
101
model. Otherwise, the fixed-effects model was performed.
102 103
Results
104
Search results
105
A total of 2301 studies were identified by searching four electronic databases. After
106
removing duplicates, we reviewed the titles and abstracts of 536 articles, and 509
107
publications were removed based on the pre-planned inclusion and exclusion criteria.
108
Seventeen publications were excluded after screening the full content of the articles.
109
Finally, ten articles satisfied the selection criteria and were accepted into the
110
qualitative analyses. More details regarding the search process are shown in Figure 1.
111 112
Quality assessment
113
An evaluation of the quality of the literature was performed separately by the two
114
reviewers. When there were different opinions between the two reviewers, another
115
author was involved until disagreements were resolved by consensus. There was only
116
one randomized controlled trial (RCT), which was of high quality with a Jadad score
117
of 5. All non-randomized controlled trials (non-RCTs) were evaluated by the
118
Newcastle-Ottawa Scale (NOS), and most of the included literature was of high
119
quality. The study scores of all articles are shown in Table 1.
120
121
Study characteristics
122
A total of ten studies (1 RCT[20], 9 non-RCTs[21-29]) were included in this study.
123
The overall number of participants in the dual antiplatelet group was 14280, whereas
124
the number of participants in the single antiplatelet group was 125850. Details about
125
the study type of the involved studies and demographic characteristics are shown in
126
Table 2. Baseline characteristics were statistically similar between the two groups,
127
and the sample size varied from 44 to 103417 participants. The studies were from the
128
UK, New England, Germany, Israel, the USA, Lebanon, and Italy. More details are
129
shown in Table 2. The methods of antiplatelet therapy in CEA between the two groups
130
are shown in Table 3.
131 132
Outcomes of the meta-analysis
133
The following eight outcomes were assessed in our meta-analysis: thirty-day death,
134
neck haematoma, major bleeding, myocardial infarction, transient ischaemic attack,
135
stroke, length of stay, and operation time (Table 4).
136 137
Thirty-day death
138
Data on 30-day mortality were provided by six studies. In the single antiplatelet group
139
(120201 participants), the incidence of thirty-day mortality was 0.48%. In the dual
140
antiplatelet group (13237 participants), the incidence of thirty-day mortality was
141
0.52%, with a statistically significant difference (RD, 0.002; 95% CI, 0.000 to 0.003;
142
P=0.014, Figure 2). No significant heterogeneity among the studies was identified
143
(I2=23.4%, p=0.258).
144 145
Neck haematoma
146
Seven studies reported the number of neck haematomas. The results showed that there
147
were 815 cases in the dual antiplatelet group and 2536 cases in the single antiplatelet
148
group. No significant heterogeneity was identified (I2 = 31.8%, P=0.185), and a
149
fixed-effects model was conducted. The cross-sectional data from various studies
150
were plotted and showed that the rate of neck haematoma was statistically higher in
151
the dual antiplatelet group than that of the single antiplatelet group (OR, 2.120; 95%
152
CI, 1.431 to 3.142; P<0.001, Figure 3).
153 154
Major bleeding
155
Eight studies focused on the major bleeding rates. We used the fixed-effects model
156
because no significant heterogeneity was observed (I2 = 0%, P=0.754), and the results
157
showed that there was a significant difference between the two groups. The
158
cross-sectional data from various studies were plotted and demonstrated the single
159
antiplatelet therapy could reduce the rate of major bleeding compared to dual
160
antiplatelet therapy (RD, 0.005; 95% CI, 0.002 to 0.008; P<0.001; Figure 4).
161 162
Transient ischaemic attack
163
Five publications mentioned the number of transient ischaemic attacks, and the data
164
pooled by a fixed-effects model demonstrated that there was no significant difference
165
between the treatment groups (RD, -0.002; 95% CI, -0.005 to -0.001; P= 0.215;
166
Figure 5).
167 168
Myocardial infarction
169
Five studies mentioned the numbers of myocardial infarction in patients. No evidence
170
of between-study heterogeneity was found, and a fixed-effects model was used
171
(P=0.418, I2＝0.0%). The cross-sectional data from various studies were plotted and
172
revealed that single antiplatelet therapy was associated with a statistically lower rate
173
of myocardial infarction compared to the dual antiplatelet group (RD, 0.004; 95% CI,
174
0.001 to 0.007; P = 0.003; Figure 6).
175 176
Stroke
177
Eight articles reported the number of strokes, and the data pooled by a fixed-effects
178
model demonstrated that no significant difference was found between the treatment
179
groups (RD, -0.001; 95% CI, -0.003 to 0.000; P= 0.130; Figure 7).
180
181
Operation duration
182
Data on the operation time were reported by the three studies involving 1489
183
participants. Of these 1489 patients who underwent CEA, 308 were assigned to the
184
dual antiplatelet group, and 1181 were assigned to the single antiplatelet group.
185
Meanwhile, no evidence of between-study heterogeneity was observed, and the data
186
were pooled using a fixed-effects model to reveal that dual antiplatelet therapy was
187
related to a longer operation time compared to single antiplatelet therapy (WMD,
188
4.000; 95% CI, 2.564 to 5.436; P<0.001, Figure 8).
189 190
Length of stay
191
Three articles provided the length of stay, and the data pooled by a fixed-effects
192
model revealed that there was no significant difference between the two groups
193
(WMD, 0.053, 95% CI, -0.127 to 0.233; P= 0.563; Figure 9).
194 195
Discussion
196
Currently, carotid atherosclerosis is an essential risk factor for transient ischaemic
197
attack and ischaemic stroke.[30] CEA has been the gold standard therapy for
198
extracranial atherosclerotic carotid disease,[31] and the beneficial effect of antiplatelet
199
therapy has been revealed for the perioperative risk of stroke reduction for individuals
200
undergoing CEA. In addition, antiplatelet therapy contributes to reducing the rate of
201
thromboembolic events, a cause of major bleeding that is significantly increased with
202
more intensive regimens.[29, 32, 33] Although dual and single antiplatelet therapies
203
are routinely used in CEA, their efficacy and safety are controversial.
204
Antiplatelet regimen in carotid intervention has been studied before.[34, 35] It
205
lowers the risk of perioperative stroke by reducing vascular occlusion events. Besides,
206
it protects the coronary artery from complications while taking carotid intervention or
207
subsequently. What to concern is that antiplatelet therapy may bring about major
208
bleeding, the chance of which may go serious as the use of high dose. In our study,
209
the purpose was to systematically compare the clinical outcomes between dual and
210
single antiplatelet therapies in CEA. The results revealed that, compared to the dual
211
antiplatelet group, the single antiplatelet group was associated with a shorter operation
212
time and a lower incidence of 30-day death, neck haematoma, myocardial infarction,
213
and major bleeding; however, there was no significant difference in the rates of
214
postoperative transient ischaemic attack, stroke, and length of stay.
215
Hale et al[36], in a retrospective comparative study of 1472 patients treated with
216
CEA, revealed that the dual antiplatelet strategy was independently associated with
217
five-fold rates of postoperative bleeding compared to antiplatelet therapy (OR, 5.1; 95%
218
CI 1.8-14.2; p<0.002). Jones et al[37] reported that patients on dual antiplatelet
219
therapy were more likely to require reoperation for bleeding than patients on single
220
antiplatelet therapy (1.3% vs 0.7%; P ＜ 0.004). Similarly, our meta-analysis
221
demonstrated that the rates of major bleeding were significantly higher in the dual
222
antiplatelet group than the single antiplatelet group (RD, 0.005; 95% CI, 0.002 to
223
0.008; P<0.001). Single antiplatelet therapy could reduce neck haematoma rates
224
compared to dual antiplatelet therapy in patients with CEA (OR, 2.120; 95% CI 1.431
225
to 3.142; P<0.001). This result is also supported by a published meta-analysis and
226
reveals that a significantly higher risk of neck haematomas was found in dual
227
antiplatelet therapy (95% CI, 0.01-0.06; P=0.001). Dual antiplatelets could obviously
228
inhibit platelet aggregation to influence effective blood clotting, which was a possible
229
explanation for the result.
230
We revealed that in the dual antiplatelet group, the rate of 30-day death was 0.52%,
231
with the difference being significant. This finding was consistent with a study by
232
Zimmermann et al[38] that demonstrated that dual antiplatelet therapy was associated
233
with a significantly decreased all-cause mortality compared with aspirin alone (RR,
234
0.67; 95% CI, 0.51-0.88; P=0.004), which seems to stem from the higher rates of
235
major bleeding. Based on the previously published meta-analysis of carotid
236
interventions, there was no significant difference in stroke rates between the dual and
237
single antiplatelet strategies.[31] Although Barkat et al.[31] found that symptomatic
238
patients accepting dual therapy had decreased rates of transient ischaemic attack or
239
stroke (1.4% dual therapy vs. 1.7% aspirin alone), composite stroke/death (1.2% dual
240
therapy vs. 1.5% aspirin alone), and any stroke (1.1% dual therapy vs. 1.2% aspirin
241
alone), the differences were not statistically significant. In the MATCH trial[39], there
242
was no difference in reducing stroke rates between the dual and single antiplatelet
243
groups. Meanwhile, no significant difference was shown in the rates of stroke
244
between the two treatment groups (RD, -0.001; 95% CI, -0.003 to 0.000; P=0.130). In
245
addition, we demonstrated that dual antiplatelet therapy could reduce the rates of
246
myocardial infarction compared to single antiplatelet therapy.
247
Chechik et al.[22] demonstrated that operation time was significantly longer
248
among patients treated with dual antiplatelet therapy (205 ± 52 minutes on combined
249
treatment versus 165 ± 33 minutes on clopidogrel alone). Similarly, our results
250
revealed that the dual antiplatelet group was related to a longer operation time
251
compared to the single antiplatelet group (WMD=4.000, 95% CI= 2.564 to 5.436,
252
P<0.001). Payne et al.[40] also revealed that the time from blood flow restoration to
253
skin closure was significantly longer in patients treated with dual antiplatelet therapy
254
(P=0.04). Zimmermann et al.[38] illustrated that dual antiplatelet method significantly
255
increased the secondary bleeding rates requiring reoperation. We speculated that these
256
factors cause a longer operation time in patients treated with dual antiplatelet therapy.
257
However, no significant difference was found between the two groups for the length
258
of stay in our study (WMD, 0.053; 95% CI, -0.127 to 0.233; P= 0.563), which is
259
similar to the study by Saadeh et al.[41],who demonstrated that the mean hospital
260
lengths of stay were not significantly different between the two groups.
261
Barkat et al.[31] recently published a meta-analysis comparing the dual with
262
single antiplatelet therapy for carotid interventions (CEA or CAS). The single
263
antiplatelet therapy was relevant to a reduced risk of bleeding complications in
264
patients undergoing CEA. However, it shows disadvantages over the dual antiplatelet
265
therapy in CAS, as indicated by an increased risk of transient ischaemic attack.
266
Differently, our results also demonstrate using single antiplatelet in CEA could reduce
267
operation time and the incidence of neck hematoma without increasing the risk of
268
stroke, and longer length of operation duration. Furthermore, our sample size is larger
269
and the comparison results are richer. The following limitations of this study should
270
be noted. First, the present study only compares perioperative clinical outcomes
271
relevant to the safety and efficiency of two kinds of antiplatelet therapy due to
272
relatively little data on these outcomes with the same long-term follow-up period.
273
Meanwhile, for the subgroup analysis, we could not divide the participants into
274
symptomatic and asymptomatic groups due to relatively little reported data.
275
Furthermore, the main inclusion and exclusion criteria of the trials and interventions
276
of antiplatelet therapy are not identical in the included studies, which may cause
277
potential bias.
278 279
Conclusion
280
Based on current evidence, using single antiplatelet therapy in CEA may reduce
281
operation time and the incidences of thirty-day death, neck haematoma, major
282
bleeding, and myocardial infarction without increasing the risks of transient ischaemic
283
attack, stroke, and a longer operation time.
284 285
Competing interests
286
The authors declare that they have no competing interests.
287 288
Acknowledgment
289
None
290 291
Funding
292
None
293 294
Abbreviations
295
PRISMA= Preferred Reporting Items for Systematic Reviews and Meta-Analyses,
296
NOS=Newcastle-Ottawa Scale, CEA=carotid endarterectomy, WMD=weighted mean
297
difference, CIs=confidence intervals, RDs=rate differences, ORs=odds ratios,
298
non-RCTs =non-randomized controlled trials, RCTs=randomized controlled trials;
299
CS= Carotid stenosis.
300 301
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28.
Stone DH, Goodney PP, Schanzer A et al. Clopidogrel is not associated with major bleeding complications during peripheral arterial surgery. Journal of vascular surgery 54(3), 779-784 (2011).
29.
Zimmermann A, Knappich C, Tsantilas P et al. Different perioperative antiplatelet therapies for patients treated with carotid endarterectomy in routine practice. Journal of vascular surgery 68(6), 1753-1763 (2018).
30.
Petty GW, Brown RD, Whisnant JP et al. Ischemic stroke subtypes: a population-based study of incidence and risk factors. Stroke 30(12), 2513-2516 (1999).
31.
Barkat M, Hajibandeh S, Hajibandeh S, Torella F, Antoniou GA. Systematic Review and Meta-analysis of Dual Versus Single Antiplatelet Therapy in Carotid Interventions. European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery 53(1), 53-67 (2017).
32.
Baigent C, Blackwell L, Collins R et al. Aspirin in the primary and secondary prevention of
387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415
vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet (London, England) 373(9678), 1849-1860 (2009). 33.
Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ (Clinical research ed.) 324(7329), 71-86 (2002).
34.
Kretschmer G, Pratschner T, Prager M et al. Antiplatelet treatment prolongs survival after carotid bifurcation endarterectomy. Analysis of the clinical series followed by a controlled trial. Annals of surgery 211(3), 317-322 (1990).
35.
Lindblad B, Persson NH, Takolander R, Bergqvist D. Does low-dose acetylsalicylic acid prevent stroke after carotid surgery? A double-blind, placebo-controlled randomized trial. Stroke 24(8), 1125-1128 (1993).
36.
B. Hale, W. Pan, T. S. Misselbeck, V. V. Lee, J. J. Livesay. Combined clopidogrel and aspirin therapy in patients undergoing carotid endarterectomy is associated with an increased risk of postoperative bleeding. Vascular 21(4), 197-204 (2013).
37.
D. W. Jones, P. P. Goodney, M. F. Conrad et al. Dual antiplatelet therapy reduces stroke but increases bleeding at the time of carotid endarterectomy. J Vasc Surg 63(5), 1262-1270 e1263 (2016).
38.
A. Zimmermann, C. Knappich, P. Tsantilas et al. Different perioperative antiplatelet therapies for patients treated with carotid endarterectomy in routine practice. J Vasc Surg 68(6), 1753-1763 (2018).
39.
Hans-Christoph Diener, Julien Bogousslavsky, Lawrence M. Brass et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. The Lancet 364(9431), 331-337 (2004).
40.
D. A. Payne, C. I. Jones, P. D. Hayes et al. Beneficial effects of clopidogrel combined with aspirin in reducing cerebral emboli in patients undergoing carotid endarterectomy. Circulation 109(12), 1476-1481 (2004).
41.
C. Saadeh, J. Sfeir. Discontinuation of preoperative clopidogrel is unnecessary in peripheral arterial surgery. J Vasc Surg 58(6), 1586-1592 (2013).
416 417
Figure & Table legends
418
Figure1: Flowchart of the study selection process.
419
Figure2: Forest plot on the assessment of the 30-days death.
420
Figure3: Forest plot on the assessment of the neck hematoma.
421
Figure4: Forest plot on the assessment of the major bleeding.
422
Figure5: Forest plot on the assessment of the myocardial infarction.
423
Figure6: Forest plot on the assessment of the transient ischemic attack.
424
Figure7: Forest plot on the assessment of the stroke.
425
Figure8: Forest plot on the assessment of the operation time.
426
Figure9: Forest plot on the assessment of the length of stay.
427
Table1: The quality assessment score of the included studies.
428
Table2: The Characteristics of Trials.
429
Table3: The intervention of antiplatelet therapy and eligibility criteria in the included
430
studies.
431
Table4: The Meta-analysis results.
Table 1. Quality assessment scores of the included studies. Study, year
Payne et al.2004
Design
randomized controlled trial
Jadad scale Randomization
Blinding
Cohort
Total Scores
2
2
1
5
NOS Selection
Comparability
Exposure
Total Scores
Stone et al. 2011
Registry
3
1
2
6
Oldag et al. 2012
Registry
3
2
3
8
Chechik et al. 2012
Retrospective cohort study
3
2
3
8
Hale et al. 2013
Retrospective cohort study
4
2
3
9
Comparative
4
1
3
8
Saadeh et al. 2013 Jones et al. 2016
Retrospective cohort study
4
2
3
9
Miguel et al. 2016
Retrospective cohort study
3
1
3
7
Prospective
3
1
2
6
Retrospective cohort study
3
2
3
8
Illuminati et al. 2017 Zimmermann et al.2018
Note: NOS= Newcastle-Ottawa scale.
Table 2. Overview of Included Studies. Author
Country
Years
Type of Study
Recruitment
Participants (n)
Gender (M)
period
Dual
Single
Dual
Single
Dual
Single
Payne et al. Stone et al. Oldag et al. Chechik et al. Hale et al. Saadeh et al. Jones et al. Miguel et al. Illuminati et al. Zimmermann et al.
UK
2004
RCT
2000-2001
46
54
78%
74%
68±8.9
69±8.5
New England
2011
Registry
2003-2009
708
3970
NA
NA
NA
NA
Germany
2012
Registry
1995-2010
112
572
NA
NA
NA
NA
Israe
2012
RCS
2007-2010
16
91
81%
70.4%
69±9
NA
USA
2013
RCS
1998-2005
315
639
63%
60%
69.9±9.7
70.5±9.4
Lebanon
2013
Comparative
2005-2012
104
73
73.2%
76.5%
69±8.6
68±9.7
USA
2016
RCS
2003-2014
7059
21624
63.2%
59.5%
69.6±9.4
70.4±9.1
Germany
2016
RCS
2010-2013
35
9
71.4%
77.8%
71.3±6.6
70.7±12.3
Italy
2017
prospective
2005-2015
188
1098
68%
NA
78
NA
Germany
2018
RCS
2009-2014
5697
97720
72.3%
67.6%
70.2±9.3
70.7±9.0
Note. NA= not available; RCT= randomized controlled trial; RCS= Retrospective comparative study; M= male.
Age (mean ± standard)
Table 3. Intervention of antiplatelet therapy and eligibility criteria in the included studies Author
Inclusion criteria
Exclusion criteria
Antiplatelet therapy Single Antiplatelet
Payne et al.
Stone et al. Oldag et al.
(1) High-grade stenosis >70%.
Not available.
(1) >50% stenosis.
(1) Aspirin intolerance, (2) Absence of a transcranial window for TCD monitoring, (1)150 mg aspirin for 4 weeks (3) Emergency CEA, prior to surgery. (4) Patients already on warfarin, dipyridamole, or (2) placebo 12 h before operation. clopidogrel therapy, (5) Vein bypass performed instead of CEA. (6) CEA performed under local anesthesia. Not available. (1) Patient on other antithrombotic
Dual Antiplatelet
(1) 150 mg aspirin for 4 weeks before operation. (2) 75 mg clopidogrel 12 h prior to surgery.
(1) Single A: aspirin (2) Single B: clopidogrel 75 mg
(1) aspirin and clopidogrel.
(1) Single A: aspirin 100-300 mg (2) Single B: clopidogrel 75 mg
(1) aspirin and clopidogrel.
(1) Involved antiplatelet therapy during perioperative period.
(1) Antiplatelet therapy was discontinued before surgery and when warfarin or low molecular weight heparin was used preoperatively
(1) Single A: clopidogrel (2) Single B: aspirin
(1) aspirin and clopidogrel.
Hale et al.
(1) Involved antiplatelet therapy during perioperative period.
(1) Patients with a history of a bleeding diathesis. (2) Patients receiving only clopidogrel therapy before operation. (3) Participants who undergoing CEA along with concomitant cardiac surgery
(1) aspirin.
(1) aspirin and clopidogrel.
Miguel et al.
(1) Underwent carotid endarterectomy (symptomatic or asymptomatic).
Not available.
(1) aspirin.
(1) aspirin and clopidogrel.
Chechik et al.
Saadeh et al.
(1) Dual group: dual antiplatelet therapy till the day of surgery.
(1) Combined open and endovascular surgery, (2) Congenital or acquired bleeding disorder, (3) Simultaneous CEA and CABG, (4) Pre-operative blood transfusions for anemia. (5) Lost to follow-up within 30 days after surgery, or informed consent not given.
Jones et al.
(1) Involved antiplatelet therapy during perioperative period.
(1) Patients on no antiplatelet medications or on clopidogrel monotherapy. (2) Patients on antiplatelet medications other than aspirin on clopidogrel.
(1) aspirin.
(1) aspirin and clopidogrel.
Illuminati et al.
(1) Involved antiplatelet therapy during perioperative period.
Not available.
(1) aspirin or clopidogrel.
(1) 100 mg daily aspirin +75 mg daily clopidogrel
(1) Only patients who underwent elective CEA treated with antiplatelet medication record were included in the analysis.
(1) Emergency indications such as crescendo TIA or stroke in evolution. (2) Patients who had surgery under special conditions, such as internal carotid artery (ICA) occlusion, restenosis, tandem stenosis, carotid (1) aspirin. aneurysm, symptomatic ICA coiling, symptomatic low-grade (<50%) stenosis with ulcerated plaque morphology, or simultaneous cardiac or aortic surgery, were excluded from the analysis.
Zimmermann et al.
(1) aspirin 81-100 mg.
(1) aspirin and clopidogrel.
(1) aspirin and clopidogrel.
Note. ICA= internal carotid artery; CEA= Carotid Endarterectomy; TIA= transient ischemic attack; CABG= coronary artery bypass grafting; TCD=transcranial doppler
Table 4. Results of Meta-Analysis Comparison of Dual Versus Single Antiplatelet Therapy in Carotid Endarterectomy. Outcomes
Studies
Death Neck hematoma Major bleeding Transient ischemic attack Myocardial infarction Stroke Length of stay Operation time Note. CIs= confidence intervals.
6 7 8 5 5 8 3 3
Groups Dual Antiplatelet 13237 815 8395 7559 7540 13980 435 308
Single Antiplatelet 120201 2536 27034 22399 22481 124180 722 1181
Overall effect Effect estimate 0.002 2.120 0.005 -0.002 0.004 -0.001 0.053 4.000
95% CI 0.000-0.003 1.431-3.142 0.002-0.008 -0.005-0.001 0.001-0.007 -0.003-0.000 -0.127-0.233 2.564-5.436
Heterogeneity p-Value 0.014 <0.001 <0.001 0.215 0.003 0.130 0.563 <0.001
2
I (%) 23.4% 31.8% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%
p-Value 0.258 0.185 0.754 1.000 0.418 0.962 0.627 1.000
Author Contributions Section We would like to show our gratitude to XKK for reviewing the data and contacting the authors; QLJ and PJW for their help with writing and extracting data; HXL and HWX for revising the article; and LLH for helping edit the work. We also appreciate all of the authors included in our studies for obtaining these important yet controversial data.
Abbreviations PRISMA= Preferred Reporting Items for Systematic Reviews and Meta-Analyses, NOS=Newcastle-Ottawa Scale, CEA=carotid endarterectomy, WMD=weighted mean difference, CIs=confidence intervals, RDs=rate differences, ORs=odds ratios, non-RCTs =non-randomized controlled trials, RCTs=randomized controlled trials; CS= Carotid stenosis.
Disclosure-Conflict of Interest: The authors have declared that no conflict interests exist.
S1878-8750(19)33099-2
DOI:
https://doi.org/10.1016/j.wneu.2019.12.070
Reference:
WNEU 13917
To appear in:
World Neurosurgery
Received Date: 25 September 2019 Revised Date:
11 December 2019
Accepted Date: 12 December 2019
Please cite this article as: Jiang Q-l, Wang P-j, Liu H-x, Huang L-l, Kang X-k, Dual versus single Antiplatelet Therapy in Carotid Artery Endarterectomy: Direct Comparison of Complications Related to Antiplatelet Therapy, World Neurosurgery (2020), doi: https://doi.org/10.1016/j.wneu.2019.12.070. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Title Page Dual versus single Antiplatelet Therapy in Carotid Artery Endarterectomy: Direct Comparison of Complications Related to Antiplatelet Therapy
Qun-long Jiang# M.D., Email: [email protected]; Department of Neurosurgery, Liaocheng people’s hospital, Liaocheng, Shandong, R.P. China, 252000. Pei-jian Wang# M.D., Email: [email protected]; Department of Neurosurgery, Liaocheng people’s hospital, Liaocheng, Shandong, R.P. China, 252000. Hui-xin Liu M.D., Email: [email protected]; Department of Medical Examination, Liaocheng people’s hospital, Liaocheng, Shandong, R.P. China, 252000. Li-li Huang M.D., Email: [email protected]; Department of Endocrinology, Liaocheng people’s hospital, Liaocheng, Shandong, R.P. China, 252000. corresponding author Xiao-kui Kang* M.D., Email: [email protected]; Tel:086-18963562676; Fax: 086 -02260362062, Department of Neurosurgery, Liaocheng people’s hospital, Liaocheng, Shandong, R.P. China, 252000. # These authors contributed equally to this work and should be considered co-first authors.
1
Dual versus Single Antiplatelet Therapy in Carotid Artery Endarterectomy:
2
Direct Comparison of Complications Related to Antiplatelet Therapy
3
Abstract
4
Background: Dual and single antiplatelet therapies are routinely used in carotid
5
artery endarterectomy (CEA). However, the efficacy and safety of these therapies are
6
controversial. The present study aimed to comprehensively compare the clinical
7
outcomes between dual and single antiplatelet therapies in CEA.
8
Method: This study retrieved available academic studies evaluating the complications
9
related to antiplatelet therapy between dual and single antiplatelet therapies in CEA
10
from the databases of ScienceDirect, the Cochrane Library, EMBASE, and PubMed.
11
References to previous reviews and related clinical trials were manually checked to
12
retrieve potential literature that was not included in our electronic search results.
13
Results: A total of ten articles (1 RCT, 9 non-RCT) were included in the study. The
14
overall number of patients in the dual antiplatelet group was 14280, whereas the
15
number of patients in the single antiplatelet group was 125850. The results revealed
16
that the single antiplatelet group had a lower incidence of thirty-day death (RD, 0.002;
17
95% CI, 0.000 to 0.003; P=0.014), neck haematoma (OR=2.120, 95% CI (1.431,
18
3.142), P<0.001), myocardial infarction (RD= 0.004, 95% CI (0.001, 0.007), P =
19
0.003), and major bleeding (RD=0.005, 95% CI (0.002, 0.008), P<0.001). Meanwhile,
20
the single antiplatelet group was associated with a shorter operation time
21
(WMD=4.000, 95% CI= 2.564 to 5.436, P<0.001). However, there was no significant
22
difference in the rate of postoperative transient ischaemic attack (P= 0.215), stroke
23
(P= 0.130), and length of stay (P= 0.563).
24
Conclusions: Based on current evidence, using single antiplatelet therapy in CEA
25
may reduce operation time and the incidences of thirty-day death, neck haematoma,
26
major bleeding, and myocardial infarction without increasing the risks of transient
27
ischaemic attack, stroke, and a longer operation time.
28 29 30
Keywords: Antiplatelet therapy; Carotid endarterectomy; Meta-analysis.
31
Introduction
32
Carotid stenosis (CS) has been recognized as the archcriminal of ischaemic strokes
33
and transient ischaemic attacks, accounting for approximately 20% of cases.[1]
34
Carotid endarterectomy (CEA) has been regarded as the standard treatment for CS [2,
35
3] After the first stroke, early adoption of antiplatelet therapy seems to be significantly
36
effective in reducing the occurrence rate, which is estimated at 5% within 48 hours
37
and 10% within 2 weeks.[4-8] However, there appears to be ongoing controversy
38
regarding the use of dual or single antiplatelet therapy. Although aspirin therapy has
39
been estimated to reduce thromboembolism risk by 20% to 25%,[9], Hayes et al.[10]
40
conducted a prospective trial involving 120 patients who underwent CEA and
41
illustrated that embolization was irrelevant to the ability of aspirin to inhibit platelet
42
aggregation. Furthermore, several studies have demonstrated an increased potential
43
for postoperative bleeding and transfusion requirements among clopidogrel-treated
44
patients.[11, 12] Recently, many researchers have shown that using dual antiplatelet
45
therapy in CEA is related to a lower incidence of restenosis[13], haemorrhagic
46
complications, and perioperative stroke.[14-16] Nevertheless, some scholars question
47
the merits of dual antiplatelet therapy, which has demonstrated increased mortality,
48
higher bleeding rates, prolonged surgical time or wound haematomas during CEA.[17,
49
18] The purpose of the present study was to conduct a comprehensive literature
50
review to assess the safety and efficiency between dual and single antiplatelet
51
therapies in patients undergoing CEA.
52 53
Materials and methods
54
Our study was performed according to the guidelines of the Preferred Reporting Items
55
for Systematic Reviews and Meta-Analyses (PRISMA).[19]
56 57
Data sources and searches
58
The online databases of the Cochrane Library, (1966-2019.6), ScienceDirect
59
(1985-2019.6), EMBASE (1980-2019.6), and PubMed (1966-2019.6) were searched
60
for all studies evaluating the complications related to antiplatelet therapy between
61
dual and single antiplatelet therapies in CEA. The following keyword search terms
62
were used in these databases: carotid endarterectomy OR CEA, antiplatelet OR
63
aspirin OR clopidogrel. Beyond that, all references to previous reviews and related
64
clinical trials were manually checked to find potential publications that were not
65
included in our electronic search results.
66 67
Inclusion and exclusion criteria
68
The studies were included in our meta-analysis if the literature met the following
69
criteria based on PICOS framework: (I) Population: limited to the participants
70
undergoing CEA; (II) Intervention: strictly used dual and single antiplatelet therapies;
71
(III) Comparison: evaluated the clinical outcomes about reducing complications
72
related to antiplatelet therapy; (IV) Outcome measures: eight outcomes including
73
death, neck haematoma, major bleeding, myocardial infarction, transient ischaemic
74
attack, stroke, length of stay, and operation time were compared in the present study;
75
and (V) an official published full-length article written in English.
76
The exclusion criteria of our study were as follows: (I) conference or commentary
77
literature, case reports, reviews, letters, and meta-analyses; (II) studies not associated
78
with humans, such as animal experiments; and (III) unclear or unavailable outcome
79
data.
80 81
Data extraction and outcome measures
82
Three authors independently extracted data by using a pre-planned, standardized data
83
extraction form, with disagreements resolved by consensus or by the third author
84
when there were different opinions. The following characteristics were extracted for
85
each included article: the first author’s name, publication year, recruitment period,
86
number of samples, study design, study outcomes and other relevant data. The
87
extracted data (range, median, mean difference and standard deviation) were inserted
88
into the data extraction form. The measurements of each outcome were thirty-day
89
death, neck haematoma, major bleeding, myocardial infarction, transient ischaemic
90
attack, stroke, length of stay, and operation time.
91 92
Statistical analysis
93
STATA version 11.0 (Stata Corporation, College Station, Texas, USA) was applied for
94
our statistical analyses. The weighted mean difference (WMD) with 95% confidence
95
intervals (CIs) for the continuous outcomes (operation duration and length of stay in
96
hospital) was calculated. For discontinuous outcomes (stroke, transient ischaemic
97
attack, myocardial infarction, major bleeding, neck haematoma, and thirty-day death),
98
the odds ratio (OR) or rate difference (RD) with 95% CIs was used for the evaluation.
99
The I2 test was performed to estimate heterogeneity. Heterogeneity was considered
100
obvious when I2>50%, and we conducted our meta-analysis using the random-effects
101
model. Otherwise, the fixed-effects model was performed.
102 103
Results
104
Search results
105
A total of 2301 studies were identified by searching four electronic databases. After
106
removing duplicates, we reviewed the titles and abstracts of 536 articles, and 509
107
publications were removed based on the pre-planned inclusion and exclusion criteria.
108
Seventeen publications were excluded after screening the full content of the articles.
109
Finally, ten articles satisfied the selection criteria and were accepted into the
110
qualitative analyses. More details regarding the search process are shown in Figure 1.
111 112
Quality assessment
113
An evaluation of the quality of the literature was performed separately by the two
114
reviewers. When there were different opinions between the two reviewers, another
115
author was involved until disagreements were resolved by consensus. There was only
116
one randomized controlled trial (RCT), which was of high quality with a Jadad score
117
of 5. All non-randomized controlled trials (non-RCTs) were evaluated by the
118
Newcastle-Ottawa Scale (NOS), and most of the included literature was of high
119
quality. The study scores of all articles are shown in Table 1.
120
121
Study characteristics
122
A total of ten studies (1 RCT[20], 9 non-RCTs[21-29]) were included in this study.
123
The overall number of participants in the dual antiplatelet group was 14280, whereas
124
the number of participants in the single antiplatelet group was 125850. Details about
125
the study type of the involved studies and demographic characteristics are shown in
126
Table 2. Baseline characteristics were statistically similar between the two groups,
127
and the sample size varied from 44 to 103417 participants. The studies were from the
128
UK, New England, Germany, Israel, the USA, Lebanon, and Italy. More details are
129
shown in Table 2. The methods of antiplatelet therapy in CEA between the two groups
130
are shown in Table 3.
131 132
Outcomes of the meta-analysis
133
The following eight outcomes were assessed in our meta-analysis: thirty-day death,
134
neck haematoma, major bleeding, myocardial infarction, transient ischaemic attack,
135
stroke, length of stay, and operation time (Table 4).
136 137
Thirty-day death
138
Data on 30-day mortality were provided by six studies. In the single antiplatelet group
139
(120201 participants), the incidence of thirty-day mortality was 0.48%. In the dual
140
antiplatelet group (13237 participants), the incidence of thirty-day mortality was
141
0.52%, with a statistically significant difference (RD, 0.002; 95% CI, 0.000 to 0.003;
142
P=0.014, Figure 2). No significant heterogeneity among the studies was identified
143
(I2=23.4%, p=0.258).
144 145
Neck haematoma
146
Seven studies reported the number of neck haematomas. The results showed that there
147
were 815 cases in the dual antiplatelet group and 2536 cases in the single antiplatelet
148
group. No significant heterogeneity was identified (I2 = 31.8%, P=0.185), and a
149
fixed-effects model was conducted. The cross-sectional data from various studies
150
were plotted and showed that the rate of neck haematoma was statistically higher in
151
the dual antiplatelet group than that of the single antiplatelet group (OR, 2.120; 95%
152
CI, 1.431 to 3.142; P<0.001, Figure 3).
153 154
Major bleeding
155
Eight studies focused on the major bleeding rates. We used the fixed-effects model
156
because no significant heterogeneity was observed (I2 = 0%, P=0.754), and the results
157
showed that there was a significant difference between the two groups. The
158
cross-sectional data from various studies were plotted and demonstrated the single
159
antiplatelet therapy could reduce the rate of major bleeding compared to dual
160
antiplatelet therapy (RD, 0.005; 95% CI, 0.002 to 0.008; P<0.001; Figure 4).
161 162
Transient ischaemic attack
163
Five publications mentioned the number of transient ischaemic attacks, and the data
164
pooled by a fixed-effects model demonstrated that there was no significant difference
165
between the treatment groups (RD, -0.002; 95% CI, -0.005 to -0.001; P= 0.215;
166
Figure 5).
167 168
Myocardial infarction
169
Five studies mentioned the numbers of myocardial infarction in patients. No evidence
170
of between-study heterogeneity was found, and a fixed-effects model was used
171
(P=0.418, I2＝0.0%). The cross-sectional data from various studies were plotted and
172
revealed that single antiplatelet therapy was associated with a statistically lower rate
173
of myocardial infarction compared to the dual antiplatelet group (RD, 0.004; 95% CI,
174
0.001 to 0.007; P = 0.003; Figure 6).
175 176
Stroke
177
Eight articles reported the number of strokes, and the data pooled by a fixed-effects
178
model demonstrated that no significant difference was found between the treatment
179
groups (RD, -0.001; 95% CI, -0.003 to 0.000; P= 0.130; Figure 7).
180
181
Operation duration
182
Data on the operation time were reported by the three studies involving 1489
183
participants. Of these 1489 patients who underwent CEA, 308 were assigned to the
184
dual antiplatelet group, and 1181 were assigned to the single antiplatelet group.
185
Meanwhile, no evidence of between-study heterogeneity was observed, and the data
186
were pooled using a fixed-effects model to reveal that dual antiplatelet therapy was
187
related to a longer operation time compared to single antiplatelet therapy (WMD,
188
4.000; 95% CI, 2.564 to 5.436; P<0.001, Figure 8).
189 190
Length of stay
191
Three articles provided the length of stay, and the data pooled by a fixed-effects
192
model revealed that there was no significant difference between the two groups
193
(WMD, 0.053, 95% CI, -0.127 to 0.233; P= 0.563; Figure 9).
194 195
Discussion
196
Currently, carotid atherosclerosis is an essential risk factor for transient ischaemic
197
attack and ischaemic stroke.[30] CEA has been the gold standard therapy for
198
extracranial atherosclerotic carotid disease,[31] and the beneficial effect of antiplatelet
199
therapy has been revealed for the perioperative risk of stroke reduction for individuals
200
undergoing CEA. In addition, antiplatelet therapy contributes to reducing the rate of
201
thromboembolic events, a cause of major bleeding that is significantly increased with
202
more intensive regimens.[29, 32, 33] Although dual and single antiplatelet therapies
203
are routinely used in CEA, their efficacy and safety are controversial.
204
Antiplatelet regimen in carotid intervention has been studied before.[34, 35] It
205
lowers the risk of perioperative stroke by reducing vascular occlusion events. Besides,
206
it protects the coronary artery from complications while taking carotid intervention or
207
subsequently. What to concern is that antiplatelet therapy may bring about major
208
bleeding, the chance of which may go serious as the use of high dose. In our study,
209
the purpose was to systematically compare the clinical outcomes between dual and
210
single antiplatelet therapies in CEA. The results revealed that, compared to the dual
211
antiplatelet group, the single antiplatelet group was associated with a shorter operation
212
time and a lower incidence of 30-day death, neck haematoma, myocardial infarction,
213
and major bleeding; however, there was no significant difference in the rates of
214
postoperative transient ischaemic attack, stroke, and length of stay.
215
Hale et al[36], in a retrospective comparative study of 1472 patients treated with
216
CEA, revealed that the dual antiplatelet strategy was independently associated with
217
five-fold rates of postoperative bleeding compared to antiplatelet therapy (OR, 5.1; 95%
218
CI 1.8-14.2; p<0.002). Jones et al[37] reported that patients on dual antiplatelet
219
therapy were more likely to require reoperation for bleeding than patients on single
220
antiplatelet therapy (1.3% vs 0.7%; P ＜ 0.004). Similarly, our meta-analysis
221
demonstrated that the rates of major bleeding were significantly higher in the dual
222
antiplatelet group than the single antiplatelet group (RD, 0.005; 95% CI, 0.002 to
223
0.008; P<0.001). Single antiplatelet therapy could reduce neck haematoma rates
224
compared to dual antiplatelet therapy in patients with CEA (OR, 2.120; 95% CI 1.431
225
to 3.142; P<0.001). This result is also supported by a published meta-analysis and
226
reveals that a significantly higher risk of neck haematomas was found in dual
227
antiplatelet therapy (95% CI, 0.01-0.06; P=0.001). Dual antiplatelets could obviously
228
inhibit platelet aggregation to influence effective blood clotting, which was a possible
229
explanation for the result.
230
We revealed that in the dual antiplatelet group, the rate of 30-day death was 0.52%,
231
with the difference being significant. This finding was consistent with a study by
232
Zimmermann et al[38] that demonstrated that dual antiplatelet therapy was associated
233
with a significantly decreased all-cause mortality compared with aspirin alone (RR,
234
0.67; 95% CI, 0.51-0.88; P=0.004), which seems to stem from the higher rates of
235
major bleeding. Based on the previously published meta-analysis of carotid
236
interventions, there was no significant difference in stroke rates between the dual and
237
single antiplatelet strategies.[31] Although Barkat et al.[31] found that symptomatic
238
patients accepting dual therapy had decreased rates of transient ischaemic attack or
239
stroke (1.4% dual therapy vs. 1.7% aspirin alone), composite stroke/death (1.2% dual
240
therapy vs. 1.5% aspirin alone), and any stroke (1.1% dual therapy vs. 1.2% aspirin
241
alone), the differences were not statistically significant. In the MATCH trial[39], there
242
was no difference in reducing stroke rates between the dual and single antiplatelet
243
groups. Meanwhile, no significant difference was shown in the rates of stroke
244
between the two treatment groups (RD, -0.001; 95% CI, -0.003 to 0.000; P=0.130). In
245
addition, we demonstrated that dual antiplatelet therapy could reduce the rates of
246
myocardial infarction compared to single antiplatelet therapy.
247
Chechik et al.[22] demonstrated that operation time was significantly longer
248
among patients treated with dual antiplatelet therapy (205 ± 52 minutes on combined
249
treatment versus 165 ± 33 minutes on clopidogrel alone). Similarly, our results
250
revealed that the dual antiplatelet group was related to a longer operation time
251
compared to the single antiplatelet group (WMD=4.000, 95% CI= 2.564 to 5.436,
252
P<0.001). Payne et al.[40] also revealed that the time from blood flow restoration to
253
skin closure was significantly longer in patients treated with dual antiplatelet therapy
254
(P=0.04). Zimmermann et al.[38] illustrated that dual antiplatelet method significantly
255
increased the secondary bleeding rates requiring reoperation. We speculated that these
256
factors cause a longer operation time in patients treated with dual antiplatelet therapy.
257
However, no significant difference was found between the two groups for the length
258
of stay in our study (WMD, 0.053; 95% CI, -0.127 to 0.233; P= 0.563), which is
259
similar to the study by Saadeh et al.[41],who demonstrated that the mean hospital
260
lengths of stay were not significantly different between the two groups.
261
Barkat et al.[31] recently published a meta-analysis comparing the dual with
262
single antiplatelet therapy for carotid interventions (CEA or CAS). The single
263
antiplatelet therapy was relevant to a reduced risk of bleeding complications in
264
patients undergoing CEA. However, it shows disadvantages over the dual antiplatelet
265
therapy in CAS, as indicated by an increased risk of transient ischaemic attack.
266
Differently, our results also demonstrate using single antiplatelet in CEA could reduce
267
operation time and the incidence of neck hematoma without increasing the risk of
268
stroke, and longer length of operation duration. Furthermore, our sample size is larger
269
and the comparison results are richer. The following limitations of this study should
270
be noted. First, the present study only compares perioperative clinical outcomes
271
relevant to the safety and efficiency of two kinds of antiplatelet therapy due to
272
relatively little data on these outcomes with the same long-term follow-up period.
273
Meanwhile, for the subgroup analysis, we could not divide the participants into
274
symptomatic and asymptomatic groups due to relatively little reported data.
275
Furthermore, the main inclusion and exclusion criteria of the trials and interventions
276
of antiplatelet therapy are not identical in the included studies, which may cause
277
potential bias.
278 279
Conclusion
280
Based on current evidence, using single antiplatelet therapy in CEA may reduce
281
operation time and the incidences of thirty-day death, neck haematoma, major
282
bleeding, and myocardial infarction without increasing the risks of transient ischaemic
283
attack, stroke, and a longer operation time.
284 285
Competing interests
286
The authors declare that they have no competing interests.
287 288
Acknowledgment
289
None
290 291
Funding
292
None
293 294
Abbreviations
295
PRISMA= Preferred Reporting Items for Systematic Reviews and Meta-Analyses,
296
NOS=Newcastle-Ottawa Scale, CEA=carotid endarterectomy, WMD=weighted mean
297
difference, CIs=confidence intervals, RDs=rate differences, ORs=odds ratios,
298
non-RCTs =non-randomized controlled trials, RCTs=randomized controlled trials;
299
CS= Carotid stenosis.
300 301
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416 417
Figure & Table legends
418
Figure1: Flowchart of the study selection process.
419
Figure2: Forest plot on the assessment of the 30-days death.
420
Figure3: Forest plot on the assessment of the neck hematoma.
421
Figure4: Forest plot on the assessment of the major bleeding.
422
Figure5: Forest plot on the assessment of the myocardial infarction.
423
Figure6: Forest plot on the assessment of the transient ischemic attack.
424
Figure7: Forest plot on the assessment of the stroke.
425
Figure8: Forest plot on the assessment of the operation time.
426
Figure9: Forest plot on the assessment of the length of stay.
427
Table1: The quality assessment score of the included studies.
428
Table2: The Characteristics of Trials.
429
Table3: The intervention of antiplatelet therapy and eligibility criteria in the included
430
studies.
431
Table4: The Meta-analysis results.
Table 1. Quality assessment scores of the included studies. Study, year
Payne et al.2004
Design
randomized controlled trial
Jadad scale Randomization
Blinding
Cohort
Total Scores
2
2
1
5
NOS Selection
Comparability
Exposure
Total Scores
Stone et al. 2011
Registry
3
1
2
6
Oldag et al. 2012
Registry
3
2
3
8
Chechik et al. 2012
Retrospective cohort study
3
2
3
8
Hale et al. 2013
Retrospective cohort study
4
2
3
9
Comparative
4
1
3
8
Saadeh et al. 2013 Jones et al. 2016
Retrospective cohort study
4
2
3
9
Miguel et al. 2016
Retrospective cohort study
3
1
3
7
Prospective
3
1
2
6
Retrospective cohort study
3
2
3
8
Illuminati et al. 2017 Zimmermann et al.2018
Note: NOS= Newcastle-Ottawa scale.
Table 2. Overview of Included Studies. Author
Country
Years
Type of Study
Recruitment
Participants (n)
Gender (M)
period
Dual
Single
Dual
Single
Dual
Single
Payne et al. Stone et al. Oldag et al. Chechik et al. Hale et al. Saadeh et al. Jones et al. Miguel et al. Illuminati et al. Zimmermann et al.
UK
2004
RCT
2000-2001
46
54
78%
74%
68±8.9
69±8.5
New England
2011
Registry
2003-2009
708
3970
NA
NA
NA
NA
Germany
2012
Registry
1995-2010
112
572
NA
NA
NA
NA
Israe
2012
RCS
2007-2010
16
91
81%
70.4%
69±9
NA
USA
2013
RCS
1998-2005
315
639
63%
60%
69.9±9.7
70.5±9.4
Lebanon
2013
Comparative
2005-2012
104
73
73.2%
76.5%
69±8.6
68±9.7
USA
2016
RCS
2003-2014
7059
21624
63.2%
59.5%
69.6±9.4
70.4±9.1
Germany
2016
RCS
2010-2013
35
9
71.4%
77.8%
71.3±6.6
70.7±12.3
Italy
2017
prospective
2005-2015
188
1098
68%
NA
78
NA
Germany
2018
RCS
2009-2014
5697
97720
72.3%
67.6%
70.2±9.3
70.7±9.0
Note. NA= not available; RCT= randomized controlled trial; RCS= Retrospective comparative study; M= male.
Age (mean ± standard)
Table 3. Intervention of antiplatelet therapy and eligibility criteria in the included studies Author
Inclusion criteria
Exclusion criteria
Antiplatelet therapy Single Antiplatelet
Payne et al.
Stone et al. Oldag et al.
(1) High-grade stenosis >70%.
Not available.
(1) >50% stenosis.
(1) Aspirin intolerance, (2) Absence of a transcranial window for TCD monitoring, (1)150 mg aspirin for 4 weeks (3) Emergency CEA, prior to surgery. (4) Patients already on warfarin, dipyridamole, or (2) placebo 12 h before operation. clopidogrel therapy, (5) Vein bypass performed instead of CEA. (6) CEA performed under local anesthesia. Not available. (1) Patient on other antithrombotic
Dual Antiplatelet
(1) 150 mg aspirin for 4 weeks before operation. (2) 75 mg clopidogrel 12 h prior to surgery.
(1) Single A: aspirin (2) Single B: clopidogrel 75 mg
(1) aspirin and clopidogrel.
(1) Single A: aspirin 100-300 mg (2) Single B: clopidogrel 75 mg
(1) aspirin and clopidogrel.
(1) Involved antiplatelet therapy during perioperative period.
(1) Antiplatelet therapy was discontinued before surgery and when warfarin or low molecular weight heparin was used preoperatively
(1) Single A: clopidogrel (2) Single B: aspirin
(1) aspirin and clopidogrel.
Hale et al.
(1) Involved antiplatelet therapy during perioperative period.
(1) Patients with a history of a bleeding diathesis. (2) Patients receiving only clopidogrel therapy before operation. (3) Participants who undergoing CEA along with concomitant cardiac surgery
(1) aspirin.
(1) aspirin and clopidogrel.
Miguel et al.
(1) Underwent carotid endarterectomy (symptomatic or asymptomatic).
Not available.
(1) aspirin.
(1) aspirin and clopidogrel.
Chechik et al.
Saadeh et al.
(1) Dual group: dual antiplatelet therapy till the day of surgery.
(1) Combined open and endovascular surgery, (2) Congenital or acquired bleeding disorder, (3) Simultaneous CEA and CABG, (4) Pre-operative blood transfusions for anemia. (5) Lost to follow-up within 30 days after surgery, or informed consent not given.
Jones et al.
(1) Involved antiplatelet therapy during perioperative period.
(1) Patients on no antiplatelet medications or on clopidogrel monotherapy. (2) Patients on antiplatelet medications other than aspirin on clopidogrel.
(1) aspirin.
(1) aspirin and clopidogrel.
Illuminati et al.
(1) Involved antiplatelet therapy during perioperative period.
Not available.
(1) aspirin or clopidogrel.
(1) 100 mg daily aspirin +75 mg daily clopidogrel
(1) Only patients who underwent elective CEA treated with antiplatelet medication record were included in the analysis.
(1) Emergency indications such as crescendo TIA or stroke in evolution. (2) Patients who had surgery under special conditions, such as internal carotid artery (ICA) occlusion, restenosis, tandem stenosis, carotid (1) aspirin. aneurysm, symptomatic ICA coiling, symptomatic low-grade (<50%) stenosis with ulcerated plaque morphology, or simultaneous cardiac or aortic surgery, were excluded from the analysis.
Zimmermann et al.
(1) aspirin 81-100 mg.
(1) aspirin and clopidogrel.
(1) aspirin and clopidogrel.
Note. ICA= internal carotid artery; CEA= Carotid Endarterectomy; TIA= transient ischemic attack; CABG= coronary artery bypass grafting; TCD=transcranial doppler
Table 4. Results of Meta-Analysis Comparison of Dual Versus Single Antiplatelet Therapy in Carotid Endarterectomy. Outcomes
Studies
Death Neck hematoma Major bleeding Transient ischemic attack Myocardial infarction Stroke Length of stay Operation time Note. CIs= confidence intervals.
6 7 8 5 5 8 3 3
Groups Dual Antiplatelet 13237 815 8395 7559 7540 13980 435 308
Single Antiplatelet 120201 2536 27034 22399 22481 124180 722 1181
Overall effect Effect estimate 0.002 2.120 0.005 -0.002 0.004 -0.001 0.053 4.000
95% CI 0.000-0.003 1.431-3.142 0.002-0.008 -0.005-0.001 0.001-0.007 -0.003-0.000 -0.127-0.233 2.564-5.436
Heterogeneity p-Value 0.014 <0.001 <0.001 0.215 0.003 0.130 0.563 <0.001
2
I (%) 23.4% 31.8% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%
p-Value 0.258 0.185 0.754 1.000 0.418 0.962 0.627 1.000
Author Contributions Section We would like to show our gratitude to XKK for reviewing the data and contacting the authors; QLJ and PJW for their help with writing and extracting data; HXL and HWX for revising the article; and LLH for helping edit the work. We also appreciate all of the authors included in our studies for obtaining these important yet controversial data.
Abbreviations PRISMA= Preferred Reporting Items for Systematic Reviews and Meta-Analyses, NOS=Newcastle-Ottawa Scale, CEA=carotid endarterectomy, WMD=weighted mean difference, CIs=confidence intervals, RDs=rate differences, ORs=odds ratios, non-RCTs =non-randomized controlled trials, RCTs=randomized controlled trials; CS= Carotid stenosis.
Disclosure-Conflict of Interest: The authors have declared that no conflict interests exist.