Keywords
carotid endarterectomy - patching - patch angioplasty - primary closure - restenosis
- ipsilateral stroke
Carotid endarterectomy is effective in preventing recurrent stroke in patients with
symptomatic carotid artery stenosis.[1]
[2] Low postoperative stroke and mortality rates below 3% are achieved nowadays.[3]
One of the debated aspects of carotid endarterectomy technique is the type of closure
applied. Restenosis rates of 1 to 36% after primary closure (PRC) implied the need
for alternative techniques to reduce these rates.[4]
[5]
[6] Many guidelines recommend routine patching for most patients to prevent restenosis,
mainly based on similar findings as Rerkasem and Rothwell published in a systematic
review and meta-analysis in 2009.[7]
[8] They found a significant reduction in restenosis and ipsilateral stroke following
patch angioplasty as compared with PRC.[7]
[8] However, the quality of included trials was generally poor and the studies were
performed over 20 years ago. It is clear that current best medical treatment and stroke
risks have significantly improved[3] and data from those trials might not be applicable to current medical practice anymore.
Moreover, none of the included studies investigated a strategy of selective patching.
Maertens et al found no difference in 30-day stroke and death rates between PRC and
patch angioplasty when performing PRC in all patients with an internal carotid artery
diameter of 5 mm or more.[9] Although patch angioplasty could reduce restenosis rates, it also increases bleeding
risk, carotid occlusion time, procedure time, thrombus formation and carries the risk
of infection and pseudoaneurysm formation.[9]
Therefore, uncertainty remains about the exact role of routine patching, PRC, and
selective patching. Objective of this study was to report the rates of restenosis,
postoperative stroke, or transient ischemic attack and complications following carotid
endarterectomy and compare these outcomes between patients where PRC and patch closure
(PAC) after carotid endarterectomy were performed.
Methods
This study was approved by the Noordwest Clinics Alkmaar Ethics Committee and the
requirement for informed consent was waived by the committee.
Patient Selection
All consecutive patients treated by carotid endarterectomy for symptomatic carotid
artery stenosis in the Northwest Clinics between January 2006 and December 2016 were
included in this study. A symptomatic carotid artery stenosis was defined as an internal
carotid artery stenosis with an ipsilateral stroke, transient ischemic attack, or
amaurosis fugax within 6 months before presentation. Carotid endarterectomy was performed
in patient with a symptomatic stenosis of 50 to 99% (males) or 70 to 99% (females).
Six dedicated vascular surgeons with broad experience with carotid endarterectomy
operated all patients.
Patients operated after previous ipsilateral carotid endarterectomy or for reasons
other than atherosclerotic stenosis (such as traumatic vascular injury or dissections)
were excluded.
Preoperative Care and Diagnostic Workup
All patients were evaluated by a neurologist for the diagnosis of transient ischemic
attack, stroke, or amaurosis fugax. Duplex ultrasound was performed to identify internal
carotid artery stenosis and to determine degree of stenosis according to the North
American Symptomatic Carotid Endarterectomy Trial criteria.[10]
Secondary prevention in the form of a daily dose of 75 mg clopidogrel and 40 mg simvastatin
was immediately started since January 2014 and continued during and after carotid
endarterectomy. Before 2014, a combination of acetylsalicylic acid (80mg, once a day)
and dipyridamole (200 mg, twice a day) was used as standard thrombocyte aggregation
inhibitor therapy instead of clopidogrel. A computed tomography angiography scan was
performed for preoperative planning and confirmation of duplex findings. Blood pressure
and diabetes management was instituted when indicated. Patients were scheduled for
carotid endarterectomy as soon as possible and at least within 2 weeks after presentation.
Surgical Technique
Carotid endarterectomy was performed under general anesthesia. For monitoring electro-encephalography
(EEG) was used and shunting was only performed if indicated by EEG abnormalities occurring
after arterial clamping. Carotid endarterectomy was performed as previously described[11] with attention to the following aspects: (1) a no-touch technique was applied; (2)
heparin (5,000 international units) was administered before clamping; (3) Kunlin sutures
to fixate the intima were only placed when indicated by a loose intimal flap; (4)
adequate flushing from the common, internal, and external carotid arteries followed
by rinsing with heparin–saline solution before completing closure of the arteriotomy;
(5) releasing flow to the external carotid artery first followed after five heartbeats
by the internal carotid artery. No routine placement of wound drains was performed.
Three surgeons used PAC only in internal carotid arteries with a diameter of < 5 mm
(selective patching), while the other three surgeons applied routine PAC. When PAC
was applied, a dacron patch was used.
After completion of the operation, patients were transferred to the recovery unit
for postoperative monitoring. Maximum systolic blood pressure thresholds were applied
based on baseline systolic blood pressure and were usually 150 to 160 mm Hg. When
systolic blood pressures were stable below the threshold for at least 4 hours, the
patient was transferred to the ward.
Data Collection and Follow-Up
Patient demographics, baseline risk factors, carotid duplex studies, indications,
intraprocedural data, closure technique, periprocedural complications, and long-term
outcomes were retrospectively collected. Data were derived from electronic medical
records, clinical records, and imaging reports. All patients had a postoperative duplex
ultrasound and a visit to the outpatient clinic 6 weeks after the procedure. The primary
outcome measures were restenosis at 6 weeks and 1 year and the occurrence of ipsilateral
stroke. Secondary outcome measures were death, incidence of perioperative complications,
and reintervention rates.
Statistical Analysis
Statistical analyses were performed using SPSS 20 software (IBM Corp, Armonk, NY).
Fisher's Exact test was used to compare categorical variables and one-way analysis
of variance was used for continuous variables. A two-tailed probability value of p < 0.05 was considered significant. Values are presented as mean ± standard deviation
or number (%), unless stated otherwise.
Results
Patient Characteristics and Follow-Up
Between January 2006 and December 2016, a total of 468 patients underwent 500 carotid
artery endarterectomies for internal carotid artery stenosis. Of these, 23 were performed
in asymptomatic patients and 36 were treated by eversion endarterectomy and were excluded
for further analysis. The remaining endarterectomies (n = 441) were performed in symptomatic internal carotid artery stenosis. PRC was performed
in 79.1% (n = 349) and PAC in 20.9% (n = 92). Patient characteristics are summarized in [Table 1] and were divided according to the type of closure that was applied following endarterectomy.
There were more patients with hyperlipidemia in the PRC group (49.5%) compared with
the PAC group (37.9%, p = 0.070) but there was no difference in use of statins. A significantly smaller proportion
of patients in the PRC group used clopidogrel (19.4%) when compared with the PAC group
(56.5%, p < 0.000). For all other baseline characteristics, there were no significant differences
between the study groups.
Table 1
Baseline characteristics
|
PRC (n = 349)
|
PAC (n = 92)
|
p Value[a]
|
|
Age, years, mean (SD)
|
70.41 (9,118)
|
69.42 (9,199)
|
0.356[b]
|
|
Male gender (%)
|
244 (69,9)
|
60 (65,2)
|
.379
|
|
Smoking (current) (%)
|
103 (42,6)
|
32 (45,1)
|
0.785
|
|
Smoking (ever) (%)
|
203 (95,3)
|
57 (96,6)
|
1.000
|
|
Hyperlipidemia (%)
|
163 (49,5)
|
33 (37,9)
|
0.070
|
|
Diabetes (%)
|
77 (22,2)
|
14 (15,2)
|
0.151
|
|
CAD (%)
|
91 (26,2)
|
24 (26,1)
|
1.000
|
|
COPD (%)
|
19 (5,5)
|
9 (9,8)
|
0.150
|
|
GFR < 60 (%)
|
85 (25,1)
|
22 (24,7)
|
1.000
|
|
Contralateral CEA (%)
|
149 (43,3)
|
40 (44,0)
|
1.000
|
|
Statin use (%)
|
167 (50,6)
|
44 (48,4)
|
0.724
|
|
Clopidogrel (%)
|
67 (19,4)
|
52 (56,5)
|
0.000
|
|
Complication (%)
|
39 (11,2)
|
11 (12,0)
|
0.854
|
Abbreviations: CAD, coronary artery disease; CEA, carotid endarterectomy; COPD, chronic
obstructive pulmonary disease; GFR, glomerular filtration rate; PRC, primary closure;
PAC, patch closure; SD, standard deviation.
a Fisher's exact test (exact sig. 2-sided).
b One-way analysis of variance.
The median follow-up was 6 weeks (range: 0–130 months). According to the local protocol,
all patients were scheduled for a follow-up visit and duplex ultrasound 6 weeks following
carotid endarterectomy. Twenty patients in the PRC group (5.7%) and eight in the PAC
group (8.7%) were lost to follow-up at 6 weeks. Four patients in the PRC group died.
The remaining patients were lost to follow-up for unknown reasons.
Follow-up data at 1 year was available for 85 patients in the PRC group and 19 in
the PAC group. Reasons for the follow-up visits beyond the 6 weeks according to the
local protocol were contralateral stenosis, patient preference, or individual surgeon's
preference. None of the patients returned with an ipsilateral symptomatic restenosis
or stroke.
Outcome Measures
Overall, there was no statistically significant difference in the number of complications
between the PRC and PAC groups (11.2 vs 12.0%, p = 0.854). There were more reinterventions for postoperative bleeding in the PAC group
(10.9 vs 5.4%), although this difference was not statistically significant (p = 0.094). No statistically significant differences in stroke, death, and other complications
were found (see [Table 2]). Four patients died, all in the primary closed group. Causes of death were hypertensive
intracranial bleeding (n = 2) and myocardial infarction (n = 2). Another four patients, all in the PRC group developed complications other than
restenosis, stroke, or death. These complications were nerve injury (n = 1), hyperperfusion syndrome (n = 1), hypotension and wound infection (n = 1, both in the same patient), and internal carotid artery occlusion (n = 1), which required reoperation and thrombectomy.
Table 2
Thirty-day complication rates
|
PRC (n = 349)
|
PAC (n = 92)
|
p Value[a]
|
|
Reintervention for bleeding (%)
|
19 (5,4)
|
10 (10,9)
|
0.094
|
|
Stroke (%)
|
12 (3,4)
|
1 (1,1)
|
0.319
|
|
Death (%)
|
4 (1,1)
|
0 (0,0)
|
0.584
|
|
Other (%)
|
4 (1,1)
|
0 (0,0)
|
0.584
|
|
None (%)
|
310 (88,8)
|
81 (88,0)
|
0.854
|
Abbreviations: PRC, primary closure; PAC, patch closure.
a Fisher's exact test (exact sig. 2-sided).
At the duplex scan, 6 weeks after carotid endarterectomy 10 out of 329 (3.0%) patients
in the PRC and 5 out of 84 (6.0%) patients in the PAC group had a significant (i.e., > 50%)
restenosis. The difference was not statistically significant. At 1 year follow-up,
a duplex scan was available for 85 out of 329 (25.8%) patients in the PRC group and
19 out of 84 (22.6%) patients in the PAC group. No statistically significant difference
could be found in the proportion of patients with a restenosis ([Table 3]). In [Table 4], the degree of stenosis found at 6 weeks and 1 year follow-up is summarized for < 50%,
50 to 70%, and > 70% stenosis, respectively. A higher proportion of patients in the
PRC group (313 out of 329; 95.1%) had no restenosis at all, compared with 75 out of
84 (89.3%) patients in the PAC group. After 1 year, the difference in the proportion
of patients without any restenosis between groups increased, although no statistical
significance could be reached.
Table 3
Restenosis after 6 weeks and 1 year
|
PRC
|
PAC
|
p Value[a]
|
|
Restenosis[b] 6 weeks (%)
|
n = 329
10 (3,0)
|
n = 84
5 (6,0)
|
0.200
|
|
Restenosis[b] 1 year (%)
|
n = 85
12 (14,1)
|
n = 19
6 (31,6)
|
0.092
|
Abbreviations: PRC, primary closure; PAC, patch closure.
a Fisher's exact test (exact sig. 2-sided).
b Significant (> 50%) restenosis according to the NASCET (North American Symptomatic
Carotid Endarterectomy Trial) criteria.
Table 4
Degree of restenosis after 6 weeks and 1 year
|
PRC
|
PAC
|
p Value[a]
|
|
Restenosis 6 weeks (%)
|
n = 329
|
n = 84
|
|
|
< 50%
|
6 (1,8)
|
4 (4,8)
|
0.124
|
|
50–70%
|
5 (1,5)
|
2 (2,4)
|
0.634
|
|
> 70%
|
5 (1,5)
|
3 (3,6)
|
0.209
|
|
None
|
313 (95,1)
|
75 (89,3)
|
0.068
|
|
Restenosis 1 year (%)
|
N = 85
|
N = 19
|
|
|
< 50%
|
6 (7,1)
|
2 (10,5)
|
0.636
|
|
50–70%
|
7 (8,2)
|
3 (15,8)
|
0.385
|
|
> 70%
|
5 (5,9)
|
3 (15,8)
|
0.159
|
|
None
|
67 (78,8)
|
11 (57,9)
|
0.078
|
Abbreviations: PRC, primary closure; PAC, patch closure.
a Fisher's exact test (exact sig. 2-sided).
Discussion
The present study compared the rate of restenosis, stroke, reinterventions, and other
complications between PRC and PAC in a large contemporary cohort of patients that
underwent carotid endarterectomy for internal carotid artery stenosis. During duplex
follow-up at 6 weeks, no statistically significant difference was found in the proportion
of patients with a significant (> 50%) restenosis between groups. The subgroup of
patients with a follow-up duplex scan after 1 year was too small and the risk for
selection bias in this group was considered too high to draw any conclusions. The
postoperative stroke rate was low in both the PRC and PAC group (3.4 vs 1.1%, respectively)
and not statistically different.
These findings are conflicting with those described in the systematic review by Rerkasem
and Rothwell from 2009,[7] where a significant reduction in stroke, ipsilateral stroke, and restenosis was
found following PAC. However, trials included in this review were published 11 to
30 years ago (1987–2006) in a time where perioperative care and medication were different
compared with current standards. Moreover, the sample sizes were relatively small,
data were not available from all trials, and there was significant loss to follow-up.
In a more recently published systematic review and meta-analysis by the same authors,
three more trials were included in the analysis and two recent trials reported nonsignificant
trends toward an increased operative risk of stroke and death with PAC, further increasing
doubt in the currently available evidence supporting the routine use of PAC.[12]
Added to that, Malas et al performed a post-hoc analysis of 1,151 patients included
in the carotid endarterectomy arm of the CREST (Carotid Revascularization Endarterectomy
versus Stenting Trial) trial and compared those that underwent PRC with PAC.[13] Although they found a significant reduction in restenosis in the PAC group at 2
years, there was no difference in perioperative stroke or 4-year ipsilateral stroke.[13] Futhermore, the NSQIP (National Surgical Quality Improvement Program) data analysis
of 3,845 patients demonstrated that in contrast to other parameters the technical
aspects of carotid endarterectomy were not predictive for postoperative stroke or
death.[14]
The most recent paper and largest cohort study by Avgerinos et al reported results
of a retrospective cohort of 1,737 carotid endarterectomies treated between 2000 and
2010 with a median follow-up of 49 months.[15] They found no significant differences in the rate of restenosis, ipsilateral stroke,
or death between PRC of PAC. On multivariate and cox-regression analysis, the type
of closure had no predictive value for restenosis or perioperative and long-term outcomes.
The only predictive factors were the presence of symptomatic stenosis, heart failure
or renal failure, and the use of statins.[15]
All these recent findings indicate that the recommendations for routine use of PAC
might be unjustified. The trials on which these recommendations were based are outdated
and performed in an era with less effective secondary prevention and higher perioperative
stroke risks. With the declining perioperative stroke rates and the recent findings
described above, it seems that the impact of closure technique on carotid endarterectomy
outcomes is overestimated. Contemporary trials such as the CREST trials demonstrated
a restenosis rate of 3 to 7% within 2 to 4 years.[5]
[13] A small minority of these are symptomatic and < 0.5% of the overall group of patients
that undergo carotid endarterectomy develop a symptomatic restenosis. This further
questions the clinical significance of the rate of restenosis.
There are some limitations to the conclusions that can be drawn from this study that
warrant further discussion. First, due to the retrospective nature of the study selection
bias cannot be ruled out and the influence of unknown confounders is hard to estimate.
Although the sample size is reasonable, the relatively low number of postoperative
events might render the study underpowered to detect some possible relevant differences,
especially for the small subgroup of patients that had data available for a follow-up
of 1 year.
The reason to use PAC or PRC in this cohort was impossible to obtain from the available
data. The most important reason to use a patch in our hospital for those surgeons
applying selective patching is an internal carotid artery diameter of < 5 mm. Thus,
smaller internal carotid arteries are more likely to be closed using a patch but these
arteries might also be more prone to (re)stenosis. This could be a source of bias
leading to a relative overestimation of the rate of restenosis in the PAC group. Additionally,
a larger part of the cohort was operated by surgeons that preferred selective patching
which is another source of selection bias. Therefore, based on the data presented
in this paper, we cannot determine the role of selective patching.
In the PRC group, a significantly smaller proportion of patients used clopidogrel.
This can be explained by the fact that in the earlier cohort acetylsalicylic acid
and dipyridamole were standard therapy and since 2014 this was replaced by clopidogrel.
In the later cohort more surgeons had adopted the routine use of PAC. These two developments
caused the higher proportion of patients receiving clopidogrel in the PAC group. Although
the use of clopidogrel might have influenced the rate of perioperative stroke, this
would most likely cause an overestimation of the stroke rate in the PRC group. If
it would be possible to correct for this, it would lead to a decrease in the rate
of strokes in the PRC groups and further confirm our findings that there is no increased
stroke risk in PRC compared with PAC. The higher proportion of patients using clopidogrel
in the PAC group might be a confounder that leads to the higher rate of postoperative
bleeding in the PAC group.
Most patients in our study had a relatively short follow-up of 6 weeks which is insufficient
to draw any conclusions on long-term outcomes. However, on physical grounds, the effect
of using a patch or not for closure is a direct effect. The patch is used to negate
the effect of the bites of the sutures into the vessel wall and this effect can reliably
be measured by duplex scanning even on short-term follow-up.
Moreover, the study of Avgerinos et al[15] showed no difference in 5- or 10-year follow-up in restenosis and most restenosis
occurred in the first year. Interestingly, a very recent study on the hemodynamics
of carotid endarterectomy closure techniques found no favorable flow dynamics after
patching because incorporation of a patch increases areas of low wall shear stress
and high oscillatory shear index at the bifurcation.[16]
Finally, all postoperative deaths (n = 4) were in the PRC group. However, when further looking into the causes of death
(myocardial infarction, intracranial bleeding and palliative care after epilepsy and
pneumonia), we were unable to relate these causes to the type of closure applied.
Conclusions
Although firm conclusions cannot be drawn on the basis of this retrospective study,
we confirmed the findings of previous recent studies that indicate that strong recommendations
for routine use of PAC might be unjustified. Since the recommendation for routine
patching is based on outdated trials of questionable methodological quality, there
is room for a high-quality randomized controlled trial comparing PRC and PAC in a
contemporary cohort of patients that require carotid endarterectomy. Ideally patients
would be stratified according to internal carotid artery diameter to explore whether
an approach of selective patching is the most beneficial. Although it seems evident
that never using a patch should not be recommended, we doubt that patching is beneficial
in all cases.
