Carotid Restenosis Following Endarterectomy in Patients Managed With Single Antiplatelet Therapy Versus Dual Antiplatelet Therapy

Abstract

Background:

Antiplatelet therapy is a cornerstone in the management of carotid artery disease following carotid endarterectomy (CEA). There is a paucity of data regarding the effect of dual antiplatelet therapy (DAPT) on restenosis rates.

Methods:

A retrospective review of patients who underwent CEA from January 1, 2007 to December 31, 2013 was performed at a single center. Study groups consisted of subjects who received DAPT and those who received single antiplatelet therapy (SAPT) following CEA. Restenosis was evaluated by carotid duplex. Severity and timing of restenosis, postoperative complications, and reinterventions were compared between study groups.

Results:

Between January 1, 2007 and December 31, 2013, 1453 patients underwent CEA. The SAPT group consisted of 245 patients and the DAPT group consisted of 1208 patients. No difference in restenosis was identified between groups at less than 6 weeks (6.5% vs. 11.7% 50-79% stenosis, 0% vs. 2.2% 80-99% stenosis, 2.2% vs. 0.6% occlusion, p = 0.368), and 6 weeks to 2 years (20.6% vs. 17.9% 50-79% stenosis, 1.1% vs. 1.0% 80-99% stenosis, 1.6% vs. 0.4% occlusion, p = 0.242). A higher rate of restenosis in SAPT was found greater than 2 years from surgery (68.4% vs. 82.4% <50% stenosis, 29.9% vs. 16.1% 50-79% stenosis, 0% vs. 0.6% 80-99% stenosis, 1.7% vs. 0.9% occlusion p = 0.004). This finding persisted on multivariable analysis with 31.6% of the SAPT group showing >50% stenosis vs. 17.6% of the DAPT group (adjusted OR 0.48, 95% CI 0.30-0.76, p = 0.002). In a propensity matched-population, 32.7% of the SAPT group demonstrated restenosis vs. 13.7% of the DAPT group (adjusted OR 0.35, 95% CI 0.16-0.77, p = 0.009). There was no difference in the need for reintervention between study groups (DAPT 3.8% vs SAPT 3.3%, p = 0.684).

Conclusion:

Following CEA, patients on DAPT exhibited lower rates of late restenosis. Despite this finding, a clinical difference in reintervention was not found during this study period.

Keywords

carotid endarterectomy athererosclerosis restenosis antiplatelet single antiplatelet therapy dual antiplatelet therapy

Introduction

Carotid endarterectomy (CEA) remains the gold standard for reducing the risk of stroke in patients with high risk atherosclerotic carotid disease.^1

-5 It has been established that antiplatelet therapy is effective in reducing the risk of thromboembolic events and decreasing the rate of restenosis following CEA.^6

-9 While low dose aspirin (81-325 mg/day) is recommended after carotid surgery, the role of dual antiplatelet therapy (DAPT) remains less clear.^5,10

-14

Carotid restenosis following endarterectomy has been reported in up to 20% of cases, with more recent studies reporting rates of less than 10%.^1,15

-18 While some studies have found reduced stoke rates when clopidogrel and aspirin are administered in combination, these results have not been reproduced in larger studies and have yet to be tested in a randomized trial.^19,20 Some literature also suggests an increased risk of adverse events in the perioperative period with the addition of a second antiplatelet agent.²¹

Due to the paucity of data the role of DAPT remains ill-defined, and practice trends vary widely.²⁰ This study aims to evaluate the effect of single antiplatelet therapy (SAPT) versus DAPT on carotid restenosis following CEA.

Methods

A retrospective review was performed of the Heart and Vascular Center database (H&Vd) of a community based tertiary referral center. All patients with symptomatic and asymptomatic carotid artery stenosis who underwent CEA from January 1, 2007 through December 31, 2013 were queried from the H&Vd and included in this study. Data collected included patient demographics (age, sex, weight/BMI, race) and comorbidities (i.e. diabetes, peripheral vascular disease, smoking, heart disease, hypertension). Degree of stenosis as measured by postoperative arterial duplex and postoperative complications (TIA/stroke, myocardial infarction, clinically significant bleeding) were collected by retrospective chart review of the electronic medical record (EMR). Electronic query of the EMR was conducted for antiplatelet and statin medications administered during hospitalization and upon discharge. Additionally, the H&Vd was queried for all patients requiring a subsequent carotid reintervention on the ipsilateral carotid artery (repeat CEA, transfemoral carotid stent, or Transcarotid Artery Revascularization procedure performed from 2007 through 2019, when performed for restenosis >70%, or >50% with symptoms or stroke or transient ischemic attack).

All patients underwent intraoperative arterial duplex at completion of the arteriotomy closure, and all follow-up arterial duplex studies were performed at the in-house vascular laboratory. Degree of restenosis was interpreted based on peak systolic and end diastolic velocity criteria.²² Categories of stenosis were: <50%, 50-79%, 80-99%, and 100% occluded; restenosis was defined as a recurrent stenosis of >50% following endarterectomy.

The exposure of interest was DAPT therapy (aspirin and clopidogrel) following CEA, and these patients were compared to those on SAPT (either aspirin or clopidogrel). The primary outcome measure was rate of restenosis as measured by postoperative surveillance duplex based on 3 time periods: immediate restenosis (0-6 weeks), intermediate restenosis (6 weeks-2 years), and delayed restenosis (greater than 2 years). Secondary outcomes were postoperative complications (stroke, myocardial infarction (MI), death, and clinically significant bleeding) and the need for carotid reintervention. Stroke was defined as a clinically identified neurologic change correlated with new imaging findings of cerebral ischemia. Clinically significant bleeding was defined as the need for blood transfusion and/or return to the operating room for evacuation of a hematoma.

This study was approved by the institutional review board. All data analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC). Continuous variables were analyzed with Wilcoxon rank sum tests, and categorical variables were analyzed with contingency table analysis (chi-square or Fisher exact test). Rates of restenosis were analyzed dichotomously (>50% or <50%) and compared between groups using a multivariable logistic regression model created using all demographic and clinical variables determined a priori as clinically significant (Table 1). As this was a non-randomized trial and DAPT vs. SAPT was assigned by clinician discretion, a propensity score was built to reflect the probability that a patient would receive DAPT using univariate logistic regressions of all baseline characteristics. The variables included in the propensity model were age, gender, race, BMI, status of alcohol and smoking, as well comorbidities of coronary artery disease, congestive heart failure, diabetes mellitus, hypertension, peripheral vascular disease, and renal failure. DAPT patients were matched to SAPT patients in a one-to-one ratio using a caliper width of 0.2 of the pooled standard deviation of the propensity score and compared with the results on the basis of greedy matching with 3 or 4 decimal places.

Table 1.

Patient Demographics and Comorbidities.

	Entire Population			Propensity Score Matched Population
Variable	SAPT (N = 245)	DAPT (N = 1208)	p-value	SAPT (N = 206)	DAPT (N = 206)	p-value
Mean Age (SD)	71.8 (10.1)	69.7 (9.9)	0.003	71.4 (9.7)	71.6 (9.8)	0.809
Gender—Male	135 (55.1)	755 (62.5)	0.030	117 (56.8)	125 (60.7)	0.423
Race—White	219 (89.4)	1085 (89.8)	0.840	185 (89.8)	188 (91.3)	0.614
Mean BMI (SD)	29.8 (24.3)	29.0 (16.2)	0.550	28.7 (13.7)	28.1 (5.9)	0.620
Alcoholism	4 (1.6)	23 (1.9)	0.205	4 (1.9)	4 (1.9)	1.000
Coronary Artery Disease	119 (48.6)	601 (49.7)	0.736	107 (51.9)	110 (53.4)	0.767
Congestive Heart Failure	47 (19.2)	183 (15.2)	0.115	38 (18.5)	42 (20.4)	0.618
Diabetes Mellitus	88 (35.9)	360 (29.8)	0.059	71 (34.5)	81 (39.3)	0.307
Hypertension	184 (75.1)	839 (69.4)	0.077	157 (76.2)	158 (76.7)	0.908
Peripheral Vascular Disease	76 (31.0)	419 (34.7)	0.270	68 (33.0)	67 (32.0)	0.833
Renal Failure	33 (13.47)	125 (10.4)	0.152	27 (13.1)	28 (13.6)	0.885
Smoker/Smoking History	175 (80.6)	880 (82.8)	0.451	171 (83.0)	162 (78.6)	0.260

All numbers are reported as n, (%) unless otherwise stated. SD = Standard Deviation, SAPT = Single Antiplatelet Therapy Group, DAPT = Dual Antiplatelet Therapy Group.

Results

During the seven-year study period 1,453 patients underwent CEA at this center and met inclusion criteria for this study. Of those, 245 were placed on SAPT after surgery, with 175 patients receiving aspirin only and 70 receiving clopidogrel only. The DAPT group (aspirin and clopidogrel) consisted of 1,208 patients. Demographic data and comorbidities of this patient population are reported in Table 1. Statin therapy was similar between the study groups (DAPT 81.54% vs. SAPT 77.96%, p = 0.193).

No difference was identified between the SAPT group and DAPT group based on any of the post-operative complications evaluated (red blood cell transfusion requirements, return to the operating room for hematoma evacuation, stroke, myocardial infarction, or mortality). (Table 2)

Table 2.

Postoperative Complications.

Entire Population
Complication	SAPT (N = 245)	DAPT (N = 1208)	OR (95% CI)	p-value	Adjusted OR (95% CI)	p-value
Bleeding Complications, n (%)	7 (2.9)	29 (2.4)	0.84 (0.36, 1.93)	0.675	1.26 (0.47, 3.37)	0.646
Stroke, n (%)	4 (1.6)	14 (1.2)	0.71 (0.23, 2.16)	0.541	1.41 (0.35, 5.63)	0.624
Myocardial Infarction, n (%)	0 (0)	4 (0.3)	N/A	0.367	100 (0.1, 100)	0.957
Death, n (%)	0 (0)	2 (0.2)	N/A	0.524	100 (0.1, 100)	0.953
Propensity Score Matched Population
Complication	SAPT (N = 206)	DAPT (N = 206)	OR (95% CI)	p-value	Adjusted OR (95% CI)	p-value
Bleeding Complications, n (%)	4 (1.9)	7 (3.4)	1.77 (0.51, 6.16)	0.359	2.08 (0.53, 8.18)	0.298
Stroke, n (%)	2 (1.0)	5 (2.4)	2.53 (0.49, 13.23)	0.253	6.88 (0.60, 49.40)	0.122
Myocardial Infarction, n (%)	0 (0)	1 (0.5)	N/A	0.317	NA	NA
Death, n (%)	0 (0)	0 (0)	N/A	NA	NA	NA

SAPT = Single Antiplatelet Therapy Group, DAPT = Dual Antiplatelet Therapy Group, OR = Odds Ratio, CI = 95% Confidence Interval, N/A = Not Applicable, Bleeding Complications = Red Blood Cell Transfusions and Hematoma Evacuations.

Surveillance carotid duplex studies did not demonstrate a significant difference in restenosis rates between the SAPT and DAPT groups for the immediate timeframe (6.5% vs. 11.7% 50-79% stenosis, 0% vs. 2.2% 80-99% stenosis, 2.2% vs. 0.6% occlusion respectively, p = 0.368), and the intermediate timeframe (20.6% vs. 17.9% 50-79% stenosis, 1.1% vs. 1.0% 80-99% stenosis, 1.6% vs. 0.4% occlusion, p = 0.242). (Table 3)

Table 3.

Postoperative Restenosis.

	Entire Population			Propensity Score Matched Population
Time Elapsed From Surgery	SAPT (N = 245)	DAPT (N = 1208)	p-value	SAPT (N = 206)	DAPT (N = 206)	p-value
0-6 weeks, n (%)			0.368			0.238
< 50%	42 (91.3)	154 (85.6)		30 (88.2)	32 (80.0)
50-79%	3 (6.5)	21 (11.7)		3 (8.8)	8 (20.0)
80-99%	0 (0)	4 (2.2)		0 (0)	0 (0)
100% Occluded	1 (2.2)	1 (0.6)		1 (2.94)	0 (0)
6 weeks-2 years, n (%)			0.242			0.342
< 50%	145 (76.7)	737 (80.6)		118 (75.6)	127 (79.4)
50-79%	39 (20.6)	164 (17.9)		33 (21.2)	31 (19.4)
80-99%	2 (1.1)	9 (1.0)		2 (1.3)	2 (1.3)
100% Occluded	3 (1.6)	4 (0.4)		3 (1.9)	0 (0)
>2 years, n (%)			0.004			0.006
< 50%	80 (68.4)	440 (82.4)		66 (67.4)	82 (86.3)
50-79%	35 (29.9)	86 (16.1)		30 (30.6)	13 (13.7)
80-99%	0 (0)	3 (0.6)		0 (0)	0 (0)
100% Occluded	2 (1.7)	5 (0.9)		2 (2.0)	0 (0)

SAPT = Single Antiplatelet Therapy Group, DAPT = Dual Antiplatelet Therapy Group.

Restenosis rates from the delayed timeframe did demonstrate a significantly increased rate of restenosis in the SAPT compared with DAPT (68.4% vs. 82.4% <50% stenosis, 29.9% vs. 16.1% 50-79% stenosis, 0% vs. 0.6% 80-99% stenosis, 1.7% vs. 0.9% occlusion respectively, p = 0.004). (Table 3) Despite this difference, no difference in the need for re-intervention in patients with recurrent stenosis was found between the study groups (DAPT 3.8% vs. SAPT 3.3%, p = 0.684).

In multivariable analysis, findings were consistent with univariate analysis and the DAPT group demonstrated less restenosis than their SAPT group counterparts only in the delayed timeframe (17.6% vs. 31.6%, adjusted OR 0.48, 95% confidence interval (CI) 0.30-0.76, p = 0.002). (Table 4) A subgroup analysis was performed to evaluate the effect of individual antiplatelets dosages and no difference in restenosis rate was identified for any of the timeframes evaluated. Due to the low numbers of patients on aspirin 162 mg and 325 mg, these patients were considered as a single group. All clopidogrel users were on 75 mg. (Table 5).

Table 4.

Adjusted Postoperative Restenosis.

Entire Population
Time Elapsed From Surgery	SAPT (N = 245)	DAPT (N = 1208)	p-value	Adjusted OR (CI)	p-value
0-6 weeks, n (%)			0.305	3.16 (0.91, 10.94)	0.070
< 50%	42 (91.3)	154 (85.6)
≥ 50%	4 (8.7)	26 (14.4)
6 weeks-2 years, n (%)			0.221	0.78 (0.53, 1.15)	0.208
< 50%	145 (76.7)	737 (80.6)
≥ 50%	44 (23.3)	177 (19.4)
>2 years, n (%)			0.001	0.48 (0.30, 0.76)	0.002
< 50%	80 (68.4)	440 (82.4)
≥ 50%	37 (31.6)	94 (17.6)
Propensity Score Matched Population
Time Elapsed From Surgery	SAPT (N = 206)	DAPT (N = 206)	p-value	Adjusted OR (CI)	p-value
0-6 weeks, n (%)			0.338	23.25 (1.82, 297.8)	0.016
< 50%	30 (88.3)	32 (80.0)
≥ 50%	4 (11.8)	8 (20.0)
6 weeks-2 years, n (%)			0.427	0.90 (0.52, 1.58)	0.722
< 50%	118 (75.6)	127 (79.4)
≥ 50%	38 (24.4)	33 (20.6)
>2 years, n (%)			0.002	0.35 (0.16, 0.77)	0.009
< 50%	66 (67.4)	82 (86.3)
≥ 50%	32 (32.7)	13 (13.7)

SAPT = Single Antiplatelet Therapy Group, DAPT = Dual Antiplatelet Therapy Group, OR = Odds Ratio, CI = 95% Confidence Interval.

Table 5.

Subgroup Analysis of Postoperative Restenosis by Antiplatelet Dosage.

	0-6 weeks		6 weeks-2 years		>2 years
Antiplatelet Regimen	≥ 50% restenosis	p-value	≥ 50% restenosis	p-value	≥ 50% restenosis	p-value
SAPT, n (%)		0.977		0.975		0.984
81 MG ASA	1 (4.4)		12 (52.2)		10 (43.5)
>81 MG ASA	1 (4.2)		13 (54.2)		10 (41.7)
Clopidogrel	2 (5.3)		19 (50.0)		17 (44.7)
DAPT, n (%)		0.699		0.826		0.612
81 MG ASA	17 (9.3)		110 (60.4)		55 (30.2)
>81 MG ASA	9 (8.0)		66 (58.4)		38 (33.6)

SAPT = Single Antiplatelet Therapy Group, DAPT = Dual Antiplatelet Therapy Group, ASA = aspirin.

A propensity matched subanalysis was conducted to evaluate the primary outcome of restenosis, and to minimize the effect of measured confounders in patient demographics and comorbidities. The population data from this analysis are included in Table 1. No difference was identified between the study groups based on postoperative complications in the propensity matched population. (Table 2) With regard to restenosis following endarterectomy, the propensity matched analysis was consistent with the nonmatched analysis and identified a higher rate of restenosis in the SAPT in the delayed timeframe (p = 0.006). (Table 3) When multivariable analysis was applied to the propensity matched population, DAPT patients still had less restenosis in the delayed timeframe (13.7% vs 32.7%, adjusted OR 0.35, 95% CI 0.16-0.77, p = 0.009). A difference in restenosis was also identified in the immediate timeframe (p = 0.016), however the wide 95% CI (1.82-297.8) indicates that with the comparative small sample size in the SAPT group, the propensity score technique is not powerful enough to match representative patients and remove the selection bias in this group. (Table 4)

Discussion

Carotid restenosis following CEA remains a topic of debate. The primary focus of this study was to assess the effect of dual agent versus single agent antiplatelet therapy on carotid restenosis after CEA. Overall freedom from restenosis is depicted in Figure 1. Increased duplex velocity in the immediate postoperative period has been considered a result of technical error and residual atherosclerotic disease, or kinking/tortuosity of the artery. The rate of immediate restenosis identified during this review was similar between the study groups, but higher overall than would be expected. Standard practice in the authors’ community is to obtain the first postoperative study within 3 months of surgery, however most often during the third month. An acute event, or abnormality during the index procedure (increased velocity without abnormality seen on intraoperative duplex) would prompt a shorter interval follow-up, and explain the small number of studies performed and the higher rate of restenosis found during the first 6 weeks.

Restenosis during the intermediate timeframe is due to intimal hyperplasia and smooth muscle cell proliferation producing a collagen-based scar within the endarterectomy site. These lesions can regress over time and have a lower risk of ulceration or thromboembolic events than atherosclerotic plaque.^23,24 Additionally, it has been shown that restenosis does not occur in a linear fashion over time, with the highest risk for restenosis occurring within the first year after surgery and decreasing steadily thereafter.^24,25 The data obtained in this study indicate that these phenomenon are not significantly influenced by the presence of a second antiplatelet agent.

Delayed restenosis is due to progression of the atherosclerotic disease process.²⁴ At the authors institution DAPT is routinely continued for 3 months postoperatively, and then patients are transitioned back to SAPT unless previously on DAPT for an alternate indication (i.e. cardiac stents). It is possible that short-term perioperative use of DAPT has an impact on the progression of atherosclerotic disease long-term but further study is needed to further delineate this relationship. Although reduction in delayed restenosis was identified, the reintervention rate in the DAPT group was not decreased. Previously reported data demonstrate an increased long-term risk of bleeding in patients on multiple antiplatelet agents.^26,27 As such, it is inappropriate to recommend DAPT as a preventative treatment for restenosis following CEA.

Postoperative stroke, MI, and mortality rates identified in this review are consistent with the national standard for both the SAPT and DAPT groups, and no difference was identified between study groups in this review.²⁸ DAPT has previously been associated with increased bleeding events perioperatively; however this finding has not been widely reproduced in the literature, and was not present in this study population.^29
-31

There are several limitations to this study. It is a retrospective review performed at a single institution and the results are representative of the local population and may not be applicable to all patient populations. It is also subject to the shortcomings inherent in all retrospective reviews. Data presented in this review are from 2007 through 2013, which is the timeframe during which all surgeons were hospital-employed, and all follow-up duplex studies were performed at the in-house vascular laboratory. After this period individual practices and private vascular laboratories were established making complete collection of more recent data impossible. The exact timeline and interval for post-operative duplex studies was provider dependent, and not standardized across all patients. Patients that were transitioned to SAPT after 3 months were not identified or analyzed separately from those that remained on DAPT indefinitely. Finally, although the standard technique employed at the authors’ institution is the perform a longitudinal arteriotomy with patch closure, this is not universal. The type of patch used, frequency of eversion endarterectomy, and primary closure of the arteriotomy were not evaluated in this study.

Conclusion

The data presented in this retrospective review do not demonstrate an increased risk of perioperative complications in patients managed with dual antiplatelet therapy following CEA. Furthermore, no statistically significant effect on early and midterm restenosis was identified. The incidence of late restenosis following carotid endarterectomy was decreased in those patients on dual antiplatelet therapy, however this did not translate into decreased carotid reinterventions.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics Statement

This project was reviewed and approved by the Institutional Review Board of Christiana Care.

CCC# 36198-The Role of Dual Antiplatelet Therapy in the Prevention of Restenosis After Carotid Endarterectomy: (DDD# 603591).

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Owen S. Glotzer

Susanna S. Hill

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