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Factors affecting cardiovascular and cerebrovascular complications of carotid artery stenting in Northern Michigan: A retrospective study
Cardiovascular Revascularization Medicine xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Cardiovascular Revascularization Medicine
Factors affecting cardiovascular and cerebrovascular complications of carotid artery stenting in Northern Michigan: A retrospective study☆,☆☆ Dalia F. Mammo a,⁎, Chin-I Cheng a, Neli P. Ragina a, Firas Alani a,b a b
Central Michigan University College of Medicine, 1280 East Campus Drive, Mount Pleasant, MI 48859, USA Covenant Cardiology, Covenant Healthcare System, 900 Cooper Ave, Saginaw, MI 48602, USA
a r t i c l e
i n f o
Article history: Received 1 March 2017 Received in revised form 15 March 2017 Accepted 22 March 2017 Available online xxxx Keywords: Carotid artery stenting Periprocedural complications MACCE
a b s t r a c t Background: This study seeks to identify factors associated with periprocedural complications of carotid artery stenting (CAS) to best understand CAS complication rates and optimize patient outcomes. Periprocedural complications include major adverse cardiovascular and cerebrovascular events (MACCE) that include myocardial infarction (MI), stroke, or death. Methods: We retrospectively analyzed 181 patients from Northern Michigan who underwent CAS. Rates of stroke, MI, and death occurring within 30 days post-procedure were examined. Associations of open vs. closed cell stent type, demographics, comorbidities, and symptomatic carotid stenosis were compared to determine significance. All patients had three NIH Stroke Scale (NIHSS) exams: at baseline, 24 h post-procedure, and at the one-month visit. Cardiac enzymes were measured twice in all patients, within 24 h post-procedure. All patients were treated with dual anti-platelet therapy for at least 6 months post-procedure. Results: Three patients (1.66%) experienced a major complication within one-month post-procedure. These complications included one MI (0.55%), one stroke (0.55%), and one death (0.55%). The following variable factors were not associated with the occurrence of MACCE complications within 30 days post-procedure: stent design (open vs. closed cell) (p = 1.000), age ≥80 (p = 0.559), smoking history (p = 0.569), hypertension (p = 1.000), diabetes (p = 1.000), and symptomatic carotid stenosis (p = 0.254). Conclusions: Age of 80 years old or above, symptomatic carotid stenosis, open-cell stent design, and history of diabetes, smoking, or hypertension were not found to have an association with MACCE within 1 month after CAS. Future studies using a greater sample size will be beneficial to better assess periprocedural complication risks of CAS, while also considering the effect of operator experience and technological advancements on decreasing periprocedural complication rates. © 2017 Elsevier Inc. All rights reserved.
1. Introduction The carotid artery stenting (CAS) procedure was approved in 2004 and is designed as an alternative for patients who are considered high risk candidates for carotid endarterectomy (CEA) and would benefit equally from stenting or surgery for carotid artery stenosis. CAS is used as an alternative to CEA as an intervention for carotid artery stenosis, as it may prove to be less invasive [1]. Both procedures seek to improve blood flow and minimize the risk of distal embolization to the brain tissue. Findings of the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial and the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) ☆ Conflicts of interest: none. ☆☆ Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. ⁎ Corresponding author at: Central Michigan University College of Medicine, 1280 East Campus Drive, Mount Pleasant, MI 48859, USA. E-mail addresses: [email protected] (D.F. Mammo), [email protected] (C.-I. Cheng), [email protected] (N.P. Ragina), [email protected] (F. Alani).
established CAS as a safe and efficacious alternative to CEA for long term stroke prevention among patients at high surgical risk for CEA [2]. Another advantage is that CAS can be utilized for high cervical lesions (i.e. at the level of C2 or above) of the carotid artery [1]. It is necessary to continuously work towards further reducing the rate of adverse events in order to optimize patient outcomes [3]. Major adverse cardiovascular and cerebrovascular events (MACCE) that may occur following CAS include myocardial infarction (MI) within 24 h post procedure, any new cerebrovascular event 1–31 days post procedure, or death 1–31 days post procedure [4]. Prior studies have found that octogenarians and patients with symptomatic carotid stenosis may be at increased risk for an MI, stroke, or death following CAS, while sex and comorbidities do not affect the risk of periprocedural complications [5–7]. Studies also suggest that use of an open cell stent may increase patients' risk for complications by virtue of creating less scaffolding of the atheromatous plaque [3,8]. This study analyzes cardiovascular and cerebrovascular periprocedural complications of CAS, seeking to identify risk factors and areas of improvement to prevent adverse outcomes in a small community hospital setting.
http://dx.doi.org/10.1016/j.carrev.2017.03.023 1553-8389/© 2017 Elsevier Inc. All rights reserved.
Please cite this article as: Mammo DF, et al, Factors affecting cardiovascular and cerebrovascular complications of carotid artery stenting in Northern Michigan: A retrospectiv..., Cardiovasc Revasc Med (2017), http://dx.doi.org/10.1016/j.carrev.2017.03.023
2
D.F. Mammo et al. / Cardiovascular Revascularization Medicine xxx (2017) xxx–xxx
2. Material and methods We retrospectively analyzed 181 patients from Northern Michigan who underwent CAS. Rates of stroke, MI, and death occurring within 30 days post procedure were examined. Statistical analysis using descriptive statistics and Fisher's Exact Test was performed. Associations of open vs. closed cell stent type, demographics (age), comorbidities, and symptomatic carotid stenosis with p-values for two-sided test ≤0.05 were considered statistically significant. Six patients were excluded from the stent type analysis as their procedures were classified as an in-stent restenosis. In determining complications, several factors were evaluated. All patients had three NIH Stroke Scale (NIHSS) exams: at baseline, at 24 h post procedure, and a third one at the one-month visit. The baseline and post procedural NIHSS exams were performed by an independent neurologist, and the same neurologist was maintained for each case (pre and post procedural). The NIHSS exams at the one-month visits were completed by the research nurse and team during the office visit. The NIH Stroke Scale was used to further subclassify cerebrovascular events into TIA, minor stroke, or major stroke. Cardiac enzymes, including Troponin I levels, were measured twice in all patients, within 24 h post procedure at intervals of 6–8 h. Additionally, all patients were treated with dual anti-platelet therapy for at least 6 months post procedure. Myocardial infarction was defined as any positive troponin I within 24 h post procedure. Major strokes were defined by an increase in NIHSS of more than 3 points from the baseline NIHSS, while minor strokes were defined by an increase in the NIHSS by equal or less than 3 points from baseline. TIAs were defined as any new neurological event that occurred and resolved spontaneously within 24 h from the time of onset. 2.1. Statistical analysis The type of stent patients received (open vs closed cell), the patient with symptomatic carotid stenosis or not (yes vs no), the patient greater than 80 years old or not (yes vs no), and the patient with comorbidities such as diabetes mellitus (yes vs no), smoking (yes vs no), and hypertension (yes vs no) are considered as categorical data. The associations of those variables to CAS complications that include myocardial infarction (MI), stroke, or death (yes vs no) were tested using the Fisher's Exact Test. Each variable was examined by performing descriptive statistics. The analytical results were considered to be significant when p values were less than or equal to 0.05. All the analysis was implemented using IBM SPSS Statistics version 23.0. 3. Results Demographics, clinical variables, and complication outcomes were collected from 181 patients of whom 37% were female, 45% had symptomatic carotid stenosis, 40% were diabetic, 93% had hypertension, 74% had a history of smoking, and 24% were octogenarians (Table 1). The mean age was 72 (range: 51–92), with the majority of patients younger than 80 years old. Of the 175 patients who received an open or closed cell stent, 76% received an open cell stent. Out of all 181 patients, only three patients (1.66%) experienced a major complication within 1-month post procedure. These complications were comprised of one MI event (0.55%), one stroke event defined as a major stroke (0.55%), and one death event (0.55%). All three CAS complications occurred in male patients who received an open cell stent type, had a history of smoking and hypertension, and did not have symptomatic carotid stenosis. Of the three patients, one was an octogenarian and two were under the age of 80. Therefore, the Fisher's Exact Test is used to account for the unequally distributed data. The results from Fisher's Exact Test indicated that there is insufficient evidence to support associations between CAS complications and the variables. The following variable factors were not associated with the occurrence of MACCE within 30 days post procedure: stent design (open vs. closed
Table 1 Descriptive statistics of demographic and clinical features of patients who underwent CAS.
Feature Age ≥80 b80 Sex Male Female Symptomatic Yes No Diabetic Yes No Hypertension Yes No Smoking History Yes No Stent Typea Open Cell Closed Cell
All Patients who Underwent CAS (n = 181)
Patients With Complications After CAS (n = 3)
Number (%)
Number (%)
43 (24) 138 (76)
1 (33) 2 (67)
114 (63) 67 (37)
3 (100) 0 (0)
81 (45) 100 (55)
0 (0) 3 (100)
73 (40) 108 (60)
1 (33) 2 (67)
169 (93) 12 (7)
3 (100) 0 (0)
134 (74) 47 (26)
3 (100) 0 (0)
133 (76) 42 (24)
3 (100) 0 (0)
CAS = Carotid Artery Stenting. a n = 175 for all patients who underwent CAS; 6 patients were excluded from the stent type analysis as neither an open or closed cell stent was used.
cell) (p = 1.000), age ≥ 80 (p = 0.559), smoking history (p = 0.569), hypertension (p = 1.000), diabetes (p = 1.000), and symptomatic carotid stenosis (p = 0.254), as presented in Table 2. Demographic and clinical characteristics are outlined in Table 1 for all patients and for patients who experienced complications. 4. Discussion This study found no association between sex, age, symptomatic carotid stenosis, stent type, smoking, hypertension, or diabetes and increased risk of MACCE within 30 days of CAS. In terms of sex-based differences for MACCE risk following CAS, in our study there was no statistical significance that the sex of the patient would increase or decrease the risk of a stroke, MI, or death when undergoing CAS. Similarly, other studies examining how sex may impact CAS patients showed no difference in MACCE rates when comparing men and women, indicating that sex does not correlate to the perioperative risk of MACCE after CAS [7]. In a study by Howard et al., 30-day stroke and death rates following CAS were comparable among 579 women and 985 men, and there was no correlation found between the effect of sex on CAS complications when looking at stroke alone, MI alone, death alone, or stroke, MI, and death compositely [7]. Considering the effect of age on CAS complications, Doig et al. found that age increased the risk of MACCE following CAS by 1.24 for each 5 years (95% CI 1.07–1.42, p = .003) [9]. Similarly, a study by Cheng et al. showed age as a risk factor (HR: 1.027, 95% CI: 1.002–1.053) for Table 2 Fisher's exact test results for the prevalence of complications after undergoing CAS. Feature
P value
Age ≥ 80 vs. b80 Symptomatic Diabetic Hypertension Smoking History Open vs. Closed Cell Stent Type
0.559 0.254 1.000 1.000 0.569 1.000
P-values ≤0.05 were considered statistically significant. CAS = Carotid Artery Stenting.
Please cite this article as: Mammo DF, et al, Factors affecting cardiovascular and cerebrovascular complications of carotid artery stenting in Northern Michigan: A retrospectiv..., Cardiovasc Revasc Med (2017), http://dx.doi.org/10.1016/j.carrev.2017.03.023
D.F. Mammo et al. / Cardiovascular Revascularization Medicine xxx (2017) xxx–xxx
every 1 year older [6]. The CREST study revealed similar results regarding age and suggested vascular tortuosity and calcification as mechanisms responsible for the increased risk of complications following CAS in octogenarians [5]. Lam et al. also found that octogenarians experienced more occurrences of MACCE than patients younger than 80 years old, at 10.8% vs. 1% (p = .012) of the 3.7% who experienced complications in their study [10]. Complementing the CREST study, Lam et al. found that octogenarians had an increased incidence of unfavorable anatomic characteristics compared to patients less than 80 years old, such as arch elongation (56% vs 82%, p = .008), arch calcification (30% vs 59%, p = .003), common carotid artery origin stenosis (22% vs 47%, p = .006), common carotid artery tortuosity (38% vs 70%, p = .0009), internal carotid artery tortuosity (50% vs 74%, p = .019), and treated lesion stenosis (56% vs 82%, p = .007) [10]. The CREST study further proposes that age should be highly considered when deciding between CAS and CEA for a patient, as younger patients have been found to have better outcomes with CAS and older patients have been found to have better outcomes with CEA when it pertains to cerebrovascular events [5]. Paradoxically, the CREST study also suggests that older patients above age 80 who undergo CEA have been found to have greater coronary events (i.e. periprocedural MI) compared to those who undergo CAS [5]. However, conflicting results are found in our study and other studies. Shawl et al. reported no differences in complications among octogenarians and younger patients. Their study focused on 42 octogenarians among a group of 170 patients with a 30-day stroke and death rate of 2.9% [1]. Whitlow also reported results of 305 CAS patients, of whom 28% were more than 80 years old, indicating that there was no significant increase in stroke, MI, or death among octogenarians [11]. Among other studies, Cheng et al. also found that symptomatic patients were at risk for MACCE following CAS (HR: 1.604, 95% CI: 1.027–2.507) [6]. It has been suggested that complications are more likely to occur in symptomatic patients due to the unstable nature of the atheromatous plaque [9]. Regarding the type of stent used during CAS, Doig et al. found that open cell stents (RR 1.92, 95% CI 1.11–3.33, p = .019) increased the risk of MACCE following CAS [9]. The SPACE study also indicated an increased risk of stroke or death when using an open cell stent design (OR 2.13, 95% CI 1.07–3.76, p = 0.029) [8]. While open cell stents are more flexible, aiding in conforming to tortuous vessels, they have larger cells and thus a smaller amount of coverage of the affected lesion compared to closed cell stent designs. The cells are smaller in closed cell stents, allowing them to more effectively protect against embolism and subsequent complications due to the greater coverage of the affected lesion, enabling them to more effectively hold fractured plaque and debris [3,8]. It is possible that an association exists between stent design, symptomatic carotid stenosis, or advanced age and periprocedural CAS complications. Nonetheless, this association was not reflected in our study among other smaller studies, possibly due to the insufficient number of events to detect true associations. Additionally, the continuous improvement in technology over the past two decades and increase in operator experience may contribute to our findings as well as a decreased risk for periprocedural MACCE. A study by Vogel et al. showed that the experience of CAS operators directly correlates to procedure outcomes [12]. The CAS procedures analyzed for our study were performed by one experienced physician at one community hospital, which may have contributed to our promising results. Similar or different analyses may result from other physicians at other locations. Velez et al. also emphasized the importance of careful case selection in decreasing complication rates [13]. As in our study, studies by Vogel et al. and Velez et al. also presented a decline in MACCE within 30 days after CAS, which may be a result of improvements in technology, technique, operator experience, and patient selection [12,13]. Going forward, it is important to consider that operator experience and advancements in technology have led to significant improvements in CAS outcomes over the past few years. Continuous improvement of these factors will only lead to
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further decline of the incidence of MACCE. Over the last decade, 30day MACCE was reduced from 8% to 10% to 2%–3% following CAS [4]. Additionally, our study's small sample size may lack the statistical power needed to adequately identify significant risk factors. Future randomized studies will be helpful in analyzing these factors among a larger number of patients. The indication for dual anti-platelet therapy has been studied, as platelet activation highly contributes to stent occlusion and embolic complications [14]. There has been prolonged platelet activation seen in stented vessels, indicating the necessity for increased platelet inhibition specifically for CAS patients [15]. This phenomenon is triggered by a decrease in peripheral platelet count after CAS, leading to an increased amount of circulating platelets, whose subsequent activation contributes to the development of stent thrombosis [15]. In our study, all patients received dual anti-platelet therapy for at least six months, a regimen that has been found to reduce adverse neurological complications [14,16]. A study by Mckevitt et al. demonstrated the importance of patients receiving aspirin and clopidogrel for reduction in neurological complications within 30 days of CAS, the benefits of which have been demonstrated in several other trials as well [14,16]. With no significant findings of risk factors, in patients with severe carotid stenosis above or equal to 80%, it may be worthwhile to perform CAS prophylactically. According to a study by Gribar, in the Beaumont CAS registry the 30-day MACCE rate was 2.6% and the 5-year risk of ipsilateral stroke was 4.5% (b1% per year). The benefit of prophylactic CAS offsets the low risk of developing stroke [4]. In this study, all three CAS complications occurred for a specific group of male patients who received an open cell stent type, had a history of smoking and hypertension, and did not have symptomatic carotid stenosis. This is reasonable since the majority of patients in our study fall into these categories, and this could have limited the study to further explore how each variable could affect the CAS complication rate individually. However, this study provides the preliminary results and further studies utilizing a larger sample size will be used to further expand on this knowledge. 5. Conclusions Age of 80 years old or above was not found to have an association with the occurrence of complications of stroke, MI, or death within 1 month after CAS. Similarly, those with symptomatic carotid stenosis, an open cell stent design, or a history of diabetes, smoking, or hypertension were not found to have an association with MACCE within 1 month after CAS. Future studies using a greater sample size will be beneficial to better assess periprocedural complication risks of CAS. Nonetheless, these findings may highlight the possibility of the effect of advanced technology and experience in the carotid artery stenting procedure on decreasing overall periprocedural complication rates, evening the playing field between different important variables, such as advanced age and symptomatic nature, and their impact on the incidence of periprocedural complication rates. References [1] Shawl F, Kadro W, Domanski MJ, Lapetina FL, Iqbal AA, Dougherty KG, et al. Safety and efficacy of elective carotid artery stenting in high-risk patients. J Am Coll Cardiol 2000;35(7):1721–8. [2] Jalbert JJ, Nguyen LL, Gerhard-herman MD, Jaff MR, White CJ, Rothman AT, et al. Outcomes after carotid artery stenting in Medicare beneficiaries, 2005 to 2009. JAMA Neurol 2015;72(3):276–86. [3] Hart JP, Peeters P, Verbist J, Deloose K, Bosiers M. Do device characteristics impact outcome in carotid artery stenting? J Vasc Surg 2006;44(4):725–30. [4] Gribar JJ, Jiddou M, Choksi N, Abbas AE, Bowers T, Kazmierczak C, et al. Carotid stenting in high-risk patients: early and late outcomes. J Interv Cardiol 2011; 24(3):247–53. [5] Brott TG, Hobson II RW, Howard G, Roubin GS, Clark WM, Brooks W, et al. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010; 363:11–23. [6] Cheng C-A, Chien W-C, Hsu C-Y, Lin H-C, Chiu H-W. Risk analysis of carotid stent from a population-based database in Taiwan. In: Hansen CL, editor. Medicine, 95(35); 2016. p. e4747.
Please cite this article as: Mammo DF, et al, Factors affecting cardiovascular and cerebrovascular complications of carotid artery stenting in Northern Michigan: A retrospectiv..., Cardiovasc Revasc Med (2017), http://dx.doi.org/10.1016/j.carrev.2017.03.023
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[7] Howard VJ, Voeks JH, Lutsep HL, Mackey A, Milot G, Sam AD, et al. Does sex matter? Thirty-day stroke and death rates after carotid artery stenting in women versus men: results from the 0carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) lead-in phase. Stroke 2009;40(4):1140–7. [8] Jansen O, Fiehler J, Hartmann M, Brückmann H. Protection or non-protection in carotid stent angioplasty: the influence of interventional techniques on outcome data from the SPACE trial. Stroke 2009;40:841–6. [9] Doig D, Turner EL, Dobson J, Featherstone RL, Lo RT, Gaines PA, et al. Predictors of stroke, myocardial infarction or death within 30 days of carotid artery stenting: results from the International Carotid Stenting Study. Eur J Vasc Endovasc Surg 2016;51(3):327–34. [10] Lam RC, Lin SC, DeRubertis B, Hynecek R, Kent KC, Faries PL. The impact of increasing age on anatomic factors affecting carotid angioplasty and stenting. J Vasc Surg 2007;45:875–80. [111] Hobson II RW, Howard VJ, Roubin GS, Brott TG, Ferguson RD, Popma JJ, et al. Carotid artery stenting is associated with increased complications in octogenarians: 30-day stroke and death rates in the CREST lead-in phase. J Vasc Surg 2004;40(6):1106–11.
[12] Vogel TR, Dombrovskiy VY, Graham AM. Carotid artery stenting in the nation: the influence of hospital and physician volume on outcomes. Vasc Endovasc Surg 2010;44: 89–94. [13] Velez CA, White CJ, Reilly JP, Jenkins JS, Collins TJ, Grise MA, et al. Carotid artery stent placement is safe in the very elderly (N or =80 years). Catheter Cardiovasc Interv 2008;72:303–8. [14] Mckevitt FM, Randall MS, Cleveland TJ, Gaines PA, Tan KT, Venables GS. The benefits of combined anti-platelet treatment in carotid artery stenting. Eur J Vasc Endovasc Surg 2005;29(5):522–7. [15] Gawaz M, Neumann FJ, Ott I, May A, Rudiger S, Schomig A. Changes in membrane glycoproteins of circulating platelets after coronary stent implantation. Heart 1996;76:166–72. [16] Müller C, Büttner HJ, Petersen J, Roskamm H. A randomized comparison of clopidogrel and aspirin versus ticlopidine and aspirin after the placement of coronary-artery stents. Circulation 2000;101(6):590–3.
Please cite this article as: Mammo DF, et al, Factors affecting cardiovascular and cerebrovascular complications of carotid artery stenting in Northern Michigan: A retrospectiv..., Cardiovasc Revasc Med (2017), http://dx.doi.org/10.1016/j.carrev.2017.03.023
Contents lists available at ScienceDirect
Cardiovascular Revascularization Medicine
Factors affecting cardiovascular and cerebrovascular complications of carotid artery stenting in Northern Michigan: A retrospective study☆,☆☆ Dalia F. Mammo a,⁎, Chin-I Cheng a, Neli P. Ragina a, Firas Alani a,b a b
Central Michigan University College of Medicine, 1280 East Campus Drive, Mount Pleasant, MI 48859, USA Covenant Cardiology, Covenant Healthcare System, 900 Cooper Ave, Saginaw, MI 48602, USA
a r t i c l e
i n f o
Article history: Received 1 March 2017 Received in revised form 15 March 2017 Accepted 22 March 2017 Available online xxxx Keywords: Carotid artery stenting Periprocedural complications MACCE
a b s t r a c t Background: This study seeks to identify factors associated with periprocedural complications of carotid artery stenting (CAS) to best understand CAS complication rates and optimize patient outcomes. Periprocedural complications include major adverse cardiovascular and cerebrovascular events (MACCE) that include myocardial infarction (MI), stroke, or death. Methods: We retrospectively analyzed 181 patients from Northern Michigan who underwent CAS. Rates of stroke, MI, and death occurring within 30 days post-procedure were examined. Associations of open vs. closed cell stent type, demographics, comorbidities, and symptomatic carotid stenosis were compared to determine significance. All patients had three NIH Stroke Scale (NIHSS) exams: at baseline, 24 h post-procedure, and at the one-month visit. Cardiac enzymes were measured twice in all patients, within 24 h post-procedure. All patients were treated with dual anti-platelet therapy for at least 6 months post-procedure. Results: Three patients (1.66%) experienced a major complication within one-month post-procedure. These complications included one MI (0.55%), one stroke (0.55%), and one death (0.55%). The following variable factors were not associated with the occurrence of MACCE complications within 30 days post-procedure: stent design (open vs. closed cell) (p = 1.000), age ≥80 (p = 0.559), smoking history (p = 0.569), hypertension (p = 1.000), diabetes (p = 1.000), and symptomatic carotid stenosis (p = 0.254). Conclusions: Age of 80 years old or above, symptomatic carotid stenosis, open-cell stent design, and history of diabetes, smoking, or hypertension were not found to have an association with MACCE within 1 month after CAS. Future studies using a greater sample size will be beneficial to better assess periprocedural complication risks of CAS, while also considering the effect of operator experience and technological advancements on decreasing periprocedural complication rates. © 2017 Elsevier Inc. All rights reserved.
1. Introduction The carotid artery stenting (CAS) procedure was approved in 2004 and is designed as an alternative for patients who are considered high risk candidates for carotid endarterectomy (CEA) and would benefit equally from stenting or surgery for carotid artery stenosis. CAS is used as an alternative to CEA as an intervention for carotid artery stenosis, as it may prove to be less invasive [1]. Both procedures seek to improve blood flow and minimize the risk of distal embolization to the brain tissue. Findings of the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial and the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) ☆ Conflicts of interest: none. ☆☆ Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. ⁎ Corresponding author at: Central Michigan University College of Medicine, 1280 East Campus Drive, Mount Pleasant, MI 48859, USA. E-mail addresses: [email protected] (D.F. Mammo), [email protected] (C.-I. Cheng), [email protected] (N.P. Ragina), [email protected] (F. Alani).
established CAS as a safe and efficacious alternative to CEA for long term stroke prevention among patients at high surgical risk for CEA [2]. Another advantage is that CAS can be utilized for high cervical lesions (i.e. at the level of C2 or above) of the carotid artery [1]. It is necessary to continuously work towards further reducing the rate of adverse events in order to optimize patient outcomes [3]. Major adverse cardiovascular and cerebrovascular events (MACCE) that may occur following CAS include myocardial infarction (MI) within 24 h post procedure, any new cerebrovascular event 1–31 days post procedure, or death 1–31 days post procedure [4]. Prior studies have found that octogenarians and patients with symptomatic carotid stenosis may be at increased risk for an MI, stroke, or death following CAS, while sex and comorbidities do not affect the risk of periprocedural complications [5–7]. Studies also suggest that use of an open cell stent may increase patients' risk for complications by virtue of creating less scaffolding of the atheromatous plaque [3,8]. This study analyzes cardiovascular and cerebrovascular periprocedural complications of CAS, seeking to identify risk factors and areas of improvement to prevent adverse outcomes in a small community hospital setting.
http://dx.doi.org/10.1016/j.carrev.2017.03.023 1553-8389/© 2017 Elsevier Inc. All rights reserved.
Please cite this article as: Mammo DF, et al, Factors affecting cardiovascular and cerebrovascular complications of carotid artery stenting in Northern Michigan: A retrospectiv..., Cardiovasc Revasc Med (2017), http://dx.doi.org/10.1016/j.carrev.2017.03.023
2
D.F. Mammo et al. / Cardiovascular Revascularization Medicine xxx (2017) xxx–xxx
2. Material and methods We retrospectively analyzed 181 patients from Northern Michigan who underwent CAS. Rates of stroke, MI, and death occurring within 30 days post procedure were examined. Statistical analysis using descriptive statistics and Fisher's Exact Test was performed. Associations of open vs. closed cell stent type, demographics (age), comorbidities, and symptomatic carotid stenosis with p-values for two-sided test ≤0.05 were considered statistically significant. Six patients were excluded from the stent type analysis as their procedures were classified as an in-stent restenosis. In determining complications, several factors were evaluated. All patients had three NIH Stroke Scale (NIHSS) exams: at baseline, at 24 h post procedure, and a third one at the one-month visit. The baseline and post procedural NIHSS exams were performed by an independent neurologist, and the same neurologist was maintained for each case (pre and post procedural). The NIHSS exams at the one-month visits were completed by the research nurse and team during the office visit. The NIH Stroke Scale was used to further subclassify cerebrovascular events into TIA, minor stroke, or major stroke. Cardiac enzymes, including Troponin I levels, were measured twice in all patients, within 24 h post procedure at intervals of 6–8 h. Additionally, all patients were treated with dual anti-platelet therapy for at least 6 months post procedure. Myocardial infarction was defined as any positive troponin I within 24 h post procedure. Major strokes were defined by an increase in NIHSS of more than 3 points from the baseline NIHSS, while minor strokes were defined by an increase in the NIHSS by equal or less than 3 points from baseline. TIAs were defined as any new neurological event that occurred and resolved spontaneously within 24 h from the time of onset. 2.1. Statistical analysis The type of stent patients received (open vs closed cell), the patient with symptomatic carotid stenosis or not (yes vs no), the patient greater than 80 years old or not (yes vs no), and the patient with comorbidities such as diabetes mellitus (yes vs no), smoking (yes vs no), and hypertension (yes vs no) are considered as categorical data. The associations of those variables to CAS complications that include myocardial infarction (MI), stroke, or death (yes vs no) were tested using the Fisher's Exact Test. Each variable was examined by performing descriptive statistics. The analytical results were considered to be significant when p values were less than or equal to 0.05. All the analysis was implemented using IBM SPSS Statistics version 23.0. 3. Results Demographics, clinical variables, and complication outcomes were collected from 181 patients of whom 37% were female, 45% had symptomatic carotid stenosis, 40% were diabetic, 93% had hypertension, 74% had a history of smoking, and 24% were octogenarians (Table 1). The mean age was 72 (range: 51–92), with the majority of patients younger than 80 years old. Of the 175 patients who received an open or closed cell stent, 76% received an open cell stent. Out of all 181 patients, only three patients (1.66%) experienced a major complication within 1-month post procedure. These complications were comprised of one MI event (0.55%), one stroke event defined as a major stroke (0.55%), and one death event (0.55%). All three CAS complications occurred in male patients who received an open cell stent type, had a history of smoking and hypertension, and did not have symptomatic carotid stenosis. Of the three patients, one was an octogenarian and two were under the age of 80. Therefore, the Fisher's Exact Test is used to account for the unequally distributed data. The results from Fisher's Exact Test indicated that there is insufficient evidence to support associations between CAS complications and the variables. The following variable factors were not associated with the occurrence of MACCE within 30 days post procedure: stent design (open vs. closed
Table 1 Descriptive statistics of demographic and clinical features of patients who underwent CAS.
Feature Age ≥80 b80 Sex Male Female Symptomatic Yes No Diabetic Yes No Hypertension Yes No Smoking History Yes No Stent Typea Open Cell Closed Cell
All Patients who Underwent CAS (n = 181)
Patients With Complications After CAS (n = 3)
Number (%)
Number (%)
43 (24) 138 (76)
1 (33) 2 (67)
114 (63) 67 (37)
3 (100) 0 (0)
81 (45) 100 (55)
0 (0) 3 (100)
73 (40) 108 (60)
1 (33) 2 (67)
169 (93) 12 (7)
3 (100) 0 (0)
134 (74) 47 (26)
3 (100) 0 (0)
133 (76) 42 (24)
3 (100) 0 (0)
CAS = Carotid Artery Stenting. a n = 175 for all patients who underwent CAS; 6 patients were excluded from the stent type analysis as neither an open or closed cell stent was used.
cell) (p = 1.000), age ≥ 80 (p = 0.559), smoking history (p = 0.569), hypertension (p = 1.000), diabetes (p = 1.000), and symptomatic carotid stenosis (p = 0.254), as presented in Table 2. Demographic and clinical characteristics are outlined in Table 1 for all patients and for patients who experienced complications. 4. Discussion This study found no association between sex, age, symptomatic carotid stenosis, stent type, smoking, hypertension, or diabetes and increased risk of MACCE within 30 days of CAS. In terms of sex-based differences for MACCE risk following CAS, in our study there was no statistical significance that the sex of the patient would increase or decrease the risk of a stroke, MI, or death when undergoing CAS. Similarly, other studies examining how sex may impact CAS patients showed no difference in MACCE rates when comparing men and women, indicating that sex does not correlate to the perioperative risk of MACCE after CAS [7]. In a study by Howard et al., 30-day stroke and death rates following CAS were comparable among 579 women and 985 men, and there was no correlation found between the effect of sex on CAS complications when looking at stroke alone, MI alone, death alone, or stroke, MI, and death compositely [7]. Considering the effect of age on CAS complications, Doig et al. found that age increased the risk of MACCE following CAS by 1.24 for each 5 years (95% CI 1.07–1.42, p = .003) [9]. Similarly, a study by Cheng et al. showed age as a risk factor (HR: 1.027, 95% CI: 1.002–1.053) for Table 2 Fisher's exact test results for the prevalence of complications after undergoing CAS. Feature
P value
Age ≥ 80 vs. b80 Symptomatic Diabetic Hypertension Smoking History Open vs. Closed Cell Stent Type
0.559 0.254 1.000 1.000 0.569 1.000
P-values ≤0.05 were considered statistically significant. CAS = Carotid Artery Stenting.
Please cite this article as: Mammo DF, et al, Factors affecting cardiovascular and cerebrovascular complications of carotid artery stenting in Northern Michigan: A retrospectiv..., Cardiovasc Revasc Med (2017), http://dx.doi.org/10.1016/j.carrev.2017.03.023
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every 1 year older [6]. The CREST study revealed similar results regarding age and suggested vascular tortuosity and calcification as mechanisms responsible for the increased risk of complications following CAS in octogenarians [5]. Lam et al. also found that octogenarians experienced more occurrences of MACCE than patients younger than 80 years old, at 10.8% vs. 1% (p = .012) of the 3.7% who experienced complications in their study [10]. Complementing the CREST study, Lam et al. found that octogenarians had an increased incidence of unfavorable anatomic characteristics compared to patients less than 80 years old, such as arch elongation (56% vs 82%, p = .008), arch calcification (30% vs 59%, p = .003), common carotid artery origin stenosis (22% vs 47%, p = .006), common carotid artery tortuosity (38% vs 70%, p = .0009), internal carotid artery tortuosity (50% vs 74%, p = .019), and treated lesion stenosis (56% vs 82%, p = .007) [10]. The CREST study further proposes that age should be highly considered when deciding between CAS and CEA for a patient, as younger patients have been found to have better outcomes with CAS and older patients have been found to have better outcomes with CEA when it pertains to cerebrovascular events [5]. Paradoxically, the CREST study also suggests that older patients above age 80 who undergo CEA have been found to have greater coronary events (i.e. periprocedural MI) compared to those who undergo CAS [5]. However, conflicting results are found in our study and other studies. Shawl et al. reported no differences in complications among octogenarians and younger patients. Their study focused on 42 octogenarians among a group of 170 patients with a 30-day stroke and death rate of 2.9% [1]. Whitlow also reported results of 305 CAS patients, of whom 28% were more than 80 years old, indicating that there was no significant increase in stroke, MI, or death among octogenarians [11]. Among other studies, Cheng et al. also found that symptomatic patients were at risk for MACCE following CAS (HR: 1.604, 95% CI: 1.027–2.507) [6]. It has been suggested that complications are more likely to occur in symptomatic patients due to the unstable nature of the atheromatous plaque [9]. Regarding the type of stent used during CAS, Doig et al. found that open cell stents (RR 1.92, 95% CI 1.11–3.33, p = .019) increased the risk of MACCE following CAS [9]. The SPACE study also indicated an increased risk of stroke or death when using an open cell stent design (OR 2.13, 95% CI 1.07–3.76, p = 0.029) [8]. While open cell stents are more flexible, aiding in conforming to tortuous vessels, they have larger cells and thus a smaller amount of coverage of the affected lesion compared to closed cell stent designs. The cells are smaller in closed cell stents, allowing them to more effectively protect against embolism and subsequent complications due to the greater coverage of the affected lesion, enabling them to more effectively hold fractured plaque and debris [3,8]. It is possible that an association exists between stent design, symptomatic carotid stenosis, or advanced age and periprocedural CAS complications. Nonetheless, this association was not reflected in our study among other smaller studies, possibly due to the insufficient number of events to detect true associations. Additionally, the continuous improvement in technology over the past two decades and increase in operator experience may contribute to our findings as well as a decreased risk for periprocedural MACCE. A study by Vogel et al. showed that the experience of CAS operators directly correlates to procedure outcomes [12]. The CAS procedures analyzed for our study were performed by one experienced physician at one community hospital, which may have contributed to our promising results. Similar or different analyses may result from other physicians at other locations. Velez et al. also emphasized the importance of careful case selection in decreasing complication rates [13]. As in our study, studies by Vogel et al. and Velez et al. also presented a decline in MACCE within 30 days after CAS, which may be a result of improvements in technology, technique, operator experience, and patient selection [12,13]. Going forward, it is important to consider that operator experience and advancements in technology have led to significant improvements in CAS outcomes over the past few years. Continuous improvement of these factors will only lead to
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further decline of the incidence of MACCE. Over the last decade, 30day MACCE was reduced from 8% to 10% to 2%–3% following CAS [4]. Additionally, our study's small sample size may lack the statistical power needed to adequately identify significant risk factors. Future randomized studies will be helpful in analyzing these factors among a larger number of patients. The indication for dual anti-platelet therapy has been studied, as platelet activation highly contributes to stent occlusion and embolic complications [14]. There has been prolonged platelet activation seen in stented vessels, indicating the necessity for increased platelet inhibition specifically for CAS patients [15]. This phenomenon is triggered by a decrease in peripheral platelet count after CAS, leading to an increased amount of circulating platelets, whose subsequent activation contributes to the development of stent thrombosis [15]. In our study, all patients received dual anti-platelet therapy for at least six months, a regimen that has been found to reduce adverse neurological complications [14,16]. A study by Mckevitt et al. demonstrated the importance of patients receiving aspirin and clopidogrel for reduction in neurological complications within 30 days of CAS, the benefits of which have been demonstrated in several other trials as well [14,16]. With no significant findings of risk factors, in patients with severe carotid stenosis above or equal to 80%, it may be worthwhile to perform CAS prophylactically. According to a study by Gribar, in the Beaumont CAS registry the 30-day MACCE rate was 2.6% and the 5-year risk of ipsilateral stroke was 4.5% (b1% per year). The benefit of prophylactic CAS offsets the low risk of developing stroke [4]. In this study, all three CAS complications occurred for a specific group of male patients who received an open cell stent type, had a history of smoking and hypertension, and did not have symptomatic carotid stenosis. This is reasonable since the majority of patients in our study fall into these categories, and this could have limited the study to further explore how each variable could affect the CAS complication rate individually. However, this study provides the preliminary results and further studies utilizing a larger sample size will be used to further expand on this knowledge. 5. Conclusions Age of 80 years old or above was not found to have an association with the occurrence of complications of stroke, MI, or death within 1 month after CAS. Similarly, those with symptomatic carotid stenosis, an open cell stent design, or a history of diabetes, smoking, or hypertension were not found to have an association with MACCE within 1 month after CAS. Future studies using a greater sample size will be beneficial to better assess periprocedural complication risks of CAS. Nonetheless, these findings may highlight the possibility of the effect of advanced technology and experience in the carotid artery stenting procedure on decreasing overall periprocedural complication rates, evening the playing field between different important variables, such as advanced age and symptomatic nature, and their impact on the incidence of periprocedural complication rates. References [1] Shawl F, Kadro W, Domanski MJ, Lapetina FL, Iqbal AA, Dougherty KG, et al. Safety and efficacy of elective carotid artery stenting in high-risk patients. J Am Coll Cardiol 2000;35(7):1721–8. [2] Jalbert JJ, Nguyen LL, Gerhard-herman MD, Jaff MR, White CJ, Rothman AT, et al. Outcomes after carotid artery stenting in Medicare beneficiaries, 2005 to 2009. JAMA Neurol 2015;72(3):276–86. [3] Hart JP, Peeters P, Verbist J, Deloose K, Bosiers M. Do device characteristics impact outcome in carotid artery stenting? J Vasc Surg 2006;44(4):725–30. [4] Gribar JJ, Jiddou M, Choksi N, Abbas AE, Bowers T, Kazmierczak C, et al. Carotid stenting in high-risk patients: early and late outcomes. J Interv Cardiol 2011; 24(3):247–53. [5] Brott TG, Hobson II RW, Howard G, Roubin GS, Clark WM, Brooks W, et al. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010; 363:11–23. [6] Cheng C-A, Chien W-C, Hsu C-Y, Lin H-C, Chiu H-W. Risk analysis of carotid stent from a population-based database in Taiwan. In: Hansen CL, editor. Medicine, 95(35); 2016. p. e4747.
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Please cite this article as: Mammo DF, et al, Factors affecting cardiovascular and cerebrovascular complications of carotid artery stenting in Northern Michigan: A retrospectiv..., Cardiovasc Revasc Med (2017), http://dx.doi.org/10.1016/j.carrev.2017.03.023