Abstract
Introduction
Proximal cervical internal carotid artery stenosis greater than 50% merits revascularization to mitigate the risk of stroke recurrence among large-vessel anterior circulation strokes undergoing mechanical thrombectomy. Carotid artery stenting necessitates the use of antiplatelets, and there is a theoretical increased risk of hemorrhagic transformation given that such patients may already have received intravenous thrombolytics and have a significant infarct burden. We investigate the outcomes of large-vessel anterior circulation stroke patients treated with intravenous thrombolytics receiving same-day carotid stenting or selective angioplasty compared to no carotid intervention.
Materials and methods
The study cohort was obtained from the National (Nationwide) Inpatient Sample database between 2006 and 2014, using International Statistical Classification of Diseases, ninth revision discharge diagnosis and procedure codes. A total of 11,825 patients with large-vessel anterior circulation stroke treated with intravenous thrombolytic and mechanical thrombectomy on the same day were identified. The study population was subdivided into three subgroups: no carotid intervention, same-day carotid angioplasty without carotid stenting, and same-day carotid stenting. Outcomes were assessed with respect to mortality, significant disability at discharge, hemorrhagic transformation, and requirement of percutaneous endoscopic gastronomy tube placement, prolonged mechanical ventilation, or craniotomy.
Results
This study found no statistically significant difference in patient outcomes in those treated with concurrent carotid stenting compared to no carotid intervention in terms of morbidity or mortality.
Conclusions
If indicated, it is reasonable to consider concurrent carotid stenting and/or angioplasty for large-vessel anterior circulation stroke patients treated with mechanical thrombectomy who also receive intravenous thrombolytics.
Keywords: Stroke, carotid stenting, endovascular, thrombectomy
Introduction
Carotid disease is associated with an increased risk of stroke. Approximately three-fourths of the strokes in patients with carotid stenosis in the 70% to 99% range have been attributed to large-vessel atherosclerosis. The risk of early stroke recurrence has been found to be the highest in patients with large-artery atherosclerosis1 among all stroke subtypes. Studies have found the risk of large-vessel stroke in patients with symptomatic carotid artery stenosis to be as high as 19.7% over a five-year period.2 For patients with symptomatic internal carotid artery (ICA) stenosis with the degree exceeding 50%, revascularization has been proven to reduce the risk of stroke recurrence.3
Acute large-vessel anterior circulation strokes (LVO-AC) attributed to ipsilateral carotid stenosis merit carotid intervention to prevent recurrent ischemic events. Although carotid endarterectomy (CEA) and carotid artery stenting (CAS) have been shown to have similar efficacy,4 CAS can be performed emergently during mechanical thrombectomy, while CEA requires a separate open procedure. CAS necessitates the use of antiplatelet agents to decrease the chances of in-stent restenosis,5,6 which theoretically increases the risk of hemorrhagic transformation in LVO-AC patients treated with intravenous (IV) thrombolytics.7 Despite the opportunity to stent stenosed vessels during mechanical thrombectomy, the lack of robust data has limited objective guidelines that favor concurrent stenting.
In our study, we investigate the outcomes of patients requiring carotid stenting or selective angioplasty compared to individuals with no carotid intervention in a cohort of LVO-AC treated with thrombolytics and mechanical thrombectomy.
Materials and methods
The study cohort was derived from the National (Nationwide) Inpatient Sample (NIS) database between 2006 and 2014. The NIS is the largest publicly available de-identified all-payer inpatient care database and is part of the Healthcare and Cost Utilization Project. The database contains a sample of 20% of US hospitals and contains information on approximately 7 million hospitalizations per year. It is published in discharge abstract safeguarding format to de-identify hospital and patient information.
Using International Statistical Classification of Diseases, ninth revision (ICD-9) discharge diagnosis and procedure codes, patients with acute ischemic stroke treated with IV thrombolytic and mechanical thrombectomy were identified. Patients with posterior circulation strokes were excluded to identify the LVO-AC population (Figure 1). The study population was subdivided into three subgroups: (1) no carotid intervention group (patients who did not receive either carotid stenting or angioplasty), (2) carotid angioplasty without carotid stenting group, and (3) carotid stenting group. Patients in the carotid angioplasty and stenting groups had the procedures on the same calendar day as they received tissue plasminogen activator (tPA) and underwent mechanical thrombectomy. Baseline characteristics of subgroups were compared with univariate analysis using the Chi-square test.
Figure 1.
Patient selection.
MT: mechanical thrombectomy; tPA: tissue plasminogen activator.
Survey procedures were used to accommodate for the hierarchical two-stage cluster design of the NIS. A multivariate logistic regression model was used to compare the results to identify predictors for outcomes including mortality, discharge to a long-term facility, hemorrhagic transformation, requirement of a percutaneous endoscopic gastronomy (PEG) tube, requirement of prolonged (>96 hours) mechanical ventilation, and requirement of craniotomy during hospitalization. All the covariates shown in Table 1 that had significant differences among the three groups in univariate analysis (with p < 0.1) (Table 2) were adjusted in the multivariate analysis. The year of admission was included as a covariate since the devices used for mechanical thrombectomy and for carotid intervention have evolved significantly in the past decade. We also used the Deyo-Charlson Comorbidity Index,8 which is a validated score to assess the burden of comorbid disease in research using large administrative databases pertaining to ICD-9 clinical modification diagnoses and codes, with age and gender adjusted for confounding by disease severity and comorbid conditions. SAS 9.2 statistical software was used for data analysis.
Table 1.
Baseline characteristics of each cohort.
| No stenting or angioplasty | Carotid angioplasty | Carotid stenting | Total | p value | |
|---|---|---|---|---|---|
| Total weighted N | 10358 | 716 | 751 | 11825 | |
| Mean age in yearsa | 67.26 (66.54–67.97) | 64.06 (61.5–66.63) | 65.49 (63.38–67.60) | 66.95 (66.28–67.62) | 0.0171 |
| Charlson Comorbidity Indexa | 3.44 (3.34–3.53) | 3.37 (3.09–3.66) | 3.51 (3.25–3.76) | 3.42(3.33–3.50) | 0.3586 |
| Female genderb | 5445 (52.57) | 335 (46.79) | 302 (40.21) | 6082 (51.43) | 0.003 |
| Raceb | 0.6292 | ||||
| Caucasian | 6501 (62.76) | 434 (60.61) | 498 (66.31) | 7433 (62.86) | |
| African American | 1190 (11.49) | 79 (11.03) | 74 (9.85) | 1343 (11.36) | |
| Others | 1472 (14.21) | 130 (18.16) | 88 (11.72) | 1690 (14.29) | |
| Unknown | 1359 (11.49) | ||||
| Atrial fibrillationb | 4821 (46.54) | 210 (29.33) | 130 (17.31) | 5161 (43.64) | <0.0001 |
| Diseases of endocardiumb | 866 (8.36) | 33 (4.61) | 15 (2.00) | 914 (7.73) | 0.0038 |
| Diabetesb | 2437 (23.53) | 193 (26.96) | 156 (20.77) | 2786 (23.56) | 0.4265 |
| Hypertensionb | 7616 (73.53) | 504 (70.39) | 596 (79.36) | 8716 (73.71) | 0.1544 |
| Hyperlipidemiab | 4566 (44.08) | 333 (46.51) | 388 (51.66) | 5287 (44.71) | 0.1663 |
| Congestive heart failureb | 2306 22.26) | 127 (17.74) | 64 (8.52) | 2497 (21.12) | 0.0002 |
| Ischemic heart diseaseb | 3357 (32.41) | 180 (25.14) | 152 (20.24) | 3689 (31.20) | 0.003 |
| Cerebral vessels atherosclerosisb | 185 (1.79) | 34 (4.75) | 20 (2.66) | 239 (2.02) | 0.0383 |
| Systemic atherosclerosisb | 242 (2.34) | 15 (2.09) | 4 (0.53) | 261 (2.21) | 0.3426 |
| Carotid artery dissectionb | 240 (2.32) | 51 (7.12) | 137 (18.24) | 428 (3.62) | <0.0001 |
| Hypercoagulable stateb | 302 (2.92) | 33 (4.61) | 15 (2.00) | 349 (2.95) | 0.3727 |
| Teaching hospitalb | 4655 (44.94) | 368 (51.40) | 288 (38.35) | 5312 (44.92) | 0.269 |
| Alcohol abuseb | 482 (4.65) | 25 (3.49) | 45 (5.99) | 552 (4.67) | 0.5727 |
| Smokingb | 1530 (14.77) | 133 (18.58) | 227 (30.23) | 1890 (15.98) | <0.0001 |
| Previous and current use of anticoagulationb | 981 (9.47) | 39 (5.45) | 5 (0.67) | 1025 (8.67) | 0.0005 |
| Previous and current use of antithromboticb | 154 (1.49) | 24 (3.35) | 0 (0) | 178 (1.51) | 0.0198 |
Variables with 95% confidence intervals in brackets. bNumbers in brackets indicate percentage of the individual treatment group (carotid angioplasty, stenting, or neither), respectively.
Table 2.
Results of univariate analysis.
| No stenting or angioplasty | Carotid angioplasty | Carotid stenting | Total | p value | |
|---|---|---|---|---|---|
| Hospital-acquired infectiona | 1828 (17.65) | 168 (23.46) | 131 (17.44) | 2127 (17.99) | 0.1701 |
| Sepsisa | 422 (4.07) | 40 (5.59) | 39 (5.19) | 501 (4.24) | 0.5515 |
| Deep venous thrombosisa | 201 (1.94) | 24 (3.35) | 14 (1.86) | 239 (2.02) | 0.4455 |
| Pulmonary embolisma | 172 (1.66) | 10 (1.40) | 16 (2.13) | 198 (1.67) | 0.8819 |
| Mortalitya | 1803 (17.41) | 158 (22.07) | 98 (13.05) | 2059 (17.41) | 0.1071 |
| Discharge to long-term facilitya | 5938 (57.33) | 397 (55.45) | 463 (61.65) | 6798 (57.49) | 0.9013 |
| Hemorrhagic transformationa | 2283 (22.04) | 137 (19.13) | 152 (20.24) | 2572 (21.75) | 0.6841 |
| PEG tube placementa | 1481 (14.30) | 113 (15.78) | 96 (12.78) | 1690 (14.29) | 0.7654 |
| Craniotomya | 344 (3.32) | 14 (1.96) | 32 (4.26) | 390 (3.30) | 0.551 |
| Prolonged intubationa | 1395 (13.47) | 132 (18.44) | 108 (14.38) | 1635 (13.83) | 0.1704 |
| Median length of stay, days (IQR 25% to 75%)b | 6.57 (3.84–11.74) | 6.71 (3.57–14.90) | 6.95 (3.93–11.02) | 6.68 (3.83–11.80) | 0.2606 |
Numbers in brackets indicate percentage of the individual treatment group (carotid angioplasty, stenting, or neither), respectively. bVariables with 95% confidence intervals in brackets.
IQR: interquartile range; PEG: percutaneous endoscopic gastronomy.
Results
A total of 11,825 (weighted N) hospitalizations were identified in which patients were admitted for LVO-AC who were treated with IV thrombolysis and mechanical thrombectomy on the day of admission. A total of 87.59% patients did not receive either carotid stenting or angioplasty (group 1), 6.05% patients had only carotid angioplasty (group 2), and 6.36% patients received carotid stents (group 3) on the same day they received mechanical thrombectomy and IV thrombolysis. The average age of group 1 (67.26 years) was higher than group 2 (64.06 years) and group 3 (65.49 years) (p = 0.0171). The proportion of female patients, the presence of atrial fibrillation, diseases of endocardium, congestive heart failure, previous use of anticoagulation, and ischemic heart disease were significantly higher in group 1 compared to groups 2 and 3. The proportion of patients with a diagnosis of cerebral vessel atherosclerosis, carotid dissection and smoking were higher in groups 2 and 3 compared to group 1. Antithrombotic use was highest in group 2 followed by 1 and 3. There was no difference in Charlson Comorbidity Index, racial distribution, and proportion of cases treated at teaching hospitals in each subgroup. The proportion of diabetes, hypertension, hyperlipidemia, systemic atherosclerosis, hypercoagulable state, and alcohol use were comparable. There was no difference in the potential complications related to hospital stay (hospital-acquired infections, prolonged mechanical ventilation requirement, sepsis, deep venous thrombosis, pulmonary embolism). Significant disability at discharge, hemorrhagic transformation, PEG tube placement, craniotomy, and mortality rates were not different.
The results of multivariate logistic regression analysis comparing group 1 with 2 and 3 did not show statistically significant difference for any of the outcomes included in the study (Table 3).
Table 3.
Results of multivariate analysis.
| Model | Covariate | Odds ratio | 95% confidence interval | p value |
|---|---|---|---|---|
| Mortality | Carotid stenting w/wo angioplasty vs no carotid intervention | 0.805 | 0.504–1.287 | 0.15 |
| Only angioplasty vs no carotid intervention | 1.359 | 0.906–2.039 | 0.0775 | |
| Hemorrhagic transformation | Carotid stenting w/wo angioplasty vs no carotid intervention | 0.993 | 0.619–1.592 | 0.877 |
| Only angioplasty vs no carotid intervention | 0.911 | 0.572–1.451 | 0.721 | |
| Discharge to long-term | Carotid stenting w/wo angioplasty vs no carotid intervention | 1.143 | 0.749–1.744 | 0.9124 |
| nursing facility | Only angioplasty vs no carotid intervention | 1.243 | 0.806–1.916 | 0.5186 |
| Prolonged intubation >96 hours | Carotid stenting w/wo angioplasty vs no carotid intervention | 1.124 | 0.726–1.742 | 0.8306 |
| Only angioplasty vs no carotid intervention | 1.406 | 0.933–2.119 | 0.2384 | |
| Requiring PEG tube | Carotid stenting w/wo angioplasty vs no carotid intervention | 0.923 | 0.534–1.597 | 0.5631 |
| Only angioplasty vs no carotid intervention | 1.207 | 0.798–1.826 | 0.3734 | |
| Requiring craniotomy | Carotid stenting w/wo angioplasty vs no carotid intervention | 0.934 | 0.370–2.359 | 0.5143 |
| Only angioplasty vs no carotid intervention | 0.435 | 0.132–1.434 | 0.2042 |
Multivariate regression models for outcomes adjusted for all the covariates that showed differences in univariate analysis with p < 0.1.
PEG: percutaneous endoscopic gastronomy; w: with; wo: without.
Discussion
Along with IV thrombolysis, endovascular procedures have become the standard of care in the emergent setting for the treatment of LVO-AC.9 Approximately 10% of patients in the thrombectomy trials10,11 needed a carotid intervention in addition to mechanical thrombectomy. Owing to the increased theoretical risk of hemorrhagic transformation, reperfusion syndrome and other possible perioperative complications, there are no clear guidelines that favor concurrent stenting in LVO-AC patients treated with thrombolytics and mechanical thrombectomy.12,13 Even the recently published findings from the DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention With Trevo (DAWN) trial14 had excluded patients who underwent ICA stenting. Our study demonstrates that if an immediate carotid intervention (stenting and/or angioplasty) is necessary for LVO-AC patients undergoing mechanical thrombectomy after IV thrombolysis, outcomes in terms of morbidity and mortality are not worsened compared to those patients who have no carotid intervention.
The differences in baseline characteristics of those requiring carotid intervention is largely attributable to differences in stroke etiology, cardioembolic versus atheroembolic. Among the three subgroups, there were no statistically significant differences in the overall Charlson Comorbidity Index, hospital-acquired infections, sepsis, deep venous thrombosis or pulmonary embolism. LVO-AC patients who had carotid artery dissection (3.62%) were identified separately, although the percentage of patients with iatrogenic dissection could not be identified. Carotid dissection predicted higher risk (odds ratio 3.287) for requiring craniotomy, which can be attributed to an overall younger population presenting with this pathology.15 Discussions on the potential impact of other variables, like atrial fibrillation, congestive heart failure, and age, are beyond the scope of this study.
Although most of the clinical trials for endovascular treatment measured 90-day modified Rankin Scale score as the functional outcome, this data point is not available in the NIS database. We used surrogate outcomes in the form of discharge disposition to long-term nursing facilities and PEG tube placement during the hospitalization to identify functional disability at the time of discharge. Assuming that the majority of the patients treated with IV thrombolysis had presented to the hospital within 4.5 hours of symptom onset and had compatible coagulation profiles, inclusion only of patients treated with IV tPA helped reduce the bias from differing door-to-needle times and coagulation profiles. Initial severity of neurological deficits were not available; however, since all the patients included in this study had large-vessel occlusions requiring mechanical thrombectomy, stroke severity was likely uniformly high. The incidence of tandem carotid occlusion, presence of reperfusion syndrome, the extent of cervical carotid disease, or the status of the collateral circulation are also not available in this dataset. In spite of all the above-mentioned limitations due to the administrative nature of the NIS database, the overall likelihood of type II error still remains very low given such a large sample size.
In conclusion, using a large nationwide sample, our findings are along the lines of previously published smaller-sized studies16–19 supporting the idea that it may be reasonable to consider immediate carotid stenting in LVO-AC patients treated with IV thrombolytics. Further research is required to better understand ideal patient selection, antiplatelet regimen, and the chronology of procedures performed during acute management of such LVO-AC patients.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
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