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Periprocedural Hemodynamic Depression Is Associated With a Higher Number of New Ischemic Brain Lesions After Stenting in the International Carotid Stenting Study-MRI Substudy

and on behalf of the ICSS Investigators
Originally publishedhttps://doi.org/10.1161/STROKEAHA.113.003397Stroke. 2014;45:146–151

Abstract

Background and Purpose—

Carotid artery stenting (CAS) is associated with a higher risk of both hemodynamic depression and new ischemic brain lesions on diffusion-weighted imaging than carotid endarterectomy (CEA). We assessed whether the occurrence of hemodynamic depression is associated with these lesions in patients with symptomatic carotid stenosis treated by CAS or CEA in the randomized International Carotid Stenting Study (ICSS)-MRI substudy.

Methods—

The number and total volume of new ischemic lesions on diffusion-weighted imaging 1 to 3 days after CAS or CEA was measured in the ICSS-MRI substudy. Hemodynamic depression was defined as periprocedural bradycardia, asystole, or hypotension requiring treatment. The number of new ischemic lesions was the primary outcome measure. We calculated risk ratios and 95% confidence intervals per treatment with Poisson regression comparing the number of lesions in patients with or without hemodynamic depression.

Results—

A total of 229 patients were included (122 allocated CAS; 107 CEA). After CAS, patients with hemodynamic depression had a mean of 13 new diffusion-weighted imaging lesions, compared with a mean of 4 in those without hemodynamic depression (risk ratio, 3.36; 95% confidence interval, 1.73–6.50). The number of lesions after CEA was too small for reliable analysis. Lesion volumes did not differ between patients with or without hemodynamic depression.

Conclusions—

In patients treated by CAS, periprocedural hemodynamic depression is associated with an excess of new ischemic lesions on diffusion-weighted imaging. The findings support the hypothesis that hypoperfusion increases the susceptibility of the brain to embolism.

Clinical Trial Registration—

URL: http://www.controlled-trials.com. Unique identifier: ISRCTN25337470.

Introduction

In patients with symptomatic carotid artery stenosis, carotid artery stenting (CAS) is associated with a higher risk of periprocedural stroke than carotid endarterectomy (CEA).1 Patients treated by CAS also more frequently have new ischemic lesions on post-treatment MRI scans with diffusion-weighted imaging (DWI).2 The cause of the higher risk of new cerebral ischemia early after CAS compared with CEA is uncertain.

Embolism from the carotid artery plaque during stent deployment or arterial dissection is generally held responsible for the majority of new ischemic lesions during carotid revascularization. During CAS and CEA, cerebral microembolic signals are often detected with transcranial Doppler.3 A high frequency of these signals has been associated with a higher risk of stroke,4 but the majority of the underlying emboli do not lead to cerebral ischemia.5 It has been proposed that under circumstances of a normal cerebral perfusion, most of these emboli are cleared by the cerebral circulation and that hypoperfusion increases the risk of a focal ischemic lesion.6 This is supported by a study that showed that patients with impaired perfusion in the hemisphere ipsilateral to the carotid artery stenosis before stenting had more ischemic lesions on DWI after the intervention than patients with a normal perfusion.7

Both CAS and CEA may be accompanied by periprocedural hemodynamic depression or other cardiovascular symptoms.8 In the International Carotid Stenting Study (ICSS),9 severe arterial hypotension, bradycardia, or asystole occurred twice as often in patients treated by CAS than by CEA.10 Such hemodynamic depression may lead to a temporary reduction in cerebral perfusion.11,12

We hypothesized that hemodynamic depression during CAS or CEA will impair the washout of emboli during revascularization and will therefore be associated with a higher risk of new DWI lesions on MRI performed soon after revascularization. Therefore, we compared the number and volume of new DWI lesions after CAS or CEA in patients who experienced hemodynamic depression with the number and volume of lesions in those without hemodynamic depression.

Methods

Subjects

All patients in this study were participants in the ICSS-MRI substudy,2 a prospective multicenter substudy in 7 centers within ICSS (ISRCTN25337470).13 ICSS is an international, randomized controlled trial comparing the risks and benefits of CAS versus CEA in patients with recently symptomatic carotid artery stenosis >50%. The design of both studies, patient eligibility criteria, the results of an interim safety analysis of ICSS, and the main results of the MRI substudy have been reported previously.2,9

Study Approval

ICSS (ISRCTN25337470) and the MRI substudy were approved by local ethics committees for non-UK centers and by the Northwest Multicentre Research Committee in the United Kingdom. All patients provided written informed consent.

Stenting and Surgery Procedures

The ICSS study protocol prescribed that all patients should receive the best medical care throughout the entire study period. The combination of aspirin and clopidogrel was recommended to cover stenting procedures. Intraprocedural heparin was mandatory at a dose determined by the operator. Approved cerebral protection devices were recommended for use during stenting, when it was feasible and safe to deploy them, as well as the intravenous administration of atropine or a similar agent just before balloon dilatation or stent placement. Endarterectomy procedures included the use of local or general anesthesia and shunts or patches as determined by the operating surgeon.13

Data Collection and Definitions of Hemodynamic Events

At study inclusion, data were collected on the patients’ presenting symptoms, demographic characteristics, and cardiovascular risk factors. Hemodynamic depression was defined as the occurrence during or soon after revascularization of ≥1 of the physiologically related symptoms of bradycardia (defined as a heart rate of <40 bpm), asystole, or hypotension requiring treatment.10 In ICSS, no fixed cutoff blood pressure value was set to define hypotension requiring treatment. Treatment of any hemodynamic complication was at the discretion of the treating physician. Investigators were asked to complete the forms as soon as possible after the revascularization procedure, but it was not mandatory to provide information on the exact timing and duration of hemodynamic changes after revascularization. Therefore, hemodynamic depression could occur at any time between the start of the intervention and discharge.

Imaging

MRI scans at field strengths of 1.5 T or 3.0 T were performed 1 to 7 days before treatment (pretreatment MRI) and 1 to 3 days after treatment (post-treatment MRI). Sixty-six patients were studied with 3-T scanners (CAS, n=37; CEA, n=29), and 165 were studied with 1.5-T scanners (CAS, n=87; CEA, n=78). Pretreatment and post-treatment scans included DWI sequences. On each scan, the number and volume of hyperintense lesions on DWI was measured. New periprocedural ischemic brain lesions were defined as hyperintense DWI lesions on post-treatment MRI that were not present on pretreatment MRI. In each patient, the total number of new DWI lesions (lesion count) and the total lesion volume were assessed. White matter lesions, or age-related white matter changes (ARWMCs), are correlates of small vessel disease on imaging of brain parenchyma.14 Quantification of these lesions was done on the pretreatment fluid-attenuated inversion recovery sequences with the ARWMC scale.15

Outcome Measures

The primary outcome measure of the present study was the total count of new hyperintense DWI lesions on the post-treatment scan that were not present on the pretreatment scan. The total volume of these lesions was a secondary outcome measure.

Statistical Analysis

For this study, we performed a per-protocol analysis including only patients who completed the allocated treatment as their first and only ipsilateral treatment. Patients who received the alternative revascularization procedure (crossovers) or received no revascularization were therefore excluded from the analyses.

Because of the differences in the occurrence of hemodynamic depression and in the risk of new ischemic lesions between CAS and CEA, we performed all analyses separately for each of the 2 treatment groups. We compared the number of new DWI lesions between patients with or without hemodynamic depression with Poisson regression and calculated crude risk ratios (RRs) with corresponding 95% confidence intervals (CIs). To accommodate the large variance in the lesion count data, we adapted the scale parameter of the Poisson model. We adjusted crude RR estimates for the 5 largest imbalances in baseline characteristics per treatment. In a post hoc analysis, we also adjusted for the use of a cerebral protection device or atropine during stenting.

For log-transformed DWI total lesion volumes, we calculated mean differences with corresponding 95% CIs between the patients with and without hemodynamic depression with linear regression and adjusted for imbalances in baseline characteristics.

Results

Baseline Characteristics

There were 231 patients included in the ICSS-MRI substudy.2 Two CAS patients with missing information on hemodynamic complications were excluded from the current analyses. Therefore, this study included a total of 229 patients, of whom 122 were treated by CAS and 107 by CEA. Fifteen patients (12%) treated by CAS and 9 (8%) treated by CEA had hemodynamic depression requiring treatment. Baseline characteristics of the patients are shown in Table 1. In patients treated by CAS, relevant baseline differences in the patients with and those without hemodynamic depression comprised baseline ARWMC score, sex, smoking history, the index ischemic event, and a history of multiple ischemic events before randomization. In patients treated by CEA, these were baseline ARWMC score, age, sex, smoking history, and systolic blood pressure at randomization.

Table 1. Patient Characteristics at Baseline

CAS (n=122)CEA (n=107)
HD+ (n=15)HD− (n=107)HD+ (n=9)HD− (n=98)
Age, y70 (8.7)70 (9.4)67 (6.8)70 (8.9)
Sex (male)13 (87%)72 (67%)7 (78%)69 (70%)
Vascular risk factors
 Treated hypertension10 (67%)73 (68%)6 (67%)68 (69%)
 Systolic blood pressure, mm Hg159 (24)156 (26)147 (22)158 (24)
 Diastolic blood pressure, mm Hg84 (11)82 (13)75 (9)84 (13)
 Cardiac failure2 (13%)1 (1%)0 (0%)6 (6.7%)
 Previous myocardial infarction4 (27%)14 (14%)0 (0%)12 (14%)
 Previous CABG1 (7%)10 (10%)2 (22%)6 (7%)
 Atrial fibrillation1 (7%)4 (4%)0 (0%)5 (6%)
 Diabetes mellitus type II2 (13%)9 (9%)4 (44%)13 (15%)
 Peripheral arterial disease1 (7%)21 (20%)1 (11%)14 (14%)
 Current smoker3 (20%)35 (36%)2 (22%)23 (26%)
 Ex-smoker8 (53%)40 (41%)7 (78%)44 (49%)
 Treated hyperlipidemia9 (60%)68 (64%)8 (89%)64 (65%)
Degree of symptomatic carotid stenosis*
 50%–69%1 (7%)14 (13%)0 (0%)8 (8%)
 70%–99%14 (93%)93 (87%)9 (100%)90 (92%)
Degree of contralateral stenosis*
 <50%9 (60%)70 (65%)4 (44%)71 (72%)
 50%–69%1 (7%)11 (10%)2 (22%)14 (14.3%)
 70%–99%3 (20%)20 (19%)3 (33%)11 (11%)
 Occluded2 (13%)6 (6%)0 (0%)2 (2%)
 ARWMCs at baseline4.7 (5.1)5.5 (4.7)4.0 (3.4)5.3 (4.4)
Most recent ipsilateral event
 Amaurosis fugax4 (27%)19 (18%)2 (22%)18 (19%)
 Transient ischemic event4 (27%)37 (35%)3 (33%)42 (44%)
 Ischemic hemispheric stroke5 (33%)48 (45%)2 (22%)36 (38%)
 Retinal infarction2 (13%)2 (2%)1 (11%)0 (0%)
 Unknown0 (0%)1 (1%)1 (11%)0 (0%)
 Multiple events before randomization6 (40%)49 (50%)2 (22%)40 (45%)
 Stroke before index event1 (7%)20 (20%)1 (11%)12 (14%)
Modified Rankin score at randomization
 0–214 (93%)88 (92%)8 (89%)79 (90%)

Data are number (%) or mean (SD). ARWMCs indicates age-related white matter changes; CABG, coronary artery bypass grafting; CAS, carotid artery stenting; CEA, carotid endarterectomy; HD, hemodynamic depression (hypotension requiring treatment, severe bradycardia, and asystole); and mRS, modified Rankin scale.

*Degree of stenosis measured by North American Symptomatic Carotid Endarterectomy Trial16 method at randomization center.

If 2 events were reported on the same day, the more serious was counted (stroke>retinal infarction>transient ischemic attack>amaurosis fugax).

Some Rankin scores of ≥3 were caused by nonstroke disability.

The mean patient stay was 3.5 days in the hospital after the intervention, without differences according to treatment or the occurrence of hemodynamic depression (data not shown). In 44 (36%) CAS procedures, a cerebral protection device was used. In 12 (10%) CAS patients, information on the use of cerebral protection devices was missing. Hemodynamic depression occurred in 6 (14%) CAS patients treated with such a device and in 9 (14%) CAS patients treated without cerebral protection (RR, 1.0; 95% CI, 0.4–2.6). Atropine was administered during stenting in 75 (61%) CAS patients; information on atropine use was not available in 21 (17%) patients. Thirteen (17%) patients treated with atropine had periprocedural hemodynamic depression and 2 (8%) patients not treated with atropine (RR, 2.3; 95% CI, 0.5–9.3).

DWI Lesions

In both patient groups, there was no difference in the proportion of patients with ≥1 new DWI lesion between patients who had hemodynamic depression compared with those without hemodynamic depression (Tables 2 and 3). After CAS, patients with hemodynamic depression had a mean of 13 new DWI lesions versus a mean of 4 in those without hemodynamic depression (RR, 3.36; 95% CI, 1.73 to 6.50). Adjustments for the potentially confounding baseline factors (ARWMC score, sex, smoking history, the index ischemic event, and history of multiple ischemic events) had no major influence on the crude effect estimate (Tables 2 and 3). The occurrence of hemodynamic depression had no effect on lesion count after CEA (RR, 0.71; 95% CI, 0.13 to 3.86; Tables 2 and 3). This did not change after adjustment for the baseline ARWMC score, age, sex, smoking history, or systolic blood pressure. Most patients had their postprocedural MRI within 1 day of the intervention. Table I in the online-only Data Supplement shows the distribution of lesions in patients with or without hemodynamic depression based on the timing of the postprocedural scan. Post hoc adjustments for the use of a cerebral protection device or atropine during stenting did not affect the outcomes (Tables 2 and 3).

Table 2. Hemodynamic Depression and New Ischemic Brain Lesions (Lesion Count)

CAS (n=122)CEA (n=107)
HD+ (n=15)HD− (n=107)RR (95% CI)HD+ (n=9)HD− (n=98)RR (95% CI)
At least 1 new DWI lesion8 (53%)52 (49%)1.10 (0.66–1.83)3 (33%)15 (15%)2.18 (0.77–6.13)
Count DWI lesions, mean (SD)13 (30)4 (10)3.36 (1.73–6.50)0.4 (0.7)0.6 (2.2)0.71 (0.13–3.86)
Adjustment
 ARWMCs3.41 (1.77–6.59)0.82 (0.15–4.40)
 Age0.76 (0.14–4.14)
 Sex3.13 (1.60–6.13)0.71 (0.13–3.87)
 Smoking (present and past)3.29 (1.71–6.35)0.83 (0.15–4.63)
 Ipsilateral index event4.08 (2.12–7.85)
 Multiple events before index event3.28 (1.71–6.30)
 SBP1.08 (0.22–5.32)
 Cerebral protection device use3.48 (1.75–6.92)
 Atropine use3.83 (1.89–7.73)

ARWMCs indicates age-related white matter changes; CAS, carotid artery stenting; CEA, carotid endarterectomy; CI, confidence interval; DWI, diffusion-weighted imaging; HD, hemodynamic depression (hypotension requiring treatment, severe bradycardia, and asystole); RR, risk ratio; and SBP, systolic blood pressure.

Table 3. Hemodynamic Depression and New Ischemic Brain Lesions (Lesion Volume)

CAS (n=122)CEA (n=107)
HD+ (n=15)HD− (n=107)MD* (95% CI)HD+ (n=9)HD− (n=98)MD* (95% CI)
Total volume median (Q1 to Q3)0.0425 (0.000–1.930)0 (0.000–0.137)0.54 (−0.10 to 1.17)0 (0.00–0.09)0 (0.00–0.00)0.08 (−0.48 to 0.64)
Adjustment
 ARWMCs0.57 (−0.06 to 1.20)0.10 (−0.47 to 0.67)
 Age0.09 (−0.48 to 0.65)
 Sex0.53 (−0.12 to 1.17)0.07 (−0.49 to 0.63)
 Smoking (present and past)0.53 (−0.11 to 1.16)0.11 (−0.46 to 0.68)
 Ipsilateral index event0.60 (−0.05 to 1.24)
 Multiple events before index event0.55 (−0.10 to 1.21)
 SBP0.17 (−0.38 to 0.73)
 Cerebral protection device use0.55 (−0.12 to 1.21)
 Atropine use0.57 (−0.12 to 1.26)

ARWMCs indicates age-related white matter change; CAS, carotid artery stenting; CEA, carotid endarterectomy; CI, confidence interval; HD, hemodynamic depression (hypotension requiring treatment, severe bradycardia, and asystole); MD, mean difference; Q1 to Q3; interquartile range; and SBP, systolic blood pressure.

*Mean difference after log transformation; a positive difference indicates larger volumes with HD+.

For both CAS and CEA, there were no differences in total DWI lesion volume between patients with hemodynamic depression and those without hemodynamic depression after log transformation. The mean differences did not change essentially after adjustment (Tables 2 and 3). Table II in the online-only Data Supplement shows the data of the combined treatment groups.

Discussion

We found that in patients who were treated by CAS, the occurrence of periprocedural hemodynamic depression was associated with a >3 times higher number of new ischemic brain lesions on DWI compared with patients without this complication. This effect was not observed in patients who had hemodynamic depression after CEA.

Our finding of an increased occurrence of new ischemic lesions on DWI in patients with hemodynamic depression after CAS is in line with previous observations in uncontrolled studies, in which periprocedural hemodynamic depression was associated with increased rates of stroke or death after CAS.1720 However, this association has not been found in every study.2123

In the current study, 12% of the patients treated by CAS had periprocedural hemodynamic depression requiring treatment, whereas uncontrolled series of patients treated by CAS have reported frequencies of arterial hypotension or hemodynamic depression ranging from 19% to 51%.17,19,2426 This difference may be explained by ascertainment bias because the assessment of hemodynamic depression was a primary aim of some of the observational studies but not of ICSS. In addition, definitions for hypotension or hemodynamic depression as a composite measure differed between ICSS and the observational studies. Most of the observational studies defined arterial hypotension as a drop in systolic blood pressure below a fixed value, or as a specific absolute fall in blood pressure, whereas in ICSS, hypotension was only reported if this required treatment.10 We therefore could have missed less severe episodes of hypotension.

In ICSS, hemodynamic depression requiring treatment occurred in 13.8% of the patients treated by CAS and in 7.2% of the patients treated by CEA.10 In the ICSS-MRI substudy, 35% of the patients treated by CAS and 9% of those treated by CEA had ≥2 new ischemic lesions on DWI.27 Because the number of patients with ≥2 new DWI lesions after CAS was substantially higher than the number with hemodynamic depression requiring treatment, it is clear that the difference in the risk of hemodynamic depression requiring treatment between CAS and CEA is not the only determinant of the difference in the occurrence of new ischemic lesions between the 2 treatments. However, smaller reductions in blood pressure that did not require treatment were not reported in ICSS, and it is possible that these may have contributed to the development of new lesions in some patients not fulfilling our definition of hemodynamic depression. Our assumption that in ICSS reductions in blood pressure after CAS did occur more frequently than reported is supported by the fact that at discharge, systolic blood pressures were ≈10 mm Hg lower after CAS than after CEA.28 Moreover, in the present study, hemodynamic depression remained strongly associated with an increased number of new ischemic lesions after adjustments for potentially confounding baseline factors.

The main source for periprocedural ischemia after CEA or CAS is thromboembolism.29 Our findings are consistent with the hypothesis that hypoperfusion increases the susceptibility of the brain to infarction from emboli by impairing washout of emboli from the cerebral circulation.6,30 Hemodynamic depression after carotid revascularization procedures occurs when carotid sinus stimulation leads to bradycardia, by affecting the sinus and atrioventricular nodes, and to hypotension, by peripheral vasodilatation.31 In ICSS as a whole, we found no evidence that the increased rate of hemodynamic depression after CAS explained the excess of stroke and death within 30 days of CAS versus CEA.9,10 However, the number of clinical outcome events was relatively small. MRI increases the number of ischemic insults detected as a result of revascularization, increasing the sensitivity to differences between patients.2 Using ischemic lesions on DWI as a surrogate marker for ischemic stroke after carotid revascularization,2 we have now been able to correlate hemodynamic depression with postprocedural cerebral ischemia.

Our study suggests that prevention of severe hypotension and bradycardia might reduce the number of new DWI lesions after CAS, but this can only be tested in a new randomized trial. It has been proposed that in case of hemodynamic depression after stenting, patients should be treated with intravenous fluids, atropine and α-agonists, and that any oral antihypertensive medication should be discontinued.32 However, treatment options may vary based on patient characteristics and on the severity of hemodynamic symptoms.

In contrast to patients treated by CAS, we found no evidence that hemodynamic depression was associated with a higher number of new ischemic lesions in patients treated by CEA. However, the number of new ischemic lesions in patients treated by CEA was very low, and we therefore lacked statistical power to detect any association. Total lesion volumes did not differ between patients with or without hemodynamic depression; however, our data suggest that the individual lesions were smaller in patients who had hemodynamic depression.

Strengths of this study are the prospective assessment of hemodynamic depression and of new ischemic lesions on DWI, in addition to its relatively large sample size. A limitation is the lack of direct periprocedural cerebral perfusion measures. We therefore cannot confirm that hemodynamic depression resulted in compromised cerebral perfusion. Second, in ICSS, it was not mandatory to report the exact timing of periprocedural hemodynamic complications, although the investigators were asked to complete the form as soon as possible after the procedure. It is therefore possible that these could have occurred at any time between the start of the revascularization and discharge. However, based on observations in uncontrolled series,17,19,2426 we expect that the majority of hemodynamic events would have occurred during or immediately after CAS or CEA. For this reason, most if not all MRI scans will have been performed after the development of hemodynamic depression. Moreover, we do not have data on the duration of hemodynamic depression; therefore, we cannot refute the possibility that duration of hemodynamic compromise influences the amount of new ischemic lesions. In the ICSS-MRI substudy, the interval to the postprocedural MRI was longer after CEA than after CAS: median 1 day (interquartile range, 1–2) and 1 (interquartile range, 1–1), respectively, P=0.008.2 And we could therefore have missed additional new ischemic lesions after CAS. Finally, apart from the severity of the stenosis, we do not have information on plaque characteristics.

Conclusions

In patients treated by CAS, hemodynamic depression was associated with a higher number of new ischemic lesions on postprocedural DWI MRI. This finding suggests that avoidance of periprocedural hypotension and bradycardia may reduce the risk of DWI lesions occurring during CAS.

Footnotes

The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.113.003397/-/DC1.

Correspondence to Aysun Altinbas, MD, Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, P.O. Box 85500, G03.228, 3508 GA Utrecht, The Netherlands. E-mail

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