Importance of Hemodynamic Factors in the Prognosis of Symptomatic Carotid Occlusion FREE

THE RELATIVE IMPORTANCE of hemodynamic as opposed to thromboembolic mechanisms in the pathogenesis of ischemic stroke remains unsettled.¹ This distinction is moot for severe symptomatic carotid stenosis since carotid endarterectomy has been demonstrated to reduce the risk of subsequent stroke.² However, there remains a large number of patients with carotid artery occlusion who comprise approximately 15% of those with carotid territory transient ischemic attacks or infarction.^3- 6 The overall risk of subsequent stroke is 5% to 7% per year and the risk of stroke ipsilateral to the occluded carotid artery is 2% to 6% per year.^7- 8 No surgical treatment has been proven to be of benefit in preventing subsequent stroke. The efficacy of anticoagulant treatment or antiplatelet agents in this particular subgroup is not known. An important role for hemodynamic mechanisms in these patients has been proposed.⁷ However, studies addressing this issue have either failed to show that cerebral hemodynamics is important or suffered from potential bias due to problems in experimental design.^1,9

To determine what role hemodynamic factors play in the prognosis and treatment of patients with carotid artery occlusion, methods for determining the hemodynamic status of the cerebral circulation, accurately and in awake subjects under normal conditions, must be available. Measurements of cerebral blood flow (CBF) alone are inadequate because they cannot distinguish reduced CBF caused by the hemodynamic effects of arterial occlusion from compensatory physiological reductions in CBF caused by reduced metabolic demands. It has been necessary, therefore, to rely on indirect assessments based on the compensatory responses made by the brain to progressive reductions in cerebral perfusion pressure (CPP). When CPP is normal (stage 0), CBF is closely matched to the resting metabolic rate of the tissue. As a consequence of this resting balance between flow and metabolism, the oxygen extraction fraction (OEF) shows little regional variation. Moderate reductions in CPP have little effect on CBF. Vasodilation of arterioles reduces cerebrovascular resistance, thus maintaining a constant CBF (stage I). As a consequence, the intravascular cerebral blood volume (CBV) is elevated. This phenomenon is known as cerebrovascular autoregulation. With more severe reductions in CPP, the capacity for compensatory vasodilation is exceeded, autoregulation fails, and CBF begins to decline. A progressive increase in OEF now maintains cerebral oxygen metabolism and brain function (stage II).^10- 11 This more severe form of stage II cerebral hemodynamic failure has also been termed misery perfusion.¹²

Two basic approaches have been used to assess regional cerebral hemodynamics in humans. The first approach is based on detecting stage I autoregulatory vasodilation by either measuring CBF and CBV or determining whether there is reduced responsiveness of CBF to a vasodilatory stimulus (such as hypercapnia or acetazolamide). A variety of techniques have been used to make the paired measurements of cerebral perfusion needed for evaluating the vasodilatory response.^7,10 The second approach is based on detecting more severe stage II hemodynamic failure by measuring increases in regional OEF.¹⁰ This second approach is currently possible only with positron emission tomography (PET). In a previous study using historical controls, we failed to demonstrate a relationship between stage I autoregulatory vasodilation and the subsequent risk of stroke.¹³ The current blinded prospective study tests the hypothesis that stage II hemodynamic failure (increased oxygen extraction) in the cerebral hemisphere distal to symptomatic carotid artery occlusion is an independent predictor of the subsequent risk of stroke in medically treated patients.

We enlisted the collaboration of 15 hospitals within the St Louis, Mo, area to assist with recruitment. Personnel at participating hospitals were asked to notify the study coordinator about all patients with carotid artery occlusion, irrespective of the presence or characteristics of cerebrovascular symptoms. The study coordinator contacted each subject and explained the purpose of the study. If the subject agreed to participate, clinical, laboratory, and radiographic information necessary to determine eligibility was obtained. Original inclusion criteria were (1) occlusion of one or both common or internal carotid arteries demonstrated by contrast angiography within 120 days prior to PET and (2) transient ischemic neurological deficits (including transient monocular blindness) or mild-to-moderate permanent ischemic neurological deficits (stroke) in appropriate carotid artery territory with last event occurring within 120 days prior to PET. Following initiation of the study, we made the following 2 changes in the inclusion criteria to improve recruitment: (1) carotid occlusion could be demonstrated by either magnetic resonance (MR) angiography or carotid ultrasound and (2) the 120-day limit for both demonstration of occlusion and most recent symptom was waived. (At the time of this protocol change, we also began to enroll asymptomatic subjects with carotid occlusion into a parallel study.¹⁴) Exclusion criteria were the following:

Patients who had undergone endarterectomy for stenosis of the ipsilateral external carotid artery or contralateral internal carotid artery prior to PET were eligible whether or not they had had recurrent symptoms. Any subsequent cerebrovascular surgery after the initial PET caused the patient to be censored from the study at the time of surgery.

All subjects were studied at Washington University Medical Center, St Louis, Mo. Just prior to PET, each subject underwent neurological evaluation including detailed questions regarding any symptoms. Focal ischemic symptoms in the territory of the occluded carotid artery were categorized as cerebral transient ischemic attack (<24 hours in duration), cerebral infarction (>24 hours in duration), or retinal event (any duration) and as single or recurrent episodes. Time from most recent symptom was recorded. Pertinent medical records, carotid ultrasound reports, computed tomography (CT) scans, magnetic resonance images (MRI), and MR and intra-arterial contrast angiograms were reviewed. The following baseline risk factors were specifically determined: age, sex, hypertension, previous myocardial infarction, diabetes mellitus, smoking, alcohol consumption, and parental death from stroke. The degree of contralateral carotid stenosis and collateral arterial circulation to the ipsilateral middle cerebral artery (MCA) was determined from intra-arterial angiograms, if available.¹⁵ These arteriograms were done for clinical purposes at the participating institutions and varied in the number of vessels injected and views obtained. Blood samples were collected for determination of hemoglobin, fasting lipid levels (triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), and fibrinogen levels. A noncontrast CT scan of the brain was performed if a CT scan done as part of usual clinical care did not permit accurate definition of infarction location. This CT scan was used only to determine the site of tissue infarction to exclude these regions from subsequent PET analysis.

Eighteen normal control subjects aged 19 to 77 years (mean [SD], 45 [18] years) were recruited by public advertisement. All were disease free and taking no medication by their own history. There were 8 women and 10 men. All underwent neurological evaluation, MRI of the head, and duplex ultrasound imaging of the extracranial carotid arteries. None had signs or symptoms of neurological disease other than mild distal sensory loss in the legs consistent with age, pathological lesions on MR scan (mild atrophy and punctate asymptomatic white matter abnormalities were not considered pathological), or more than 50% stenosis of the extracranial carotid arteries by duplex ultrasound.

PET studies were performed on 2 different scanners with similar sensitivity and axial and transverse resolution (Siemens models 953B and 961, Siemens Medical Systems, Hoffman Estates, Ill).^16- 17 All normal control subjects were studied with the model 961 scanner. The position of the head relative to the plane of the PET scan was recorded by a lateral skull film marked with a radio-opaque line. Each patient underwent a transmission scan with gallium 68–germanium 68 rod sources to provide individual attenuation data necessary for the quantitative reconstruction of subsequent scans. Regional OEF was measured by the method of Mintun et al using H₂¹⁵O, C¹⁵O, and O¹⁵O.^18- 19 When technical difficulties precluded collection of arterial time-activity curves necessary to determine quantitative OEF, the ratio image of the counts in the raw H₂¹⁵O and O¹⁵O images was normalized to a whole brain mean of 0.40 and substituted for the quantitative OEF image. The counts in this H₂¹⁵O/O¹⁵O image are linearly proportional to OEF except for small contributions from intravascular oxygen and recirculating labeled water. The resultant errors are small (<5%) when regional oxygen metabolism is normal as it was under these circumstances.¹⁸

Images were reconstructed using filtered back projection and scatter correction with a ramp filter at the Nyquist frequency. All images were then filtered with a 3-dimensional gaussian filter to a uniform resolution of 16 mm full width half maximum. For each subject, 7 spherical regions of interest, each 19 mm in diameter, were placed in the cortical territory of the MCA in each hemisphere using stereotactic coordinates.^15,20 If any portion of a region overlapped a well-demarcated area of reduced oxygen metabolism that corresponded to areas of infarction by CT scan or MRI, that region and the homologous contralateral region were excluded. The mean OEF for each MCA territory was calculated from the remaining regions and a left-to-right MCA OEF ratio was calculated. The maximum and minimum ratios from the 18 normal control subjects were used to define the normal range (0.914-1.082). A separate range of normal for H₂¹⁵O/O¹⁵O images was determined (0.934-1.062). Patients with left-to-right OEF ratios outside the normal range were categorized as having stage II hemodynamic failure in the hemisphere with higher OEF. These categorizations were made without knowledge of the side of the carotid occlusion or of the clinical course of the patients since the initial PET study. No information regarding the PET results was provided to the patients, treating physicians, or investigator responsible for determining end points.

Patients were followed up by the study coordinator for the duration of the study through telephone contact every 6 months with the patient or next of kin. The interval occurrence of any symptoms of cerebrovascular disease, other medical problems, and functional status was determined. Interval medical treatment on a monthly basis was recorded as warfarin (with or without other medication), antiplatelet drugs (without warfarin), or no antithrombotic medication. The occurrence of any symptoms suggesting a stroke was thoroughly evaluated by 1 designated blinded investigator based on history from the patient or eyewitness and review of medical records ordered by the patient's physician. If necessary, follow-up examination and brain imaging were arranged. This investigator (R.L.G.) remained blinded to the PET data. All living patients were followed up for the duration of the study.

The primary end point was subsequent ischemic stroke defined clinically as a neurological deficit of presumed ischemic cerebrovascular cause lasting more than 24 hours in any cerebrovascular territory. Secondary end points were ipsilateral ischemic stroke and death.

Subjects were divided into 2 groups, those with stage II hemodynamic failure and those with normal (symmetric) OEF. Comparison of 17 baseline risk factors (Table 1) and subsequent medical treatment between the 2 groups was performed with unpaired t tests for continuous variables and χ² analysis for categorical variables. Uncorrected P values are reported. No adjustment was made for increased type I error because of the multiplicity of comparisons. The primary analysis compared the 2 groups with respect to the length of time before reaching the primary end point by means of the Mantel-Cox log-rank statistic and Kaplan-Meier survival curves. A value of P<.05 was used as the criterion of statistical significance. Secondary end points were analyzed in a similar manner. The day of the PET scan was considered to be the date of enrollment into the study. Survival analysis of subsequent end points began at that time. No interim analysis was planned or performed and no subgroup analyses were prespecified by the trial design.

The Cox proportional hazards model was used to test 20 candidate predictor variables in a univariate analysis. All variables except medical treatment were treated as time-constant variables whereas medical treatment was treated as a time-dependent variable. All variables with P<.20 in the univariate analysis were included in a subsequent multivariate analysis. Both forward and backward stepwise selection based on maximum partial likelihood estimates were used. Those variables that were significant at P<.05 in the multivariate analysis were included in the final model. Statistical analyses were performed with SPSS software, Version 7.0 (SPSS Inc, Chicago, Ill) and SAS software, Version 6.12 (SAS Institute Inc, Cary, NC).

We estimated that we would achieve 80% power to exclude a 4-fold difference in the primary end point between groups with a sample size of 100 patients, a 3-fold increase with a sample size of 150, and a 2-fold increase with a sample size of 350. We projected enrolling a minimum of 250 patients over 5 years. This research was approved by the institutional review boards of all participating hospitals. Written informed consent was obtained from all subjects.

Enrollment began on May 5, 1992. In July 1997, with funding due to expire in 4 months, we made the decision to stop the study and analyze all subjects enrolled by November 30, 1996, based on their status as of June 30, 1997. As of November 30, 1996, 419 subjects had been referred for screening. Eighty-seven subjects were enrolled in the study. Approximately four fifths of the remaining subjects refused to participate and the other one fifth were willing to participate but were ineligible. Of 87 patients who consented to participate, 81 successfully underwent initial data collection and PET measurements and were enrolled in the study. In 4 patients, no useful PET data were obtained because of technical difficulties. In 2 patients, large infarctions made regional analysis of the PET data impossible (Figure 1).

The diagnosis of carotid artery occlusion was made by intra-arterial contrast angiography in 75 of the 81 subjects. In the remaining 6, carotid artery occlusion was demonstrated by MR angiography in 4 and by carotid ultrasound in 2. In 60 (75%) of 81 patients, carotid occlusion was demonstrated within the 120-day period specified by the original protocol. Seventy-four (90%) of 81 patients had demonstration within 1 year prior to PET. There were no subjects with bilateral carotid occlusion. Prior to PET, 12 patients had undergone endarterectomy of contralateral internal carotid artery stenosis and one had undergone endarterectomy of ipsilateral external carotid artery stenosis.

Of 81 patients, 39 had stage II hemodynamic failure (increased OEF) in one hemisphere and 42 did not. In all 39 patients with stage II hemodynamic failure, the hemisphere with increased OEF was ipsilateral to the occluded carotid. The 2 groups were well matched for most baseline risk factors (Table 1). Retinal symptoms were less common in stage II subjects (3/39 vs 13/26). High-density lipoprotein cholesterol levels were lower in stage II subjects (1.01 ±0.26 vs 1.16 ±0.39). Stage II subjects spent a higher fraction of follow-up months on neither warfarin nor antiplatelet treatment (0.07 vs 0.02). Arteriographic collateral circulation did not permit distinction between the 2 groups (Table 2). Four subjects who underwent cerebrovascular surgery subsequent to enrollment were censored at the time of surgery. Three of these 4 subjects underwent contralateral carotid endarterectomy prior to occurrence of ipsilateral ischemic stroke and were censored after being followed up for 13 months, 29 months, and 29 months, respectively. Two had not reached any end point and 1 had experienced a vertebrobasilar stroke. The fourth patient experienced an ipsilateral stroke and underwent subsequent contralateral endarterectomy at 13 months. All subjects were followed up until the end of the study or until death (Figure 1).

Mean follow-up duration was 31.5 months. Fifteen total and 13 ipsilateral ischemic strokes occurred. There were no hemorrhages. In the 39 stage II subjects, 12 total and 11 ipsilateral strokes occurred. In the 42 subjects with normal OEF, there were 3 total and 2 ipsilateral strokes. The Kaplan-Meier estimates for the risk of subsequent stroke at 1 and 2 years are given in Table 3. The risks of all stroke and ipsilateral ischemic stroke in stage II subjects were significantly higher than in those with normal OEF (P=.005 and .004, respectively; Figure 2). Twelve deaths occurred, 6 in each group (P=.94).

We performed a subgroup analysis of the 57 subjects who met original entry criteria for symptoms within 120 days prior to PET. All strokes except 1 nonipsilateral stroke in a patient with normal OEF occurred in these patients. In this subgroup, the risk of all stroke (P=.008) and ipsilateral stroke (P=.02) was significantly higher in the 31 stage II patients than in the 26 patients with normal OEF.

The univariate analysis of risk factors for the primary end point of all stroke is shown in Table 4. Six variables with P<.20 were entered into the multivariate model (Table 5). In the multivariate model, only age and stage II hemodynamic failure remained significant independent predictors of all stroke. Similar univariate analysis for ipsilateral ischemic stroke (data not shown) yielded 5 variables for entry into the multivariate model (Table 5). Again, only age and stage II hemodynamic failure remained significant independent predictors of ipsilateral ischemic stroke. The age-adjusted relative risk conferred by stage II hemodynamic failure was 6.0 (95% confidence interval [CI], 1.7-21.6) for all stroke and 7.3 (95% CI, 1.6-33.4) for ipsilateral ischemic stroke.

Due to the previously described lower risk of stroke with retinal ischemia, we wanted to determine whether the imbalance between the occurrence of retinal symptoms in the 2 groups could explain our results.²¹ However, since no strokes occurred in these 16 subjects during follow-up, it was not possible to use the Cox proportional hazards method for this purpose. We therefore performed a subgroup analysis excluding the 16 patients with retinal symptoms. In the remaining 65 subjects, the risk of stroke was significantly higher in stage II subjects (12/36) than in subjects with normal OEF (3/29, P=.04). Similarly, the risk of ipsilateral ischemic stroke was also significantly higher in stage II subjects (11/36) than in subjects with normal OEF (2/29, P=.03).

We have demonstrated that stage II hemodynamic failure (increased oxygen extraction) distal to a symptomatic occluded carotid artery is an independent predictor of subsequent ischemic stroke. This study was prospective and blinded and addressed the possible effect of treatment and other risk factors for stroke. As with any study that requires informed consent, these patients did not constitute a consecutive series and thus there remains the possibility of some bias in the selection because of the high refusal rate, which might limit the generalizability of the conclusions. However, the rates for stroke and ipsilateral ischemic stroke in the total group of 81 patients are similar to those reported by others and the risk factor profile is typical for patients with carotid artery disease.^2,8,22

Following initiation of the study, we waived the 120-day limit for symptoms and documentation of carotid occlusion in an attempt to improve recruitment. In retrospect, this action was not necessary and had little effect on our results. All strokes except 1 nonipsilateral stroke in a patient with normal OEF occurred in the 57 subjects who met original entry criteria for symptoms within 120 days prior to PET. In this subgroup, the risks of all stroke (P=.008) and ipsilateral stroke (P=.02) were significantly higher in stage II patients than in those with normal OEF. We also included subjects with retinal symptoms who are known to have a lower risk of subsequent stroke.²¹ Most (13/16) of these patients were part of the low-risk group with normal OEF. Due to the small number of patients and the lack of subsequent strokes, we were unable to determine if the low risk of subsequent stroke reported in those with retinal events is attributable to the rarity of stage II hemodynamic failure or is independent of hemodynamic factors.

The development of modern imaging techniques has made it possible to indirectly assess the hemodynamic status of the human cerebral circulation in vivo. Most of these methods rely on identification of preexisting autoregulatory vasodilation by the measurement of CBV or by the CBF response to vasodilatory stimuli as a criterion for hemodynamic compromise.⁷ Physiologically, this approach can be expected to detect less severely affected subjects than the measurement of OEF.¹⁰ We therefore believe that it would be inappropriate to extrapolate our findings to other modalities. In fact, Yokota and colleagues⁹ have recently completed a longitudinal study similar in design to ours in which the relationship between reduced vasodilatory response to acetazolamide and the subsequent risk of stroke was evaluated. They prospectively followed up 105 symptomatic patients with severe stenosis or occlusion in the internal carotid or the MCA for a median of 2.7 years. There was no difference in subsequent stroke occurrence between the group with reduced vasodilatory response (7/55) and the group with normal vasodilatory response (6/50). Yamauchi et al²³ have also reported increased risk of stroke in patients with increased OEF measured by PET in a smaller study with 1-year follow-up. This study, although consistent with our results, is not entirely comparable since the absolute value of the OEF, rather than the hemispheric ratio, was used as the criterion for hemodynamic failure. Furthermore, this study suffered from possible bias due to lack of blinding and failure to consider the role of other risk factors.

Although this study establishes that stage II hemodynamic failure is a strong predictor of subsequent stroke in patients with symptomatic carotid occlusion, it cannot establish the mechanism for these subsequent strokes. The demonstration of hemodynamic failure at baseline does not necessarily prove that all subsequent strokes are hemodynamically mediated. Low-flow states may predispose to the formation of thromboemboli or, alternatively, thromboemboli may cause infarction more readily in areas with poor collateral circulation.

The results of medical treatment of stage II patients were poor and comparable with those reported for medically treated patients with symptomatic severe carotid stenosis.² Surgical approaches to improve cerebral hemodynamics, such as extracranial-intracranial (EC-IC) arterial bypass surgery, may appear to be logical treatment for these patients. However, a large, multicenter randomized trial conducted from 1977 to 1985 showed no benefit of EC-IC bypass surgery in preventing subsequent stroke in patients with symptomatic carotid occlusion.²² At the time that this trial was conducted, there was no reliable and proven method for identifying a subgroup of patients in whom cerebral hemodynamic factors were of primary pathophysiologic importance. We have now established that such a subgroup can be identified and, furthermore, that they are at high risk for subsequent stroke when treated medically. In stage II patients, EC-IC bypass surgery will return hemispheric OEF ratios to normal.^12,24- 26 However, in the absence of an empirical trial, it cannot be assumed that the surgery would be of benefit in this subgroup of patients. The morbidity and mortality due to surgery and the long-term stroke risk in patients who were operated on are not known. However, given our documented ability to identify this high-risk subgroup, it is appropriate at this time to consider performance of a new trial of EC-IC bypass surgery restricted to patients with stage II symptomatic carotid occlusion.