Ischemic Stroke Events and Carotid Atherosclerosis
Results of the Osaka Follow-up Study for Ultrasonographic Assessment of Carotid Atherosclerosis (the OSACA Study)
Background and Purpose To clarify the clinical significance of carotid atherosclerosis for ischemic stroke events, a follow-up study was performed in Japanese patients.
Methods Two hundred fourteen patients were registered from nine hospitals in the Osaka community. All patients were checked for a prior history of stroke, and the risk factors for stroke and atherosclerosis were evaluated. Carotid atherosclerosis was assessed by 7.5-MHz duplex ultrasonography. We studied the relationship between the ischemic stroke event rate and the severity and appearance of the carotid atherosclerosis. We also studied the relationship between stroke events and various risk factors.
Results The average duration of follow-up was 16 months. Ten patients suffered new ischemic stroke episodes during this follow-up period. At the initial ultrasonographic study, 16 patients had high-grade stenosis and 21 had ulcerated plaque. Proportional hazard regression analysis showed that grade of stenosis and plaque ulceration were positively related to the event rate. Patients with ulcerated plaque had a sevenfold higher hazard ratio for stroke in comparison to those without (P<.01). The ipsilateral stroke recurrence rate was 11 times higher in patients with ulcerated high-grade stenotic carotid lesions.
Conclusions The present findings demonstrate that the severity of carotid atherosclerosis as evaluated by ultrasonography is a useful indicator of the risk of ischemic stroke in symptomatic patients.
Cardiovascular disease based on atherosclerosis is the major cause of morbidity and mortality in Japan. Extracranial carotid atherosclerosis is not only a major cause of ischemic CVD disease but is also known to be a reliable marker of systemic atherosclerosis.1 2 3 Hemodynamic or embolic effects on the brain may arise from these lesions. Although intracranial vascular lesions are more common than extracranial lesions in Japanese stroke patients, extracranial lesions are increasing with changing lifestyles.4 5 In recent years, several authors have reported that the stroke event rate was closely related to the severity of carotid atherosclerosis.1 2 3 Large multicenter prospective studies like NASCET or ECST have shown that there is a high incidence of recurrence in patients with high-grade carotid stenosis. These studies also have shown that endarterectomy could reduce the recurrence rate in such patients.6 7 We have previously assessed the relationship between carotid atherosclerosis evaluated by ultrasonography and ipsilateral brain lesions evaluated by CT or MRI in Japanese patients.8 9
In our previous studies, we used B-mode ultrasonography for the evaluation of carotid lesions and demonstrated the clinical usefulness of this method for the assessment of carotid atherosclerosis in patients with risk factors for stroke.4 To determine the risk of ischemic stroke in Japanese patients with carotid atherosclerosis, we performed a multicenter follow-up study: the Osaka Follow-up Study for Ultrasonographic Assessment of Carotid Atherosclerosis (the OSACA study). The aims of the OSACA study were to clarify (1) the relationship between carotid lesions and ischemic stroke event, (2) the relationship between progression of carotid atherosclerosis and risk factors, and (3) the effectiveness of antiatherothrombotic agents (elastase) on the progression of the atherosclerosis. In this article, we describe primarily the results of the first aim in this OSACA study. We have already reported the preliminary results in abstract form.10 11
Subjects and Methods
The OSACA study is a prospective, hospital-based study on the pathophysiology and prevention of cardiovascular disease. Patient recruitment was performed at nine hospitals in the Osaka community (Osaka University Medical School Hospital, National Osaka Hospital, National Osaka-Minami Hospital, Osaka Rousai Hospital, Hoshigaoka-Kouseinenkin Hospital, Yao Municipal Hospital, Hyogo College of Medicine, Kagawa Medical School, and Kobe Ekisaikai Hospital). To be eligible for the trial, patients had to give informed consent, be less than 80 years old, and have at least one of the following diseases: hypertension, hypercholesterolemia, diabetes mellitus, ischemic stroke, ischemic heart disease, or arteriosclerosis obliterans. Patients were excluded from the study if they had a cardiac valvular or rhythm disorder likely to be associated with cardiogenic embolism; if they had organ failure of the kidney, liver, heart, or lung, or had cancer; or if they did not have ultrasonographic carotid images of good quality. Six hundred patients were nominated by nine hospitals to participate in the study, but half of these patients were excluded because they met the above exclusion criteria or met criteria making them temporarily ineligible (patients with uncontrolled hypertension, diabetes mellitus, unstable angina, or acute myocardial infarction). Finally, a total of 214 patients were enrolled in the trial. All patients were checked for a prior history of stroke and then underwent neurological examination and evaluation of risk factors for stroke and arteriosclerosis with laboratory tests. All of them were also evaluated for carotid atherosclerosis by 7.5-MHz B-mode Doppler ultrasonography. All clinical data were collected by the management office of the OSACA study at Osaka University Medical School and were registered. After the observation period, prospective follow-up was started. The end point of this study was when the patients had a new CVD event, ischemic heart attack, or death from any cause. Entry was started in April 1989, and the final follow-up was in April 1993. Patient eligibility and events were assessed by the participating medical doctors at each hospital, by the steering committee at the management office, and by the controllers who were not otherwise involved in the trial.
High-resolution B-mode ultrasonography was performed with a 7.5-MHz duplex-type scanner (Hitachi EUB-450, 555). Before beginning the study, we held an ultrasonographic evaluation protocol conference to determine standard methods for scanning, image recording, and evaluation of carotid lesions. Three different longitudinal views (anterior oblique, lateral, and posterior oblique) and transverse views of both carotid systems were obtained. Each ultrasound image was recorded on s-VHS videotape with an on-line videotape recorder. The IMT was evaluated as the distance between the luminal-intimal interface and the medial-adventitial interface, and it was measured using two calipers on the frozen frame of a suitable longitudinal image. On the basis of our previous studies and the consensus of the conference, the upper limit of normal for the IMT was defined as 1.0 mm, and lesions with an IMT ≥1.1 mm were defined as atheromatous plaques. To assess the severity of atherosclerosis, we used a “plaque score,” which was calculated by summing all plaque thicknesses in both carotid systems.4 To study lesion site specificity and allow easy comparison of lesion progression, the extracranial carotid artery was divided into four segments of 15 mm each from the flow divider (Fig 1⇓). The degree of stenosis was calculated from the ratio between the residual lumen and that of the original lumen. Doppler peak flow velocities >1.5 m/s were used to estimate >50% stenosis, and peak flow velocities >2.0 m/s indicated >70% high-grade stenosis.12 Referring to Moore’s criteria, we defined ulcerated lesions by the presence of large, obvious excavations (Moore’s type B ulcer) and/or plaque with multiple cavities or a cavernous appearance (Moore’s type C ulcer).13 Obstructive lesions or hairline stenosis were diagnosed easily using duplex. All ultrasonographic images that were recorded on s-VHS videotape were collected with other clinical records by the management office of the OSACA study, and the analysis was performed in a blinded manner. The data analyst was unaware not only of the outcome event but of the other clinical data also.
Age, sex, and four other risk factors for atherosclerosis were evaluated in all patients, together with symptoms of CVD. Hypertension was diagnosed when the blood pressure measured in the hospital was >160/95 mm Hg or if the patient was taking antihypertensive agents. Glucose intolerance was diagnosed if a patient was using oral hypoglycemic agents or insulin and/or if the fasting blood glucose level in the hospital exceeded 6.1 mmol/L and/or the glycosylated hemoglobin level exceeded 6.4%. Hypercholesterolemia was diagnosed if a patient was taking lipid-lowering agents and/or if the serum cholesterol level exceeded 5.7 mmol/L. Patients were categorized as being either nonsmokers (never smoked cigarettes or quit >3 years ago) or smokers (recently [<3 years] gave up cigarettes or current smoker). The subtype of CVD was classified from the history, neurological examination, and findings of CT and/or MRI scans according to the National Institute of Neurological Disorders and Stroke classification III of CVD.14 All patients were assessed for cardiac status on the basis of history, electrocardiogram, and transthoracic echocardiogram. If a patient was suspected of ischemic heart disease, Master’s double-load test or ergometer test with electrocardiogram was performed.
Statistical analysis was performed with the sas package and a personal computer (PC-9801PA, NEC). Cox proportional hazard regression analysis was used to assess the relationship between plaque appearance and the risk of various outcomes. The hazard ratio and 95% CI were used to assess the results. The relative risk was indicated by the hazard ratio. To compare categorical values, χ2 analysis was used. Log-rank test was used for analyzing the data of the Kaplan-Meier curves. For analyzing the changes of numerical data, such as the plaque score, Student’s paired or unpaired t test was used.
The characteristics of the subjects are shown in Table 1⇓. Of the 214 patients, 177 had carotid atherosclerosis. The initial ultrasonographic study showed that 16 patients (7%) had high-grade stenosis (>70% stenosis) and 21 patients (10%) had ulcerated plaque. On the basis of our PS categories, 107 patients (50%) had mild atherosclerosis (PS, 1.1 to 5.0), 49 (23%) had moderate atherosclerosis (PS, 5.1 to 10.0), and 21 (10%) had severe lesions (PS >10.0). Ulcerative lesions were mainly observed in large complex atheromatous plaques. Average PS, IMT, and grade of stenosis of ulcerated lesions were 9.26, 2.78 mm, and 58%, respectively, and these values were significantly larger than those of nonulcerated lesions (PS, 4.89; IMT, 2.26 mm; and stenosis, 32%). Ten patients had both ulceration and high-grade stenosis (48% of ulcerated lesions, 63% of high-grade stenosis), and 11 had both ulceration and low-grade stenosis (52% of ulcerative lesions, 7% of low-grade stenosis).
The average duration of follow-up was 16 months (range, 4 to 48 months). In this follow-up period, 10 patients suffered a new CVD episode. Fig 2⇓ is a flow chart of the annual stroke event rate in groups defined by the PS category and prior CVD. Transient ischemic attacks occurred in 2 patients, lacunar infarcts occurred in 2 patients, and 6 patients had new atherothrombotic brain infarcts. Seven patients had a disabling stroke, and 1 had a minor stroke. The stroke was ipsilateral to the carotid lesions in 8 patients and contralateral in 1. The remaining 1 stroke patient had no carotid lesions. Two non-CVD patients with moderate to severe carotid atherosclerosis suffered their first CVD attack (4.3% per year), and the remaining 8 patients had recurrent CVD (6.9% per year). Table 2⇓ summarizes the background characteristics of carotid lesions and type of stroke events in the above 10 patients.
Cox proportional hazard regression analysis was used to relate the risk of stroke events to plaque appearance and the severity of atherosclerosis. The grades of carotid stenosis and plaque ulceration were found to be positively related to stroke event rate. Patients with severe atherosclerosis (PS >10) had a ninefold higher hazard ratio (95% CI ranging from 1.00 to 82.11, P<.05; Table 3⇓). The patients with high-grade stenosis (≥70%) had a 21-fold higher risk for all stroke events than those without (95% CI ranging from 2.68 to 178.43, P<.004; Table 3⇓). The patients with ulcerated plaque showed a higher incidence of recurrent CVD than did those without (19.2% versus 4.8%, P<.05; Table 3⇓). Among recurrent CVD patients, those with ulcerated plaque were 11 times more likely to suffer an ipsilateral stroke than those without ulcerated plaque (Table 4⇓). Ipsilateral disabling stroke was 14 times more common in the patients with ulcerated high-grade carotid stenosis. For further analysis of the relationship between ulceration and grade of stenosis, we compared event rate and recurrence rate among four subgroups. Event rates with subgrouping of ulceration and grade of stenosis were as follows: 3 of 10 high-grade stenosis with ulcer (30%), 2 of 6 high-grade stenosis without ulcer (33%), 1 of 11 low-grade stenosis with ulcer (9%), and 3 of 150 low-grade stenosis without ulcer (2%).
Comparing the outcome event rate and the initial stroke type, patients with atherothrombotic infarction had a threefold higher risk of recurrence than those with lacunar infarction (Table 3⇑). Kaplan-Meier survival curves for three categories of carotid atherosclerosis are shown in Fig 3⇓. These were the result of all stroke events. High-grade stenosis was the most effective factor for survival curves; other factors (PS category and ulceration) were also significant factors (log-rank test).
Ninety-one patients (63 CVD patients and 28 non-CVD patients) took antiplatelet agents for the treatment of stroke, IHD, or arteriosclerosis obliterans. CVD recurred in 2 of 38 patients (6.8%) taking ticlopidine, 2 of 25 patients (8.0%) taking aspirin, and 4 of 25 patients (16%) without antiplatelet agents. Ticlopidine reduced the risk of stroke by at least 30% at 16 months of follow-up, but this was not significant.
During follow-up, the average plaque score increased significantly from 4.5±4.9 to 5.3±5.0 (P<.0001). There was no significant difference in plaque progression between event cases and event-free cases (ΔPS, 0.93 versus 0.71). Only one disabling stroke occurred in a patient with apparent plaque progression. Autopsy showed intraplaque hemorrhage, and this was suspected to be the cause of acute plaque progression.
Extracranial carotid lesions are known to be a major cause of ischemic CVD. Large multicenter prospective studies like NASCET6 or ECST7 have shown the etiologic significance of carotid lesions for ischemic stroke events in a symptomatic population. However, in Japanese stroke patients atherosclerosis more often affects the intracranial than the extracranial cerebral arteries when compared with Caucasian patients. In recent years, our ultrasonographic cross-sectional study4 and the angiographic study of Nagao et al5 have shown that this apparently racial difference in cerebral atherosclerosis decreases with changes in diet and other environmental factors. Evaluation of the relationship between carotid lesions and the stroke event rate is important both to prevent stroke and to investigate the mechanisms underlying stroke events.
The present study demonstrated that the severity of carotid atherosclerosis evaluated by ultrasonography in symptomatic patients was a useful marker of the prognosis for ischemic stroke events. Eliasziw et al15 also demonstrated that plaque ulceration with symptomatic high-grade stenosis was associated with a several-fold increased risk of stroke. Their study emphasized that high-grade stenosis and ulceration were associated with a high risk of stroke. Although plaque ulceration was sometimes found in early carotid atheroma (7% of low-grade stenosis in this study), ulcers were usually detected in large high-grade carotid lesions. Although there was a relatively small number of events, our study showed a close relationship between the severity of carotid atherosclerosis and stroke as well as a relationship between plaque appearance and stroke. Although there was no statistical significance of stroke event rate between patients of low-grade stenosis with ulcer and those without, ulceration in low-grade stenosis might show a potential risk for stroke. This close correlation between carotid lesions and stroke suggests the mechanism of artery-to-artery embolism. However, it is difficult to obtain clinical evidence of such embolism. This is because patients with severe carotid atherosclerosis frequently suffer from ischemic heart disease, which is a major cause of cardiogenic embolism. They also have generalized atherosclerosis including the small intracerebral arteries, which is the main cause of lacunar infarction.
The annual CVD recurrence event rate was 15% to 20% in the patients with severe carotid lesions under medical treatment. Large intervention trials have demonstrated the effectiveness of carotid endarterectomy in these patients. For example, NASCET6 showed that the risk of any stroke within 2 years was 27.6% in a medically treated group with high-grade stenosis and 12.6% in a surgically treated group. There was a 54% reduction of stroke events on comparison of the two groups. Our results support this pattern in Japanese patients with symptomatic high-grade stenosis.
Only two patients had a first CVD event in the follow-up period, and they had moderate to severe asymptomatic carotid lesions. One patient had ipsilateral carotid disease with ulcerated high-grade stenosis, and the other patient had a nonulcerated lesion. To assess the relationship between asymptomatic carotid lesions and stroke, a larger sample of asymptomatic patients and a longer follow-up period would be needed.
Carotid atherosclerosis progressed during the follow-up period, but we could not demonstrate a clear correlation between plaque progression and stroke events. Only one disabling stroke occurred in a patient with apparent plaque progression. Autopsy showed intraplaque hemorrhage, and this was suspected to be the cause of acute plaque progression. A study evaluating the relationship between plaque progression and risk factors is now ongoing, and we hope to publish the results in the future.
In conclusion, the OSACA study was designed to provide the clinical significance of carotid atherosclerosis for stroke events and also to show the effect of antiatherothrombotic agents on the progression of carotid atherosclerosis. The results of the study support the evidence showing that the severity of carotid atherosclerosis is a major predictive marker for future ischemic stroke events. However, we need to address with care the readings of the data, such as the high recurrence rate in the patients with high-grade stenosis, because of the relatively small sample size and the marginal number of event cases.
Selected Abbreviations and Acronyms
|ECST||=||European Carotid Surgery Trial|
|NASCET||=||North American Symptomatic Carotid Endarterectomy Trial|
The following persons and institutions participated in the Osaka Follow-up Study for Ultrasonographic Assessment of Carotid Atherosclerosis (the OSACA study).
Steering and Writing Committee of the Executive Committee: T. Kamada, MD; K. Kimura, MD*; M. Matsumoto, MD; N. Handa, MD (First Department of Medicine, Osaka University Medical School, Osaka Seamen’s Hospital*). T. Nukada, MD; H. Etani, MD (Division of Cardiovascular Medicine, National Osaka-Minami Hospital). M. Imaizumi, MD; K. Ashida, MD (Department of Internal Medicine, National Osaka Hospital). Y. Sugitani, MD (Internal Medicine, Hoshigaoka-Kouseinenkin Hospital). S. Yoneda, MD (Yao Municipal Hospital). M. Kusunoki, MD; T. Asai, MD (Department of Internal Medicine, Kobe Ekisaikai Hospital). K. Sueyoshi, MD; R. Fukunaga, MD (Internal Medicine, Osaka Rousai Hospital). O. Uyama, MD (Fifth Department of Medicine, Hyogo College of Medicine). Y. Tsuda, MD; K. Nagatsuka, MD†; Y. Ayada, MD (Second Department of Medicine, Kagawa Medical School, National Cardiovascular Center†).
The participating hospitals and researchers are listed in order of the number of eligible patients entered in the study.
Osaka University Medical School, Suita: K. Kimura, MD*; M. Matsumoto, MD; N. Handa, MD; S. Ogawa, MD; H. Maeda, MD; H. Hougaku; T. Itoh; Y. Tsukamoto; O. Iiji. National Osaka-Minami Hospital, Kawachinagano: H. Etani, MD; K. Terayama, MD*. National Osaka Hospital, Osaka: K. Ashida, MD. Hoshigaoka-Kouseinenkin Hospital, Hirakata: Y. Sugitani, MD; K. Tanaka, MD; Y. Nagai. Yao Municipal Hospital, Yao: S. Yoneda, MD. Kobe Ekisaikai Hospital, Kobe: M. Kusunoki, MD; T. Asai, MD. Osaka Rousai Hospital, Sakai: K. Sueyoshi, MD; R. Fukunaga, MD; M. Yamaguchi, PhD (ultrasonographer). Hyogo College of Medicine, Nishinomiya: O. Uyama, MD; T. Matsuyama, MD; Z. Matsumoto, MD; H. Michishita; MD. Second Department of Medicine, Kagawa Medical School, Takamatsu: Y. Tsuda, MD; K. Nagatsuka, MD†; Y. Ayada, MD‡.
*Osaka Seamen’s Hospital; †National Cardiovascular Center; ‡Sakaide Municipal Hospital.
This work was supported by the research grant for cardiovascular diseases (6A-1) from the Japanese Ministry of Health and Welfare and was also supported in part by the Smoking Research Foundation. We wish to thank M. Kubo (MDS Co, Ltd) for the statistical analysis. We also wish to thank M. Shimomura, M. Tsunoda, M. Manabe, and R. Manabe for their invaluable secretarial assistance.
- Received January 23, 1995.
- Revision received June 16, 1995.
- Accepted June 16, 1995.
- Copyright © 1995 by American Heart Association
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