Alcohol and Acute Ischemic Stroke Onset - Stroke Journal

Alcohol and Acute Ischemic Stroke Onset The Stroke Onset Study Elizabeth Mostofsky, MPH; Mary R. Burger, MD; Gottfried Schlaug, MD, PhD; Kenneth J. Mukamal, MD, MPH; Wayne D. Rosamond, PhD; Murray A. Mittleman, MD, DrPH

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Background and Purpose—Previous research suggests that regular heavy alcohol consumption increases the risk for ischemic stroke, whereas frequent light to moderate alcohol intake may decrease the risk. However, the risk of ischemic stroke associated with transient exposure to alcohol remains unclear. In this study, we used a case– crossover approach to test the hypothesis that alcohol consumption affects the acute risk of ischemic stroke, to determine the length of time between alcohol intake and the onset of symptoms (induction time), and to examine whether the risk varies by the type of alcohol. Methods—In this multicenter study, we interviewed 390 patients (209 men, 181 women) between January 2001 and November 2006 (median 3 days after stroke). Alcohol consumption in the hour before stroke symptoms was compared with its expected frequency based on the usual frequency of alcohol consumption over the prior year. Results—Of the 390 patients, 248 (64%) reported alcohol consumption in the prior year, 104 within 24 hours and 14 within 1 hour of stroke onset. The relative risk of stroke in the hour after consuming alcohol was 2.3 (95% CI, 1.4 to 4.0; P⫽0.002). The relative risks were similar for different types of alcoholic beverages and when the sample was restricted to those who were not simultaneously exposed to other potential triggers. Conclusions—The risk of stroke onset is transiently elevated in the hour after alcohol ingestion. (Stroke. 2010;41:00-00.) Key Words: alcohol 䡲 case– crossover 䡲 cerebrovascular disorders 䡲 epidemiology 䡲 stroke

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oderate1 and high2– 4 intakes of alcohol have been documented to have acute potentially deleterious physiological effects within hours after consumption, including impaired fibrinolysis2,3 and increased platelet activation,4 blood pressure, and heart rate.1 On the other hand, moderate consumption of alcohol has been associated with protective effects within hours,5–7 weeks,8 –12 or years,13–15 including enhanced fibrinolytic activity7,8 and improvements in lipid profile,12 inflammatory markers,8,11 flow-mediated vasodilatation,5,6 soluble vascular adhesion molecules,11,14 insulin sensitivity,9,15 and adipokines.9,14 However, only a few studies16 –18 have examined the risk of ischemic stroke associated with transient exposure to alcohol. In this study, we used a case– crossover approach to test the hypothesis that alcohol consumption affects the acute risk of ischemic stroke, to determine the length of time between alcohol intake and the onset of symptoms (induction time), and to examine whether the risk varies by the type of alcohol.

Carolina Hospitals, Chapel Hill, NC; Vancouver Island Health Authority, Victoria, British Columbia, Canada). Between January 2001 and November 2006, 390 patients (209 men and 181 women) were interviewed a median of 3 days (range, 0 to 14 days) after sustaining an acute ischemic stroke. Research staff identified eligible patients by reviewing admission logs and charts of patients admitted to each hospital’s stroke service. Additionally, patients with new onset of an acute neurological syndrome compatible with stroke were screened on admission to emergency departments. Presumed stroke etiology was classified using an abbreviated Trial of Org 10172 in Acute Stroke Treatment system.19 Study personnel using standardized abstraction forms recorded data on demographics, medical history, and admission laboratory results. Eligible participants had a neurologist-confirmed diagnosis of acute ischemic stroke either by clinical diagnosis or appropriate imaging studies, were English-speaking, and free of dementia before the index event. Patients were excluded if they could not identify the time of onset of their stroke symptoms or if the treating clinician deemed them unable to complete the structured interview because they were cognitively impaired, had poor memory around the time of the stroke, experienced aphasia, or they were too ill to complete the structured interview that lasted 30 to 45 minutes. Across all sites, 43% of patients with confirmed ischemic stroke met all inclusion criteria. Of these, 83% agreed to participate, 5.5% refused, and 12.5% were discharged from the hospital before the interviewers were able to approach them. The protocol was approved by the

Methods Study Population The Stroke Onset Study was conducted in 3 medical centers (Beth Israel Deaconess Medical Center, Boston, Mass; University of North

Received January 28, 2010; final revision received March 19, 2010; accepted April 1, 2010. From the Cardiovascular Epidemiology Research Unit (E.M., K.J.M., M.A.M.), Department of Medicine, Department of Neurology (G.S.), and the Division of General Medicine & Primary Care (K.J.M.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass; the Department of Epidemiology (E.M., M.A.M.), Harvard School of Public Health, Boston, Mass.; Cincinnati Children’s Hospital Medical Center Heart Institute (M.R.B.), Cincinnati, Ohio; and the Department of Epidemiology (W.D.R.), University of North Carolina School of Public Health, Chapel Hill, NC. The preliminary results were previously presented in an abstract at the 2006 International Stroke Conference. Correspondence to Murray A. Mittleman, MD, DrPH, Cardiovascular Epidemiology Research Unit, Beth Israel Deaconess Medical Center, 375 Longwood Avenue, Room 423, Boston, MA 02215. E-mail [email protected] © 2010 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org

DOI: 10.1161/STROKEAHA.110.580092

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Institutional Review Boards at each participating center and informed consent was obtained from each patient. Interviewers used a structured questionnaire and asked patients to report the date and time of their first symptoms heralding their stroke. Patients were asked if they had consumed any alcoholic beverage in the year before their stroke. Patients who reported any alcohol consumption were also asked to report the last time that they had consumed an alcoholic beverage, their usual frequency of alcohol consumption over the prior year, the usual number of servings consumed each time they drank an alcoholic beverage, and the types of alcohol consumed (beer, wine, or liquor). A serving size of alcohol was defined as 12 ounces of beer, 4 ounces of wine, or 1.5 ounces of liquor straight or in a mixed drink. Patients were also asked to report the timing of their last exposure to other potential triggers and usual frequency of these factors over the prior year, including caffeine, cigarette smoking, marijuana, cocaine, stress, anger, and physical activity. Other information collected from the interview included medication use and symptoms on the day of the stroke.

Table. Clinical Characteristics of the Stroke Onset Study Population*

Reliability and Validity of the Questionnaire

Atrial fibrillation

The test–retest reliability of the Stroke Onset Study questionnaire was assessed in 25 patients who were reinterviewed up to 6 days after their initial interview. The intraclass correlation for the usual frequency of alcohol consumption was excellent (0.84), and there was perfect agreement for reporting of any alcohol consumption during the past year and during each of the first 2 hours before stroke onset (␬⫽1.0). In the subset of 181 subjects interviewed at Beth Israel Deaconess Medical Center who had high-density lipoprotein cholesterol levels measured at the time of hospitalization, the partial correlation between estimated alcohol consumption and high-density lipoprotein cholesterol level adjusting for sex, age, race, smoking, education, and physical activity was 0.35 (P⫽0.003), comparable to that found in the Second National Health and Nutrition Examination Survey.20

History of

Study Design The Stroke Onset Study used a case– crossover study design to assess the change in risk of acute ischemic stroke onset during a brief “hazard period” after consumption of alcohol. In the case– crossover design, control information for each patient is based on his or her own past exposure experience. Self-matching eliminates confounding by risk factors that are constant within individuals over the sampling period but differ between subjects. Alcohol use in the hazard period, the 1-hour period immediately before the onset of ischemic stroke symptoms, was compared with its expected frequency based on control data obtained from the patients. We used the usual frequency of alcohol consumption over the year before stroke to estimate its expected frequency in an average 1-hour period.

Statistical Analysis Each patient in a case– crossover study forms his or her own stratum and thus is his or her own control.21,22 The ratio of the observed exposure frequency in the hazard period to the expected frequency was used to calculate estimates of the rate ratio as a measure of relative risk (RR). We multiplied the usual annual frequency of alcohol consumption by the hypothesized window of its physiological effect (1 hour in the primary analysis) to estimate the amount of person-time exposed to alcohol. The unexposed person-time was calculated by subtracting this value from the number of hours in 1 year. The data were analyzed using methods for cohort studies with sparse data in each stratum. To estimate the length of time from alcohol consumption to the onset of ischemic stroke, RRs were calculated by comparing exposure within different hypothesized windows of its physiological effect with the estimated person-time exposed to alcohol in the previous year. We conducted stratified analyses to assess the effect of drink type (beer, wine, liquor), sex, age (⬍65 years of age versus ⱖ65 years of age), smoking status (current smokers versus nonsmok-

Alcohol Drinkers (n⫽248)

Nondrinkers (n⫽142)

P

Age, years

68⫾14.5

69⫾13.7

0.11

Male

143 (58%)

66 (47%)

0.03

Never

72 (29%)

56 (39%)

Former

122 (49%)

63 (44%)

Current

54 (22%)

23 (16%)

Obesity (body mass index ⱖ30 kg/m2)†

59 (24%)

31 (22%)

0.68

Diabetes

56 (23%)

39 (27%)

0.28

Smoking status

0.09

Hypercholesterolemia

101 (41%)

45 (32%)

0.08

Hypertension

152 (61%)

100 (70%)

0.07

32 (13%)

22 (15%)

0.48

MI

36 (15%)

14 (10%)

0.19

Stroke

41 (17%)

32 (23%)

0.14

TIA

29 (12%)

18 (13%)

0.77

Coronary revascularization

11 (8%)

31 (13%)

0.15

2 (1%)

5 (2%)

Carotid endarterectomy Stroke etiology‡

0.66 0.31

Small vessel

67 (29%)

44 (37%)

Large vessel

46 (20%)

21 (18%)

Cardioembolic

57 (25%)

24 (20%)

Other/undetermined

60 (26%)

32 (26%)

*Mean⫾SD or no. (%). †There was no data available on body mass index for 7 subjects. ‡At 1 of the centers, stroke etiology was not determined (n⫽39). MI indicates myocardial infarction; TIA, transient ischemic attack.

ers), and stroke etiology and compared the RRs by means of a test for homogeneity.23 To evaluate whether potential triggers could account for the observed association, we conducted a sensitivity analysis excluding patients who engaged in other potentially triggering activities (ie, vigorous physical exertion and anger) in the hour before their stroke. In another sensitivity analysis, we used the number of drinks consumed in the week before the stroke as the control information. We were not able to examine the association between binge drinking and ischemic stroke, because only 1 person reported drinking ⬎2 servings of alcohol in the hour before stroke onset. All reported probability values are 2-sided.

Results The characteristics of the Stroke Onset Study patients are presented in the Table. Of the 390 patients with acute ischemic stroke, 248 (64%) reported that they had consumed alcohol in the prior year (wine, n⫽45; beer, n⫽29; liquor, n⫽32; ⬎1 type, n⫽142). Compared with nondrinkers, subjects who reported alcohol consumption were more likely to be male and to have ever smoked cigarettes. Among the 248 subjects who drank alcohol in the prior year, 47 (12%) reported drinking at least 1 serving of alcohol per day, 38 (10%) reported drinking at least once per week, and 163 (66%) reported drinking at least once per month. The median frequency of consumption among drinkers in the prior year

Mostofsky et al

Figure 1. Time of onset of stroke after an episode of alcohol consumption. Each of the 3 hours before the onset of stroke was assessed as independent hazard periods, and drinking during each hour was compared with that during the control period. The error bars indicate the 95% confidence limits. The dashed line indicates the baseline risk. Downloaded from http://stroke.ahajournals.org/ by guest on November 5, 2017

was 2.0 times per week. Subjects reported that they typically drank small amounts each time (median⫽1 drink) and only 13 reported typically drinking ⬎2 servings. There were 169 subjects who reported exposure during the week before stroke, 104 subjects drank alcohol within 24 hours of stroke onset, and 14 drank within 1 hour of stroke onset. We found that within 1 hour after alcohol consumption, the risk of stroke onset was 2.3-fold higher (95% CI, 1.4 to 4.0; P⫽0.002) compared with periods of nonuse. The RR was 1.6 (95% CI, 1.0 to 2.5; P⫽0.05) in the second hour after drinking and returned to baseline thereafter (Figure 1). By 24 hours, there was a 30% lower risk (RR⫽0.7, 95% CI, 0.5 to 0.9; P⫽0.02). Among the 14 participants who consumed alcohol in the hour before stroke onset, 7 drank liquor, 5 drank beer, and 2 drank wine. The RR for alcohol consumption in the hour before stroke onset was strongest for liquor and weakest for wine, although the difference was not statistically significant (P for interaction⫽0.28; Figure 2). The RRs for alcohol consumption in the hour before stroke did not vary by sex, age, smoking status, or stroke etiology (P for interaction⫽0.62, 0.62, 0.12, and 0.43, respectively). Among the 248 participants exposed to alcohol in the prior year, 63 participants were exposed to other potential triggers in the hour before stroke onset. Of the 14 people exposed to alcohol in the hour before stroke onset, 4 were also exposed to vigorous physical activity and 1 drank a caffeinated beverage. When we conducted an analysis excluding the 63 people exposed to any potential stroke trigger in the hour before stroke onset, the results remained similar. The mean usual frequency of alcohol consumption during the past year was 4.42 times per week, similar to the mean frequency of reported alcohol consumption during the past week (4.23). In a sensitivity analysis using each patient’s reported frequency of consumption in the past week as the control information, the risk of ischemic stroke onset was 3.3-fold higher (95% CI, 1.2 to 9.3; P⫽0.03) within 1 hour of consuming at least 1 serving of alcohol compared with periods with no alcohol intake. Excluding the 1 person who reported drinking ⬎2 servings of alcohol in the 2 hours before stroke onset did not meaningfully alter the results.

Alcohol and Stroke Onset: The Stroke Onset Study

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Figure 2. Relative risk of stroke according to beverage type. The error bars indicate the 95% confidence limits. The dashed line indicates the baseline risk.

Discussion In this study, alcohol consumption was associated with a transient increased risk of ischemic stroke in the subsequent hour that was 2.3 times higher than the risk during periods with no alcohol consumption. This finding is consistent with previous research indicating an acute detrimental effect of alcohol consumption.17,18 The risk returned to baseline by 3 hours and there was a modestly lower risk by 24 hours. Few studies have evaluated the role of alcohol as a trigger of ischemic16 –18,24 and hemorrhagic stroke.25 For instance, Hillbom et al18 found that moderate (151 to 300 g) and heavy (⬎300 g) consumption of alcohol within the week before stroke onset is associated with a significantly higher risk of stroke with adjusted ORs of 3.6 (95% CI, 1.7 to 7.8) and 3.7 (95% CI, 1.6 to 8.7), respectively. Consistent with our data, Gorelick et al24 reported that after accounting for coexposures including smoking, there was no statistically significant increase in risk of ischemic stroke in the 24 hours after alcohol consumption. Previous studies on the acute effects of alcohol consumption indicate that heavy alcohol intake is associated with impaired fibrinolysis,2,3 increased platelet activation,4 and increases in blood pressure and heart rate.1 Furthermore, heavy consumption may acutely lead to dehydration, further increasing the transient risk of stroke. However, such heavy consumption was rare and unlikely to explain our findings. Even moderate drinking may have acutely adverse consequences. In a clinical trial of 8 healthy men, Hendriks and colleagues7 found that plasminogen activator inhibitor was significantly higher after 40 g of alcohol than water after 1, 3, and 5 hours but was not significantly different after 9 hours. On the other hand, there is evidence that moderate drinking may provide transient health improvements.5–9,11,12,26 Shortterm randomized trials indicate that moderate alcohol consumption may have beneficial effects through changes in flow-mediated vasodilatation5,6 within minutes to hours and improvements in lipid profile,12 inflammatory markers,11 soluble vascular adhesion molecules,11 and adipokines9,26 within weeks. In contrast to the evidence on acute effects of alcohol consumption, there is consistent evidence that habitual heavy alcohol consumption is associated with an increased risk of ischemic27,28 and hemorrhagic stroke.28 –30 However, the evidence regarding light to moderate consumption is mixed.

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Although some studies reported no association with ischemic or hemorrhagic stroke,31–35 recent comprehensive reviews28,36 indicate a decreased risk of ischemic stroke and a higher risk of hemorrhagic stroke associated with light to moderate consumption. Integrating the short-term effects observed here with other studies on alcohol use and long-term risk is difficult. Although speculative, it is possible that the transiently increased stroke risk from moderate alcohol consumption may be outweighed by the health benefits for the next 24 hours, but consuming multiple drinks at once may result in a sharp increase in acute risk with potential increased long-term risk as well. Mukamal and colleagues27 found that, compared with complete abstention from alcohol, light consumption (⬍1 drink daily) is not associated with stroke risk, moderate alcohol consumption (1 to 2 drinks daily) is protective, and intake of ⬎2 drinks per day is associated with an increased risk of ischemic stroke. Our finding of an acute detrimental effect and a suggestion of a decreased risk over the 24-hour period after alcohol consumption seem consistent with these findings. For example, one may hypothesize that over time, individuals who drink large amounts infrequently primarily experience the acute detrimental effect, whereas subjects who drink small amounts frequently may still experience a transient increase in risk, but this may be offset in part by the subsequent reduction in risk that follows. There are some limitations to our study. Because the case– crossover design uses subjects as their own controls, there can be no confounding by risk factors that are stable over time.22 Confounding by factors that change over time within individuals can occur. However, excluding subjects reporting other potential triggers in the hour before stroke onset did not materially alter the results. In an effort to minimize reporting bias, efforts were made to ensure the patient’s privacy during the interview. We used a standardized structured interview and patients were not informed of the duration of the hypothesized hazard period. Because most of the participants drank small amounts of alcohol in the hour before stroke onset, we could not examine the acute effects of different doses of alcohol. We had limited power to evaluate the effect of beverage type because few participants were exposed to each type. A larger study would help elucidate such effects. Finally, our results may not be generalizable to patients presenting with a severe or fatal stroke.

Summary In conclusion, we found that the risk of ischemic stroke was transiently elevated for 2 hours after drinking as little as 1 serving of alcohol. The risk rapidly returned to baseline and was modestly lower by 24 hours. When examined in the context of long-term studies of alcohol consumption, the net clinical impact on ischemic stroke risk appears to depend on the frequency and quantity of alcohol consumption. Definitive evidence would require a long-term clinical trial, although such a trial would be logistically difficult and is unlikely to be carried out in the near future.

Acknowledgments We thank Cindy Aiello for outstanding administrative assistance.

Sources of Funding This work was supported by an Established Investigator Grant (0140219N) from the American Heart Association, Dallas, Texas, and T32-A1007535-11.

Disclosures None.

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20. Linn S, Carroll M, Johnson C, Fulwood R, Kalsbeek W, Briefel R. High-density lipoprotein cholesterol and alcohol consumption in US white and black adults: data from NHANES II. Am J Public Health. 1993;83:811– 816. 21. Mittleman MA, Maclure M, Robins JM. Control sampling strategies for case– crossover studies: an assessment of relative efficiency. Am J Epidemiol. 1995;142:91–98. 22. Maclure M. The case– crossover design: a method for studying transient effects on the risk of acute events. Am J Epidemiol. 1991;133:144 –153. 23. Rothman KJ, Greenland S, Lash TL. Modern Epidemiology. Philadelphia: Lippincott Williams & Wilkins; 2008. 24. Gorelick PB, Rodin MB, Langenberg P, Hier DB, Costigan J, Gomez I, Spontak S. Is acute alcohol ingestion a risk factor for ischemic stroke? Results of a controlled study in middle-aged and elderly stroke patients at three urban medical centers. Stroke. 1987;18:359 –364. 25. Anderson C, Ni Mhurchu C, Scott D, Bennett D, Jamrozik K, Hankey G. Triggers of subarachnoid hemorrhage: role of physical exertion, smoking, and alcohol in the Australasian Cooperative Research on Subarachnoid Hemorrhage Study (ACROSS). Stroke. 2003;34:1771–1776. 26. Beulens JW, van Loon LJ, Kok FJ, Pelsers M, Bobbert T, Spranger J, Helander A, Hendriks HF. The effect of moderate alcohol consumption on adiponectin oligomers and muscle oxidative capacity: a human intervention study. Diabetologia. 2007;50:1388 –1392. 27. Mukamal KJ, Ascherio A, Mittleman MA, Conigrave KM, Camargo CA Jr, Kawachi I, Stampfer MJ, Willett WC, Rimm EB. Alcohol and risk for ischemic stroke in men: the role of drinking patterns and usual beverage. Ann Intern Med. 2005;142:11–19.


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28. Reynolds K, Lewis B, Nolen JD, Kinney GL, Sathya B, He J. Alcohol consumption and risk of stroke: a meta-analysis. JAMA. 2003;289: 579 –588. 29. Feigin VL, Rinkel GJ, Lawes CM, Algra A, Bennett DA, van Gijn J, Anderson CS. Risk factors for subarachnoid hemorrhage: an updated systematic review of epidemiological studies. Stroke. 2005;36: 2773–2780. 30. Ariesen MJ, Claus SP, Rinkel GJ, Algra A. Risk factors for intracerebral hemorrhage in the general population: a systematic review. Stroke. 2003; 34:2060 –2065. 31. Djousse L, Ellison RC, Beiser A, Scaramucci A, D’Agostino RB, Wolf PA. Alcohol consumption and risk of ischemic stroke: the Framingham Study. Stroke. 2002;33:907–912. 32. Sturgeon JD, Folsom AR, Longstreth WT Jr, Shahar E, Rosamond WD, Cushman M. Risk factors for intracerebral hemorrhage in a pooled prospective study. Stroke. 2007;38:2718 –2725. 33. Jousilahti P, Rastenyte D, Tuomilehto J. Serum gamma-glutamyl transferase, self-reported alcohol drinking, and the risk of stroke. Stroke. 2000;31:1851–1855. 34. Leppala JM, Paunio M, Virtamo J, Fogelholm R, Albanes D, Taylor PR, Heinonen OP. Alcohol consumption and stroke incidence in male smokers. Circulation. 1999;100:1209 –1214. 35. Gorelick PB. The status of alcohol as a risk factor for stroke. Stroke. 1989;20:1607–1610. 36. Mukamal K. Alcohol intake and noncoronary cardiovascular diseases. Ann Epidemiol. 2007;17:S8 –S12.

Alcohol and Acute Ischemic Stroke Onset. The Stroke Onset Study Elizabeth Mostofsky, Mary R. Burger, Gottfried Schlaug, Kenneth J. Mukamal, Wayne D. Rosamond and Murray A. Mittleman Downloaded from http://stroke.ahajournals.org/ by guest on November 5, 2017

Stroke. published online July 15, 2010; Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2010 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628

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Clinical Science 酒精与急性缺血性卒中起病：卒中起病研究 Alcohol and Acute Ischemic Stroke Onset The Stroke Onset Study

Elizabeth Mostofsky, MPH; Mary R. Burger, MD; Gottfried Schlaug, MD, PhD; Kenneth J. Mukamal, MD, MPH; Wayne D. Rosamond, PhD; Murray A. Mittleman, MD, DrPH 背景和目的：早前的研究提示规律性大量饮酒会增加缺血性卒中的风险，而经常性的少 - 中量的饮酒则能减少其风险。然而，一过性饮酒的缺血性卒中风险仍不明确。本研究采用病例交叉研究来检验饮酒对急性缺血性卒中风险的影响，以了解饮酒开始至症状出现的时程 ( 诱发时间 ) 并观察不同种类酒精饮料对卒中风险的影响。方法：本多中心研究在 2001 年 1 月至 2006 年 11 月间，共问询 390 名患者 ( 男性 209 人，女性 181 人，中位时间为卒中发病后 3 天 )。基于既往前一年中通常的饮酒频率，将卒中症状出现前 1 小时内酒精的摄入与预期频率进行比较。结果：390 名患者中，248 例 (64%) 在前一年内饮酒，104 例在卒中发生前 24 小时内曾有饮酒，14 人在起病前 1 小时内曾有饮酒。饮酒后 1 小时内卒中发生的相对危险为 2.3(95% 可信区间为 1.4-4.0 ；P=0.002)。当严格控制样本于那些并未同时暴露于其他诱因的患者时，不同种类酒精饮料具有相类似的相对危险度。结论：饮酒后 1 小时内卒中发生的风险会短暂地升高。关键词：酒精，病例交叉研究，脑血管病，流行病学，卒中 (Stroke. 2010;41:1845-1849.　上海交通大学附属仁济医院神经内科曹雯炜译李焰生校 )

有报道中到大量的饮酒数小时内，酒精对生理功能具有急性的潜在恶化的作用用

[2,3]

，增加血小板激活

[4]

[1-4]

及升高血压和心律 [1]。另

一方面，中等量饮酒可有数小时年

[13-15]

质谱

、改善炎性标志物

扩张作用

、数周

[8-12]

或数

[7,8]

、改善脂

[8,11]

、改善血流介导的血管

[5,6]

岛素敏感性究

[5-7]

的保护作用，包括增加纤溶活性

[12]

[16-18]

，包括损害纤溶作

医学中心 ( 马萨诸塞州波士顿的 Beth Israel Deaconess 医学中心，北卡罗来纳州的北卡罗来纳大学医院，加拿大不列颠哥伦比亚省温哥华岛卫生局 ) 中进行。在 2001 年 1 月至 2006 年 11 月期间，共纳入 390 例患者 ( 男性 209 例，女性 181 例 )，在急性缺血性卒中发病后 ( 中位数 3 天，范围在 0-14 天 ) 进行访谈。

、调节可溶性血管黏附因子 [11,14]、增加胰

研究人员通过回顾各医院卒中中心收治患者的入院

[9,15]

日志和病例记录明确入组患者。另外，对急诊入院

和脂联素

[9,14]

。然而，只有少部分研

检验了一过性饮酒后的缺血性卒中的危险度。

本研究中，我们使用了病例交叉研究来验证饮

时符合新发急性卒中表现的患者进行筛查。患者卒中的病因学诊断使用 TOAST 分型 [19]。研究人员使用标准化简要表格记录患者的人口

酒会影响缺血性卒中的急性风险的假说，明确饮酒至症状出现 ( 诱发时间 ) 的时程，检验不同种类酒精

统计学资料、既往史和入院时实验室结果等数据。

饮料是否具有相类似的风险。

合格的参与者应符合神经科临床诊断或相关的影像学检查明确的急性缺血性卒中的诊断，语言为英语，

方法研究人群卒中起病研究 (Stroke Onset Study, SOS) 在三个

在卒中事件前无痴呆。排除标准包括：无法明确卒中症状的发生时间；或因认知损害、不能回忆卒中发病时间、有失语或疾病危重无法完成持续 30-45

From the Cardiovascular Epidemiology Research Unit (E.M., K.J.M., M.A.M.), Department of Medicine, Department of Neurology (G.S.), and the Division of General Medicine & Primary Care (K.J.M.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass; the Department of Epidemiology (E.M., M.A.M.), Harvard School of Public Health, Boston, Mass.; Cincinnati Children’s Hospital Medical Center Heart Institute (M.R.B.), Cincinnati, Ohio; and the Department of Epidemiology (W.D.R.), University of North Carolina School of Public Health, Chapel Hill, NC. The preliminary results were previously presented in an abstract at the 2006 International Stroke Conference. Correspondence to Murray A. Mittleman, MD, DrPH, Cardiovascular Epidemiology Research Unit, Beth Israel Deaconess Medical Center, 375 Longwood Avenue, Room 423, Boston, MA 02215. E-mail [email protected] © 2010 American Heart Association, Inc.

50

Mostofsky et al

分钟访谈等原因而无法完成结构性访谈。所有中心中，43% 的明确的缺血性卒中患者符合入选标准，其中 83% 患者同意入组，5.5% 拒绝入组，12.5% 患者在接触前已出院。研究方案经各分中心伦理委员会批准并获得每位患者的知情同意。访谈人员使用结构性问卷询问患者出现症状的时间及起病前一年内是否饮酒。要求所有曾经有饮酒的患者提供末次酒精饮料摄入时间、前一年里饮酒的频率、每次饮酒量和饮酒种类 ( 啤酒、葡萄酒或烈性酒 ) 等信息。一份酒精量的定义为 12 盎司啤酒或 4 盎司葡萄酒或 1.5 盎司烈性酒的直接或混合饮用。患者同时被要求提供最后一次其他潜在诱因 ( 包括咖啡因、烟草、大麻、可卡因、应激、愤怒和体力活动 ) 的暴露时机及最近一年中这些诱因的暴露频率。其他在访谈中收集的信息还包括药物的使用和卒中当天的症状。问卷的信度和效度在 25 名患者中进行 SOS 问卷的重测信度评估，他们均在首次访谈后 6 天再次接受访谈。饮酒的既往频率在组内的相关性高度一致 (0.84)，对最近一年的和卒中发生前 2 小时的饮酒报道也具有良好的一致性 (k =1.0)。181 例在 Beth Israel Deaconess 医学


表　卒中起病研究人群的临床特征 * 年龄，岁性别，男吸烟史　从未　既往　目前肥胖 (BMI ≥ 30 kg/m2)† 糖尿病高脂血症高血压心房颤动既往史　心肌梗死　卒中　短暂性脑缺血发作　冠脉成形术　颈动脉内膜切除术卒中病因 ‡

饮酒者 (n=248) 68±14.5 143 (58%)

非饮酒者 (n=142) 69±13.7 66 (47%)

72 (29%) 122 (49%) 54 (22%) 59 (24%) 56 (23%) 101 (41%) 152 (61%) 32 (13%)

56 (39%) 63 (44%) 23 (16%) 31 (22%) 39 (27%) 45 (32%) 100 (70%) 22 (15%)

36 (15%) 41 (17%) 29 (12%) 11 (8%) 2 (1%)

14 (10%) 32 (23%) 18 (13%) 31 (13%) 5 (2%)

P值 0.11 0.03 0.09

0.68 0.28 0.08 0.07 0.48 0.19 0.14 0.77 0.15 0.66 0.31

　小血管性 67 (29%) 44 (37%) 　大血管性 46 (20%) 21 (18%) 　心源性 57 (25%) 24 (20%) 　其他 / 不明原因 60 (26%) 32 (26%) * 数据以均数 ± 标准差或数量 (%) 形式表示。 †7 例患者缺乏体重指数 (BMI) 数据。 ‡ 在 1 个中心未进行卒中病因学诊断 (n=39)。

中心住院的患者接受了高密度脂蛋白胆固醇的检测，

性生理作用的时间窗 ( 初步分析为 1 小时 ) 来估计暴露于酒精数量的人 / 时数，并将未暴露的人 / 时数在

在校正性别、年龄、种族、吸烟史、教育、体力活

一年中减去。每层中所缺失数据的分析采用队列研

动等因素后，饮酒的估计量与高密度脂蛋白水平存在相关性 (0.35，P=0.003)，与第二次国家健康与营

究方法。

养检验调查的发现一致

[20]

。

研究设计 SOS 使用了病例交叉对照设计，来评估饮酒后的短时间“危险期”中，急性卒中发生风险的变化。在病例交叉设计中，每位患者自身既往所存在的暴露作为其对照信息。自身对照控制了患者在研究期间持续存在但又与其他个体不同的混杂因素，将患者危险期，即缺血性卒中症状发病前 1 小时的饮酒情况

为了明确饮酒至缺血性卒中发生的时间长度， RR 值的计算比较了按生理作用使用不同假设时间窗的酒精暴露和估计所得的过去一年里暴露于酒精的人 / 时数。我们通过分层分析来评估不同酒精饮料种类 ( 啤酒、葡萄酒、烈性酒 )、性别、年龄 (300 g) 饮酒是卒中发生的显著高危因素，校正后的 OR 值为 3.6(95%

中发生的相对危险为 1.6 (95% CI，1.0-2.5 ；P=0.05)，之

CI，1.7-7.8)，与本研究相一致。但 Gorelick 等 [24] 研

后相对危险回落至基线水平 ( 图 1)。在 24 小时，风险则下降了 30% (RR=0.7，95% CI，0.5-0.9 ；P=0.02)。

究表明，在校正了包括吸烟在内的协同暴露因素后，饮酒后 24 小时内的缺血性卒中风险未见明显升高。

169 例患者在卒中前一周内有饮酒，104 例则在卒

在卒中发生前 1 小时内饮酒的 14 例中，7 人饮烈

早前对饮酒的急性作用的研究显示，大量的饮

性酒，5 人饮啤酒，2 人饮葡萄酒。卒中前 1 小时内饮

酒与纤溶损害 [2,3]、促进血小板聚集 [4] 及血压和心律

烈性酒的相对危险较高，葡萄酒较低，但没有达到统计学意义 ( 交互后的 P 值为 0.28 ；图 2)。卒中前 1 小

的上升 [1] 相关。另外，大量饮酒会造成急性脱水，

时饮酒的相对风险与性别、年龄、吸烟史或卒中病因无关 ( 交互后的 P 值分别为 0.62、0.62、0.12 和 0.43)。

并进一步增加了短期发生卒中的风险。然而，这样大量的饮酒十分少见，也无法解释我们的研究结果。

在 248 例一年内饮酒的患者中，63 例在卒中发

即使中量饮酒也可能导致急性的不良反应。在一项对 8 例健康男性的研究中，Hendriks 等 [7] 发现相对

生前 1 小时内暴露于其他潜在的诱因。在卒中发生

于饮水，在饮酒 40 g 后的第 1、3、5 小时内，血纤

前 1 小时内的饮酒的 14 例中，4 例曾进行剧烈的体

溶酶原激活抑制物显著升高，9 小时后则无显著差异。

力活动，1 例摄入含有咖啡因的饮料。当排除了 1

另一方面，有证据表明适度饮酒能短暂地改善

小时内具有其他潜在卒中诱因的 63 例患者后，研究

机体健康状态 [5-9,11,12,26]。短期随机试验显示，适度饮

结果与之前相似。

酒可在饮酒数分钟至数小时引起血流介导的血管扩

患者在最近的一年中平均饮酒频率为每周 4.42 次，与最近一周内的平均饮酒频率相似 (4.23 次 )。

张 [5,6]，并在饮酒后数周内改善血脂组成 [12]、炎性标志物 [11]、可溶性的血管黏附因子 [11] 和脂联素 [9,26]。

用每位患者所报告的最近一周的平均饮酒频率为对

与饮酒的急性作用相反，一系列证据显示长期

照所做的灵敏度分析，饮用至少 1 个单位酒后 1 小时

大量饮酒与缺血性 [27,28] 和出血性 [28-30] 卒中的风险增加相关。然而，少 - 中等量饮酒研究的相关证据并

内的缺血性卒中发病风险是未饮酒期的 3.3 倍 (95% 52

Mostofsky et al

不一致。尽管一些研究报道了其与缺血性或出血性卒中并无相关性 [31-35]，但近期系统综述 [28,36] 表明，少中等量饮酒与缺血性卒中风险的下降及出血性卒中

3. 4.

风险的上升相关。

5.

将本研究中饮酒的短期作用与长期风险相整合是十分困难的。据推测，中度饮酒后 24 小时内的益

6.

处可能超过短期卒中风险的增加作用，但单次多种饮酒可能导致急性风险和潜在长期风险的同时增加。 Mukamal 等 [27] 发现，与从不饮酒相比，少量饮酒 ( ≤ 1 单位 / 天 ) 与卒中风险无关，中度饮酒 (1-2 单位 / 天 ) 则有保护性，而每日 2 单位及以上的饮酒则与缺血

7. 8. 9. 10.

性卒中风险的上升相关。我们发现饮酒的急性损害作用及在 24 小时后风险的下降与这些研究相一致。

11.

可以假设，偶尔大量饮酒者通常可能在一开始即发

12.

生酒精的急性损害作用，而少量规律饮酒者可能也

13.

同样发生卒中风险的短期升高，但这又会得到之后一系列益处的补偿。本研究仍存在一些不足之处。由于病例交叉研究中的患者，以自身作为对照，则不会受到研究期 [22]

14. 15. 16.

，但患者个体的危险因素可能发生变化。然而，排除了那些在卒中前 1 小

17.

时内存在其他潜在诱因的个体后，对结果无重大影

19.

间稳定的危险因素的影响

18.

响。为了尽可能减少报道偏倚，访谈期间尽可能对患者的隐私进行保密。我们使用了标准化结构性访谈，且研究期间患者未被告知其潜在的危险期。由于大多数患者在卒中发生前 1 小时内有少量饮酒史，故无法

20. 21. 22.

确定不同剂量的酒精的急性损害作用。由于很少患者

23.

仅饮用一种酒精饮料，我们也无法评估不同种类的作

24.

用差异。大型研究有助于阐明这些作用。最后，我们的研究结果可能无法推广至危重或致死性卒中。

总结总之，我们发现缺血性卒中风险在饮酒 1 单位

25.

26.

27.

后 2 小时内有短暂的升高。这一风险在之后迅速回落至基线水平，24 小时后的卒中风险则有轻度降低。

28.

早前一些饮酒的长期研究证实饮酒对缺血性卒中风

29.

险的综合作用则取决于饮酒的频率和剂量。这也需

30.

要长期的临床试验来提供决定性的证据，但从逻辑

31.

上看，此类试验难以开展，在近期无法实现。

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