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Clinical Science

Alcohol and Acute Ischemic Stroke OnsetThe 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

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.

Result0f 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:P0.002). 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.

ConclusionsThe risk of stroke onset is transiently elevated in the hour after alcohol ingestion.

Moderate and high intakes of alcohol have been documented to have acute potentially deleterious physiological effects within hours after consumption, including impaired fibrinolysis and increased platelet activation, blood pressure, and heart rate. On the other hand, moderate consumption of alcohol has been associated with protective effects within hours, weeks, or years, including enhanced fibrinolytic activity, and improvements in lipid profile, inflammatory markers, flow-mediated vasodilatation, soluble vascular adhesion molecules, insulin sensitivity, and adipokinesis. However, only a few studies 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.

Methods

Study PopulationThe Stroke onset Study was conducted in 3 medical centers (Beth Israel deaconess Medical center, Boston, Mass; University of North 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 hospitals stroke service. Additionally, patient 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.

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

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Institutional Review Hoards ax each participating cernez and in

fanned consent was obtained from each paient

Interviewers used a structured questionnaire and asked patient to

report date and time of their first symptoms heralding their

stroke, Patients were asked if bey had consumed any alcoholic

beverage in the year before their stroke. Patcnrs who reponed any

alcohol consumption were aLso asked ro 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 definral 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 ro report the timing of their lass 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 collectes! from the

interview included medication ase and symptoms on the day of the

strrtke

Reliability and Validity of the Questionnaire

The restretest reliability of she Stroke Onset Study questionnaire

was assessed in 25 patients who were renteniewerl up ro 6 days

after their initial interview. The intradass correlation for the usual

frequency of alcohol consumption was excellent (1)84), and these

was perfect agreement for reporting of any alcohol consumption

dunng the past year and daring each of the first 2 hours before stroke

onset f x1,0). In the subset of lilt subjects interviewed at Beth

israel Deaconess Medical Center who had highdensiry Irpoprotein

cholesterol levels measured at the time of hospitalization, rire partial

correlation between estimated alcohol consronption and high-density

lipoprotein cholesterol level adjusting for sex. age. rare, smoking,

education, and physical activity was 0,35 (P0.(X)3), comparable to

thai found in the Second National Health and Nutrition Examination

Survey.20

Study Design

The Stroke Onset Study used a easecross over sum 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 avenge 1-hour period.

Statistical Analysis

Each patient in a casecrossover study forms his tr her own stratum

and titus is his tsr ber tiwn control.2m.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 masure of

relative risk (KR) We multiplied the usual annual frequency nf

alcohol consumption by the hypothesized window of its physiolog

ical effect (I hour in the pnrnaiy analysis) ro estimare the amount of

person-time exposed to alcohol. The unexposed person-rime was

calculated by subtracting this value from the number of heurs in I

year. The data were analyzed using methods for cohen studies wnh

sparse data in each stratum.

To estimate the length of tizne floro alcohol consumption tri tIr

onset of isehemic stroke, RRs were calculated by comparing expo-

stat within different bypoehesized windows of its physiological

effect with the estimated person-rinse exposed ro alcohol in the

previous year. We conducted snatifted analyses to assess the effect

of drink type fbccr. wine, liquor), sex, age (2

senings 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

preaented in the Table. Of the 390 patients with acute

isehemie stroke, 248 (64%) reported that they had consumed

alcohol in the prior year (wine, n45; beer, n29; liquor,

n-32; >1 type, n-142). Compared with nondrinkers, sub

jects who reponed 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%) reponed drinking at least once per week, and 163

(66%) reported drinking al least oocc per month. The median

ftcqucncy of consumption among drinkers in the prior year

Table. Clinical Characteristics at tite Sfroke Onset

Study Population*

Age years

Ma

p

0.11

003

009

Nnndrlnkers

(n = 142)

69-- 137

66(47%)

56(39%)

63(44%)

23(16%l

31 (22%(

Alcohol Drinkers

(n 248)

6814.5

143(56%)

72 (29

t 22 (49% j

54(22%)

59(24%)

56(23%)

101 (41%)

0.68

Diabetes

Hypercholenlerotenta

Hypertension

AlrW librillatort

History of

I.e

39(27%) 028

45 (32%( 0.08

152(61%) 100(70%) 0.07

32 (13%) 22(15%) 0.48

0 19

0.14

0.77

0,15

066

0-31

36(15%)

41(17%)

29(12%)

11 (61w

2(1%)

67(29%)

46(20%)

57(25%)

60(26%)

14(10%)

32(23%)

18(13%)

31(13%)

5(2%)

44(37%)

21(18%)

24(20%)

32(26%)

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Figure 1. lime 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 dur

ng each hour was compared with that during the ccntrol

period. The error bs indicate the 95% confidence tinets. The

dashed line indicates the baseiwie risk,

was 2.0 times per week. Subjects reported that they typically

drank small amounts each time (median= I drink) and only

13 reported typically drinking 2>2 servings,

There were 169 subjects who reponed exposure dining the

week before stroke, 104 subjects drank alcohol within 24

hours of stroke onset, and 14 drank within I hour of stroke

onset. We found that within I hour after alcohol consump

ion, the risk of stroke onset was 2.3-fold higher (95% CL, 1.4

to 4.0; P=0.02) compared with periods of nonuse. The RR

was 1.6(95% Cl, 1.0 to 2.5; P0.05) in the second hour after

drinking and returned to baseline thereafter (Figure 1). By 24

hours, there was a 30% lower risk (RR-07, 95% CI, 0.5 to

0.9; P0.02).

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 interaction0.28; Figure 2). The RRs for alcohol

consunsptioii in the hour before stroke did not vary by sex.

age. smoking status, or stroke etiology (P for interne

tioo=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 (riggers

in the hour before stroke onset. Of the 14 people exposed lo

alcohol in the hour before stroke onset. 4 were also exposed

to vigorous physical activity and I drank a caffeinated

bcvcragc. 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 patients

reported frequency of consumption in the past week as the

control information, the risk of ischcmic stroke onset was

3.3 -fold higher (95%. Cl, 1.2 ro 9.3; P=0.03) within 1 hour of

consuming at least I serving of alcohol compared with

periods with no alcohol intake. Excluding the I person who

reported drinking >2 servings of alcohol in the 2 hours

before stroke onset did not meaningfully alter the results.

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 conaumphon.i7.hi 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 ax a trigger

of ischemicw and hemorrhagic strnke. For instance,

Hiilbom et al5 found that moderate(l5l to 34X1 g)imd heavy

(>300 gj 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% Cl. 1.7 to 7.8) and 3.7

(95% CI, 1.6 to 117), respectively. Con.sisient with our data,

C,orelick et aP reported that after accounting for coexposures

including smoking, there was no statistically significant

increase in risk of isehemic stroke in the 24 hours after

alcohol consumption.

Previous studies on the acute effects of alcohol cohisump

tino indicate that heavy alcohol intake is associated with

impaired fihrinnlysis,2- increased platelet activation,4 and

increases in blood pressure and heart rate. 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 cOisse

quenccs. [n a clinical trial of S healthy men, Hcndriks and

colleagues7 found that plasininogen activator inhibitor was

significantly higher after 40g of alcohol than water after 1.3.

and S hours but was not significantly different after 9 hours.

On the other hand, there is evidence that moderate drinking

may provide transient health imprnvemnenls.5 Short-

term randomized trials indicate that moderate alcohol con

sumption may have beneficial effects through changes in

flow-mediated vasodilat.a(ion within minutes to hours and

improvements in lipid profile.2 inflammatory markers,

soluble vascular adhesion molecules, and adipokin&-6

within weeks.

In contract to the evidence no acute effects of alcohol

consumption, there is consistent evidence that habitual heavy

alcohol consumption is associated with an increased risk of

ischcrnic2-> and hemorrhagic stroke!- However, the ev

idence regarding light to moderate consumption is mixed.

, -

..

i

iw.

Figure 2. Relative mba of stroke according to beverage type.

The error bas indicate the 95% confidence units. The dashed

line itsdicates the basehee nsk

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HAL 4Although some studies reponed no association with ischctnic

or hcmotrhagic stroke,3 7recent comprehensive revicws6

indicate a decreased risk of ischemic stroke and a higher risk

of hemorrhagic stroke associated with light so moderate

consumption.

Integrating the .short-tenn effects obscncd here with other

studics on alcohol use and long-term risk is difficuls. Al

though speculative, it is possihle that the transiently increased

stroke risk from moderate alcohol consumption may he

outweighed hy the health benefits for the next 24 hours, hut

consuming multiple drinks at once may result in a sharp

increase in acute risk with potential increased long-tam risk

as well. Mukamal and colleagues7 found that, compared with

complete ahsaention from alcohol, light consumption (2 drinks per day is associated with an increasedrisk of isehcmie stroke. Our finding of an acute detrimentaleffect and a suggestion of a decreased risk over the 24-howperiod afta alcohol consumption seem consistent with thesefindings. Por example. one may hypothesize that over time,individuals who drink large amounts infrequently primarilyexperience the acute detrimental effect, whereas suhjects whodrink sinai] amounts frequently may still experience a transient increase in risk, hut this may he offset in part by thesuhsequeot reduction in risk that follows.There arc some limitations to our study. Because theeasecrossover design uses subjects as their own controls,there can he no confounding by risk factors that are stahleover time.7 Confounding by factors that change ova timewithin individuals can occur. However, excluding subjectsreporting other potential triggers in the hour before strokeonset did not materially alter the results. In an effort tomnini,nize reporting bias, efforts were made to ensure thepatients privacy during the interview. We used a standardized structured interview and patients were not informed ofthe duration of the hypothesized hazard period. Because mostof the participants drank small amounts of alcohol in the hourbefore stroke onset, we could not examine the acute effects ofdifferent doses of alcohol. We had limited power to evaluatethe effect of beverage type hecatise few participants wereexposed to each type. A larger study would help elucidatesuch effects. Finally, our results may not he generalizable topatients presenting with a severe or fatal stroke.SummaryIn conclusion, we found that the risk of ischemic stroke wastransiently elevated for 2 hours after drinking as little as Iserving of alcohol. The risk rapidly returned to baseline andwas modestly lower by 24 hours. When examined in thecontext of long-term studies of alcohol consumption, the netclinical impact on isehemie strokc risk appears to dcpcnd onthe frequency and quantity of alcohol consutnpton. Definitive evidence would require a long-term clinical trial, although auth a nial would he logistically difficult and isunlikely to he carried out in the near future.AcknowlcdgmcntsWe thank Cindy AicIlo for outstanding administrative assistancaSources of Fundinglisis work nc supponed hy an Established Investigator Grant(t)140219N) froto the Ainetican Heart Acsoeiasion, flattas, Tenc,and fl2-At007535-l t.Nonr.DisclosuresReferencesI Srank I, bterkwcn AC, Soleas (U. Tomnluoson (I. Monis RL Piano P,Notanus CE, Chas a, floras 1S Dose-related effects of rest wine andatcnhot on hemodynamies. sympathetic nerve activity, and annuldianteter. Am J Phnd tiran (in- Plis-dol. 2otat:294:t1605tjota.2. ICivinmem, It). 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