Alcohol consumption and risk and prognosis of atrial fibrillation among older adults: The Cardiovascular Health Study

Alcohol consumption and risk and prognosis of atrial fibrillation among older adults: The Cardiovascular Health Study Kenneth J. Mukamal, MD, MPH,a Bruce M. Psaty, MD, PhD, MPH,b,c,d Pentti M. Rautaharju, MD, PhD,e Curt D. Furberg, MD, PhD,e Lewis H. Kuller, MD, DrPH,f Murray A. Mittleman, MD, DrPH,a John S. Gottdiener, MD,g and David S. Siscovick, MD, MPHb,c Boston, MA; Seattle, WA; Winston-Salem, NC; Pittsburgh, PA; and Baltimore, MD

Background

The relationship of alcohol consumption with risk of atrial fibrillation (AF) is inconsistent in previous studies, and its relationship with prognosis of AF is undetermined.

Methods As part of the Cardiovascular Health Study, a population-based cohort of adults 65 years and older from 4 US communities, 5609 participants reported their use of beer, wine, and spirits yearly. We identified cases of AF with routine study electrocardiograms and validated discharge diagnoses from hospitalizations. Results A total of 1232 cases of AF were documented during a mean of 9.1 years of follow-up. Compared with longterm abstainers, the multivariable-adjusted hazard ratios were 1.25 (95% CI, 1.02-1.54) among former drinkers, 1.09 (95% CI, 0.94-1.28) among consumers of less than 1 drink per week, 1.00 (95% CI, 0.84-1.19) among consumers of 1 to 6 drinks per week, 1.06 (95% CI, 0.82-1.37) among consumers of 7 to 13 drinks per week, and 1.09 (95% CI, 0.88-1.37) among consumers of 14 or more drinks per week ( P trend = 0.64). In analyses of mortality among participants with AF, the hazard ratios were 1.27 (95% CI, 1.06-1.52) among former drinkers, 0.94 (95% CI, 0.76-1.18) among consumers of less than 1 drink per week, 0.98 (95% CI, 0.78-1.23) among consumers of 1 to 6 drinks per week, 0.73 (95% CI, 0.51-1.03) among consumers of 7 to 13 drinks per week, and 0.81 (95% CI, 0.59-1.11) among consumers of 14 or more drinks per week ( P trend = 0.12). Conclusions Current moderate alcohol consumption is not associated with risk of AF or with risk of death after diagnosis of AF, but former drinking identifies individuals at higher risk. (Am Heart J 2007;153:26026.) Moderate alcohol consumption is associated with a lower risk of cardiovascular disease than abstention or heavy drinking among older adults in observational

From the aDepartment of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, b Department of Epidemiology, University of Washington, Seattle, WA, cDepartment of Medicine, University of Washington, Seattle, WA, dDepartment of Health Services, University of Washington, Seattle, WA, eDepartment of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, fDepartment of Epidemiology, University of Pittsburgh, Pittsburgh, PA, and gDivision of Cardiology, University of Maryland Hospital, Baltimore, MD. The research reported in this article was supported by contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, and N01 HC-15103 from the National Heart, Lung, and Blood Institute, which has approved the paper. A full list of participating Cardiovascular Health Study investigators and institutions can be found at http:// www.chs-nhlbi.org. Submitted July 31, 2006; accepted October 23, 2006. Reprint requests: Kenneth J. Mukamal, MD, MPH, Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, 1309 Beacon St, 2nd Floor, Brookline, MA 02446. E-mail: [email protected] 0002-8703/$ - see front matter n 2007, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2006.10.039

studies.1 Although anecdotal evidence implicates episodic heavy drinking as a trigger of atrial fibrillation (AF),2 the relationship of the full range of alcohol consumption with the risk of AF in observational studies is far less consistent. Several case-control studies have found relatively similar odds of AF among abstainers and moderate drinkers, but significantly higher odds of AF among heavier drinkers,3-6 a finding confirmed in a prospective analysis of the Copenhagen City Heart Study.7 However, a second Danish cohort study found 25% to 46% higher risks of AF associated with the 3 highest quintiles of alcohol intake, representing approximately 20 g (~1O drinks) or more per day, when compared with the lowest quintile, but only among men.8 Paradoxically, alcohol administration decreases susceptibility to and duration of AF in canine studies,9,10 although these were directed toward acute effects of alcohol exposure. Intriguingly, in an analysis of 3 years of follow-up of the Cardiovascular Health Study (CHS),11 alcohol use among older adults was inversely associated with risk of

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AF, with 4% lower risk for each additional drink per week. However, alcohol consumption was evaluated as a continuous variable, follow-up time was limited, and the analysis was directed toward general determinants of AF rather than alcohol per se. To address the prospective association of alcohol use and risk of AF more fully, we reexamined the incidence of AF during more than 9 years of follow-up of CHS, a population-based cohort study of community-dwelling older adults. We also examined the association of alcohol intake with subsequent mortality among individuals with AF, which has not been previously assessed to our knowledge.

Methods Study population and design The CHS is a longitudinal study of 5888 men and women aged 65 years or older who were randomly selected from Medicare-eligibility lists in 4 communities in the United States. Participants were not institutionalized or wheelchair-dependent, did not require a proxy for consent, and were not under treatment for cancer at the time of enrollment. In 1989 and 1990, 5201 participants were recruited (the original cohort); in 1992 and 1993, an additional 687 black participants were recruited (the minority cohort). The institutional review board at each center approved the study, and each participant gave informed consent. For all analyses, we excluded 23 participants with missing information on baseline alcohol use, 74 with preexisting implanted pacemakers, and 21 with missing information on pacemakers, leaving 5770 participants potentially eligible for analysis. Of these, we excluded an additional 152 with preexisting AF at baseline and 9 missing this information for analyses of incident AF. For analyses of subsequent mortality, we included the 152 participants with AF at baseline and 1232 who developed AF during follow-up. The CHS study design and objectives have been published previously.12 The baseline examination included standardized questionnaires, physical examination, resting electrocardiography (ECG), echocardiography, and laboratory examination. Follow-up contact occurred every 6 months, alternating between telephone calls and clinic visits.

Alcohol consumption At the baseline visit and annually until 1999, participants reported their usual frequency of consumption of beer, wine, and liquor, and the usual number of 12-oz cans or bottles of beer, 6-oz glasses of wine, and shots of liquor that they drank on each occasion. For administrative reasons, alcohol consumption was not determined at the 1990-1991 CHS visit. In 1995-1996, alcohol consumption was assessed only with a validated food frequency questionnaire13 rather than quantity-frequency items used in other years. At baseline, participants reported whether they changed their pattern of consumption during the past 5 years and whether they ever regularly consumed 5 or more drinks daily. Participants who reported abstention at baseline but responded yes to either of these questions were classified as former drinkers.

Mukamal et al 261

We categorized participants into categories according to weekly ethanol consumption as follows: none, former, less than 1 drink weekly, 1 to 6 drinks weekly, 7 to 13 drinks weekly, and 14 and more drinks weekly. For regression analyses, abstainers without former use served as the reference category.

Determination of incident AF Details of the CHS protocol for confirmation of incident cardiovascular disease have been published.14,15 Participants reported hospitalizations and other acute events at annual clinic visits and interim telephone interviews. Discharge summaries and diagnoses were obtained for all hospitalizations. As in previous analyses,16,17 cases of AF were identified by annual 12-lead ECGs, centrally reviewed at the CHS ECG Reading Center,18 or by hospital discharge diagnoses (International Classification of Diseases, Ninth Revision [ICD 9] codes 427.3, 427.31, or 427.32). Hospital discharge diagnoses have a positive predictive value of 98.6% for diagnosing AF in CHS.11 Furthermore, review of 24-hour Holter monitoring performed in 819 participants demonstrated only 1 individual with AF not otherwise identified.17 For exploratory analyses, we evaluated cases of persistent AF, using the established CHS definition,19 of AF diagnosed on at least 2 routine ECGs during follow-up. Deaths were identified and centrally adjudicated by review of obituaries, medical records, death certificates, and the Centers for Medicare and Medicaid Services health care–utilization database for hospitalizations and from household contacts.

Other covariates Hypertension, diabetes, anthropomorphic measures, physical activity, smoking, marital status, and income were assessed and categorized as in previous CHS analyses.20,21 Psychoactive medication use included antidepressants, benzodiazepines, and antipsychotic agents. Details of the CHS protocol for adjudication and confirmation of congestive heart failure and coronary heart disease have been published.14,15 Depressive symptoms were assessed at baseline with the Centers for Epidemiologic Studies Depression Scale.22 The apoE genotype (which modifies several effects of alcohol consumption in this cohort20,23) was evaluated as described.24 Of the 5609 eligible participants for analyses of incident AF, 267 declined consent for genetic testing for cardiovascular diseases and 357 did not have necessary DNA stored or were not successfully genotyped, yielding 4985 participants with information on apoE genotype.

Statistical analysis For analyses of incident AF, participants accrued person-time from study entry until their first hospitalization with AF, the first examination at which AF was noted, death, or June 2002. We tested Kaplan-Meier estimates of AF-free survival across all categories of alcohol intake with the log-rank test. In initial Cox proportional hazards models, we simultaneously controlled for age, sex, and race. Based on previously described predictors of AF in this cohort,11 we then additionally adjusted for height, waist circumference, depressive symptom score, physical activity, and total cholesterol (as continuous variables)

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262 Mukamal et al

Table I. Selected baseline characteristics of 5629 CHS participants according to incident AF during follow-up

Figure 1

AF during follow-up

Age (y) Male African American Married Income z$16,000 Body mass index (kg/m2) Standing height (cm) Waist circumference (cm) Leisure-time physical activity (kJ) CES-D Current smoker Former smoker Current use of Estrogen among women Aspirin Psychoactive medication History of Hypertension Diabetes Coronary heart disease Congestive heart failure Systolic blood pressure (mm Hg) Left atrial size (cm) Fasting serum levels of Total cholesterol C-reactive protein Glucose Potassium Creatinine Total drinks per wk Drinks per wk of Beer Wine Liquor

Yes (n = 1232)

No (n = 4377)

P

73.8 F 5.7 615 (50) 121 (10) 824 (67) 665 (57) 26.9 F 4.8 166.4 F 9.6 96.0 F 13.2 6753 F 7904

72.4 F 5.4 1726 (39) 758 (17) 2884 (66) 2371 (58) 26.6 F 4.7 164.3 F 9.3 94.1 F 13.2 7360 F 8711

b.001 b.001 b.001 .54 .40 .04 b.001 b.001 .02

4.8 F 4.7 140 (11) 523 (42)

4.7 F 4.6 532 (12) 1802 (41)

.52 .49 .43

64 (10) 616 (51) 174 (14)

328 (12) 1982 (46) 523 (12)

.19 .003 .04

808 (66) 232 (19) 325 (26) 71 (6) 135 F 21

2478 (57) 657 (15) 730 (17) 134 (3) 138 F 23

b.001 .002 b.001 b.001 b.001

4.0 F 0.7

3.8 F 0.6

b.001

207.4 4.2 113.5 4.18 1.11 2.6

F F F F F F

37.6 7.9 40.3 0.39 0.50 7.0

0.7 F 3.6 0.6 F2.2 1.3 F 4.6

213.4 3.4 110.1 4.16 1.04 2.4

F F F F F F

39.3 5.5 35.9 0.38 0.34 6.1

0.5 F 2.9 0.6 F 2.3 1.1 F 4.0

b.001 .002 .01 .04 b.001 .38 .11 .67 .27

Means, SDs, and P values from t tests are shown for continuous variables; and frequencies, proportions and P values from exact tests are shown for categorical variables. CES-D indicates Centers for Epidemiologic Studies Depression Scale.

and diabetes, hypertension, coronary heart disease, congestive heart failure, income, and use of psychoactive medication (as binary variables). Further adjustment for marital status, current and former smoking, body mass index, aspirin use, estrogen use, systolic blood pressure, serum glucose, and serum creatinine did not influence our results, nor did exclusion of hypertension, coronary heart disease, and congestive heart failure (potential mediators) as covariates. Adjustment for nonfried fish intake17 and echocardiographically determined left atrial size (a potential mediator), which were available in the original cohort at baseline, also did not influence our results. We tested the proportional hazards assumption using time-varying covariates25 and found no violations. For tests of linear trend, we excluded former drinkers and treated the midpoints of the categories of alcohol use as a linear variable.

Kaplan-Meier estimates of survival free of AF among CHS participants according to baseline alcohol consumption.

We performed both baseline and updated, time-dependent analyses, in which we prospectively assessed the relative risk of AF in yearly increments, based upon alcohol consumption derived from each preceding questionnaire. In these latter analyses, we grouped participants who stopped drinking during follow-up with former drinkers at baseline and included hypertension, congestive heart failure, and coronary heart disease as time-varying covariates. We conducted stratified analyses according to median age, sex, race, presence of hypertension, and presence of an apoE4 allele. We tested for interaction by comparing the linear relationships of alcohol intake and risk of AF across strata. In analyses of post-AF mortality, we examined mortality after the diagnosis of AF according to alcohol consumption at the time of diagnosis. This was set to baseline consumption for participants diagnosed at baseline, to the level of intake reported at the clinic visit at which the diagnosis was made for participants diagnosed by ECG during follow-up, and at the visit immediately after hospitalization for participants diagnosed by discharge codes. In Cox models of mortality, we simultaneously controlled for the same covariates as in models of incident AF with the addition of smoking, body mass index, and hormone replacement therapy (the only additional covariates in the more inclusive model associated with mortality). We adjusted for oral anticoagulant use in sensitivity analyses; if physicians include current alcohol use in their determination of the appropriateness of oral anticoagulant administration (ie, alcohol use helps predict warfarin use, which in turn influences outcome), then its inclusion may represent overadjustment.

Results Baseline characteristics Of the 5609 eligible participants, 1232 participants developed AF during a mean of 9.1 years of follow-up; their characteristics at baseline are shown in Table 1. As

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Table II. Hazard ratios and 95% CIs for risk of AF according to usual alcohol consumption Drinks per wk

Baseline Cases Person-years Age-, sex-, race-adjusted 95% CI MV modely 95% CI Updated Age-, sex-, race-adjusted 95% CI MV model4 95% CI

None

Former

bb 1

1-6

7-13

14+

491 21 047 1.00 – 1.00 –

125 3957 1.30 (1.06-1.58) 1.25 (1.02-1.54)

244 10 040 1.03 (0.88-1.20) 1.09 (0.94-1.28)

197 8999 0.86 (0.73-1.02) 1.00 (0.84-1.19)

72 3069 0.87 (0.68-1.11) 1.06 (0.82-1.37)

103 3994 0.98 (0.79-1.22) 1.09 (0.88-1.37)

1.00 – 1.00 –

0.99 (0.85-1.16) 1.06 (0.90-1.24)

0.88 (0.74-1.04) 0.99 (0.83-1.17)

0.80 (0.66-0.96) 0.95 (0.78-1.15)

0.87 (0.68-1.11) 1.06 (0.82-1.36)

1.00 (0.79-1.27) 1.18 (0.93-1.49)

P4

0.39 0.64

0.92 0.16

MV indicates multivariable model. 4P values were derived from tests of trend. yThe multivariable model adjusted for age, sex, race, income, height, waist circumference, physical activity, use of psychoactive medication, diabetes, hypertension, coronary heart disease, congestive heart failure, and total cholesterol level.

Table III. Adjusted hazard ratios for risk of AF according to baseline consumption of individual alcoholic beverages Drinks per wk

Beer Cases Person-years Hazard ratioy 95% CI Wine Cases Person-years Hazard ratioy 95% CI Spirits Cases Person-years Hazard ratioy 95% CI

0

bb1

1-6

7+

923 38 533 1.00 –

181 6981 1.02 (0.85-1.22)

74 3835 0.74 (0.57-0.96)

54 1758 1.21 (0.90-1.61)

775 31 326 1.00 –

280 11 570 1.13 (0.97-1.32)

126 5892 1.04 (0.84-1.28)

51 2319 1.06 (0.78-1.42)

862 34 739 1.00 –

169 7777 0.92 (0.77-1.11)

106 4643 1.01 (0.80-1.26)

95 3948 0.94 (0.74-1.18)

P*

.72

.90

.79

Footnotes as in Table II.

previously reported,11,16 age, sex, race, height, history of cardiovascular disease, and serum levels of cholesterol, glucose, and C-reactive protein were associated with incident AF in CHS. Neither total alcohol intake nor intake of any specific alcoholic beverage differed significantly between those who did and those who did not develop AF.

Risk of incident AF Figure 1 shows Kaplan-Meier estimates of survival free of AF among CHS participants according to baseline alcohol consumption. The curves were significantly different, primarily because the risk of AF was highest among former drinkers. Consumers of 14 or more drinks

per week initially tended to have the lowest risk, but had higher risk with longer follow-up. Table II shows adjusted analyses of the risk of AF according to alcohol consumption at baseline. Although former drinkers were at higher risk, we found no evidence of substantially higher or lower risk in any other drinking category, regardless of the degree of multivariable adjustment. When we stratified heavier drinkers into finer categories, the multivariableadjusted hazard ratios were 1.14 (95% CI, 0.89-1.45) among consumers of 14 to 27 drinks per week and 0.94 (95% CI, 0.60-1.48) among consumers of 28 or more drinks per week. When we evaluated alcohol consumption with updating during follow-up (Table II),

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264 Mukamal et al

Figure 2

Kaplan-Meier estimates of survival among CHS participants with AF according to alcohol consumption at the time of diagnosis.

initial analyses demonstrated a modest U-shaped relationship that was completely attenuated after multivariable adjustment. In stratified analyses, we found no consistent differences in the association of alcohol intake with risk of AF among participants stratified by age ( P interaction = .97), sex ( P interaction = .16), race ( P = .26), or hypertension ( P = .97). The risk of AF was almost 80% higher among apoE4-positive individuals who consumed 7 to 13 drinks per week than among apoE4-positive abstainers (hazard ratio, 1.76; 95% CI, 1.09-2.85), a finding that was not seen among apoE4-negative individuals (hazard ratio, 0.91; 95% CI, 0.67-1.25). Although a post hoc test of interaction at this level of intake was significant ( P = .04), no difference was seen at higher or lower levels of consumption; and the prespecified test of interaction across all levels of intake was not significant ( P = .52). Table III shows results from beverage-type analyses. The relationships of each beverage type with risk of AF were generally null, with no clear evidence of higher or lower risk for any individual beverage. We also explored the association of baseline alcohol intake with the subset of 154 cases with AF identified on at least 2 study ECGs.19 The hazard ratios for consumption of less than 1, 1 to 6, 7 to 13, and 14 or more drinks per week were 1.06 (95% CI, 0.67-1.68), 1.16 (95% CI, 0.73-1.86), 1.34 (95% CI, 0.70-2.56), and 1.39 (95% CI, 0.79-2.42), respectively ( P trend = .18).

Mortality among participants with AF We examined mortality among the 1384 participants with AF either at baseline or during follow-up as a

function of their alcohol intake at the time of diagnosis. A total of 855 (62%) participants died during a mean follow-up of 4.1 years. Figure 2 shows unadjusted estimates of survival according to alcohol consumption. Much like what was seen for risk of AF, the curves were significantly different because the risk of death among those with AF was highest among former drinkers. In multivariable-adjusted analyses, the hazard ratios for death were 1.27 (95% CI, 1.06-1.52) among former drinkers, 0.94 (95% CI, 0.76-1.18) among consumers of less than 1 drink per week, 0.98 (95% CI, 0.78-1.23) among consumers of 1 to 6 drinks per week, 0.73 (95% CI, 0.51-1.03) among consumers of 7 to 13 drinks per week, and 0.81 (95% CI, 0.59-1.11) among consumers of 14 or more drinks per week ( P trend = .12). In a post hoc analysis, the hazard ratio among consumers of 7 to 13 and 14 or more drinks combined was 0.76 (95% CI, 0.60-0.97). With further adjustment for oral anticoagulant use assessed concurrently with alcohol intake, the hazard ratios among consumers of 7 to 13 and 14 and more drinks per week were 0.68 (95% CI, 0.45-1.02) among consumers of 7 to 13 drinks per week and 0.65 (95% CI, 0.44-0.97) among consumers of 14 or more drinks per week ( P trend = .03).

Discussion In this prospective cohort study, current alcohol intake was not associated with a higher risk of AF, at least in the range of intake commonly consumed by these older adults. There was also no significant association of current alcohol intake with mortality among participants with AF. Our findings differ somewhat from that of a previous CHS analysis that examined multiple short-term predictors of incident AF.11 There are several likely explanations for this discrepancy. First, former drinkers were not previously separated from longer-term abstainers. We found a higher risk of AF (and of mortality among those with AF) among former drinkers, possibly related to underlying health conditions that led them to discontinue alcohol use.26 Second, KaplanMeier estimates suggested that the heaviest drinkers may initially have had somewhat lower risk of AF, but the advantage attenuated over time. This attenuation may reflect a healthy-user phenomenon, in which only healthy older adults are able and willing to consume the largest amounts of alcohol. The large number of comorbidities with which alcohol use is cross-sectionally associated27 may limit the degree to which even multivariable adjustment can account for this. Over time, however, the adverse health effects of heavier drinking may appear. To our knowledge, ours is the first study to examine alcohol use as a predictor of prognosis among older

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adults with diagnosed AF. Although mortality rates are consistently higher among individuals with AF,28-30 few studies have focused upon predictors of mortality among such individuals. The Framingham Heart Study investigators defined a novel risk score for the combined end point of stroke or death among 868 adults with AF31 but did not assess alcohol intake. Likewise, in a study of 77 patients with AF, of whom 22 died, age was the only factor independently associated with death; but alcohol intake was not assessed.32 In view of the trend toward lower risk of mortality among consumers of 7 to 13 drinks per week with AF, our results may suggest that patients with AF need not discontinue alcohol consumption altogether, a suggestion also supported by an inverse association of moderate alcohol use with excessive levels of anticoagulation among patients taking warfarin.33 However, the possibility that alcohol consumption leads to suboptimal levels of anticoagulation or accentuated traumatic bleeding among such patients still needs to be addressed. Specific limitations of our study warrant discussion. As in any observational study, our results could be influenced by differences between participants in factors other than alcohol consumption for which we did not control. It is difficult to distinguish reliably in CHS between paroxysmal and chronic AF, and we likely missed asymptomatic cases of paroxysmal AF that would not have been detected on yearly ECGs. The degree to which these distinctions limit our findings is uncertain because both paroxysmal and chronic AFs increase the risk of stroke34 and both seem to be associated with heavy alcohol intake in other populations.6,35 We also could not evaluate the impact of alcohol on the frequency and duration of AF episodes in patients who developed such problem, an issue that may be better addressed in ongoing AF registries.36 We relied on self-reported alcohol consumption, although older adults generally report alcohol intake as accurately as younger individuals37; and we found a correlation of alcohol use and high-density lipoprotein cholesterol of the expected magnitude.13 However, no measure of binge drinking was available; and we have no information on the timing of last alcohol use before onset of AF. Although CHS is a population-based cohort study, participants were generally healthy, communitydwelling older adults. As a result, our results must be generalized to other populations with an appropriate degree of caution. We identified former drinkers using questions administered at baseline that identified individuals who were either heavy drinkers at any time in the past or who had changed their intake in the preceding 5 years. Hence, we may have misclassified individuals who were

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previously moderate drinkers but had ceased consumption more than 5 years earlier. Although CHS documented a larger number of cases of AF than similar studies conducted previously, our power to examine the associations of beverage type and heavier drinking with risk of AF was limited by the relatively modest amounts of alcohol consumed by these older adults. Likewise, our power to conduct subgroup analyses was limited, increasing the likelihood that the observed interaction with apoE genotype was a chance finding, although alcohol consumption is specifically associated with higher levels of inflammatory markers in apoE4-positive individuals,20 which in turn may be positively related to risk of AF.16 In summary, alcohol consumption in the moderate range was not associated with risk of AF among older adults, nor was it associated with mortality among participants with diagnosed AF. However, given the widespread and growing prevalence of AF,38 further studies are still needed to outline the full risks and benefits of even moderate alcohol intake among the increasing number of patients with this condition.

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