Lack of association between tea and cardiovascular disease in college alumni

Howard D Sesso1,2, Ralph S Paffenbarger, Jr1,3, Yuko Oguma1 and I-Min Lee1,2

1 Department of Epidemiology, Harvard School of Public Health, Boston, MA USA.
2 Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA USA.
3 Division of Epidemiology, Stanford University School of Medicine, Stanford, CA USA.

Howard D Sesso, Brigham and Women’s Hospital, 900 Commonwealth Avenue East, Boston, MA 02215, USA. E-mail: hsesso{at}hsph.harvard.edu Reprints: Howard D Sesso, Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA.


    Abstract
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 Abstract
 Methods
 Results
 Discussion
 References
 
Background Epidemiological studies suggest that tea intake, a major dietary source of flavonoids, may be associated with a decreased risk of cardiovascular disease (CVD).

Methods We prospectively followed 17 228 subjects (mean age, 59.5 years) initially free of CVD and cancer from the College Alumni Health Study. Participants provided baseline self-reports of tea consumption (cups/day) and coronary risk factors. During a median follow-up of 15 years, there were 3372, 2615, and 757 cases of CVD, coronary heart disease (CHD), and stroke, respectively, ascertained from either self-reports or death certificates.

Results Overall, the median level of tea consumption was 1 cup/day. Compared with participants consuming no tea, the multivariate relative risks (RR) of CVD for those drinking <1, 1, 2, 3, and >=4 cups/day were 0.99, 0.96, 0.95, 0.91, and 0.95, respectively (P, trend = 0.19). The multivariate RR were 0.97, 0.98, 0.93, 0.85, and 0.98 for CHD (P, trend = 0.25), and 1.05, 0.89, 1.00, 1.09, and 0.83 for stroke (P, trend = 0.53). There was no evidence of effect modification. Changes in tea intake were assessed in a subgroup of 7730 men, with those continuing to drink tea having a non-significant 33% reduction in the risk of stroke.

Conclusions Tea intake, likely consumed as black tea, was not strongly associated with a reduced risk of CVD in this population of US college alumni.


Keywords Tea, nutrition, cardiovascular disease, cohort study

Accepted 10 January 2003

Some recent epidemiological studies have suggested that tea intake may be associated with a decreased risk of cardiovascular disease (CVD). Tea is a major source of flavonoids, a diverse group of more than 3000 polyphenolic compounds with antioxidant properties found in many fruits and vegetables.1 The potential inverse association attributed to tea has tended to come from prospective investigations in some European countries,2–8 where tea intake is higher in the UK and The Netherlands yet lower in Finland.9 American studies on tea intake, where tea intake is also lower, have generally been unable to replicate the promising European studies with limited numbers of cases.9–11

We therefore examined the association between tea intake and the risk of incident CVD using data from the College Alumni Health Study (CAHS), an ongoing prospective cohort study of middle-aged and older men and women.


    Methods
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 Abstract
 Methods
 Results
 Discussion
 References
 
College Alumni Health Study (CAHS)
The CAHS is an ongoing cohort study of men matriculating as undergraduates at Harvard University between 1916 and 1950, and of men and women matriculating as undergraduates or graduates at the University of Pennsylvania between 1928 and 1940.12 The cohort was established when 35 924 alumni returned an initial health questionnaire in either 1962 or 1966. Subsequent questionnaires have been sent periodically to update information on health habits and medical history.

For this study, we were interested in information from a mailed questionnaire in 1977 to Harvard men, and in 1980 to University of Pennsylvania men and women. Questionnaires were mailed to all surviving alumni, regardless of prior questionnaire returns, with response rates for the 1977 Harvard and 1980 University of Pennsylvania alumni of 66% and 55%, respectively. Of the 17 839 Harvard men returning these questionnaires, we excluded 2736 men with a history of CVD or cancer, plus another 900 men with incomplete data on tea intake or other potential coronary risk factors. Of the remaining 14 203 Harvard men, we successfully followed 12 759 or 90% (i.e. they returned subsequent questionnaires in 1988 and/or 1993, or were known to have died by the end of 1995). Of the 8737 University of Pennsylvania men and women returning the 1980 questionnaire, we excluded 2190 subjects with a history of CVD or cancer, and 659 participants with incomplete data on tea intake or other potential risk factors for CVD. We successfully followed 4469 (75%) of the remaining 5988 men and women (i.e. they returned a subsequent questionnaire in 1993, or were known to have died by the end of 1995). In total, our study population consisted of 17 228 subjects.

Assessment of tea intake and other covariates
Tea consumption and all other baseline covariates were assessed at the same time and in a similar manner on either the 1977 or 1980 questionnaires. Alumni were asked to report their tea intake by first responding to the question ‘Do you drink tea now?’ (no or yes) followed by an open-ended question, ‘How many cups per day?’ No time frame (e.g. average use in past year) was asked. Based on the overall distribution of tea intake, we a priori created six categories of intake: none, <1, 1, 2, 3, and >=4 drinks/day. We believe self-reports of tea intake to be reasonably reliable and valid, as indicated by previous studies of tea and other beverages in population-based groups.10,13 For example, a previous study in well-educated men has shown a high correlation of 0.77 for tea measured by self-report versus dietary record.10

Information was additionally collected on age (in years), sex (male, female), body mass index (calculated from height and weight; in kg/m2), physical activity (calculated from walking, climbing stairs, and participating in sports and recreational activities; in kcal/wk14), physician-diagnosed hypertension (yes, no), physician-diagnosed diabetes mellitus (yes, no), smoking status (not smoking, smoking 1–20 cigarettes/day, smoking >20 cigarettes/day), alcohol consumption (none, <100 g/week, >=100 g/week), and early parental death before 65 years of age (no parents, one parent, both parents).

Ascertainment of incident cardiovascular disease
We ascertained cases of first CVD (including myocardial infarction, coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, and stroke) through self-reports on follow-up questionnaires sent in 1988 and 1993 to Harvard men, and sent in 1993 to University of Pennsylvania men and women. The year of diagnosis was taken as the earliest reported year of diagnosis for any event from questionnaires. If different events occurred in the same year, the event was selected in hierarchical fashion: myocardial infarction, stroke, revascularization, then death. Self-reported, physician-diagnosed CVD has been shown to be valid when compared with physician reports in the CAHS.15 Self-reports on the 1993 questionnaire were confirmed in 47 of 49 (96%) randomly selected men for coronary heart disease (CHD), and in 12 of 15 (80%) randomly selected men for stroke. In addition, deaths were compiled continuously by the Alumni Office of both universities, which maintain a listing of deceased alumni. We traced deaths through the end of 1995. For each reported death, we requested and obtained death certificates from the appropriate state. We included deaths with either underlying or contributing causes from CVD. Mortality follow-up in this cohort is >99% complete.15,16 Of the 17 228 men and women comprising the baseline population for the present study, 4965 subjects had died by the end of 1995.

Data analyses
All analyses were performed using SAS.17 We first examined the distribution of baseline characteristics according to categories of tea intake. We calculated person-years of follow-up from the baseline questionnaire in 1977 or 1980 to the year in which CVD was first reported, the year of death, or 1995, whichever occurred first. Relative risks (RR) and 95% CI for CVD were calculated for each tea consumption category using Cox proportional hazards, always using non-drinkers of tea as the referent. The proportional hazards assumption was satisfied by testing for the interaction between follow-up time and categories of tea (P = 0.58). After considering crude models for tea and CVD, models were then adjusted for age and gender, followed by multivariate models adjusted for all variables described and categorized in Table 1Go. Tests for linear trend treated the categories of tea intake as a single ordinal variable, using the median values for each category.


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Table 1 Baseline characteristics of 17 228 Harvard and University of Pennsylvania alumni free of baseline cardiovascular disease by level of tea consumption
 
Stratified analyses examined whether the association between tea intake differed according to gender, age, and the presence of hypertension or diabetes. In secondary analyses, we excluded those developing CVD during the first 2 years of follow-up to minimize any bias due to illnesses that might have affected baseline tea consumption. We then considered the pattern of tea intake among 7730 male Harvard alumni who remained free of CVD until they completed a follow-up questionnaire in 1988 and provided updated information on tea intake. Four patterns of tea consumption from 1977 to 1988 included men who never drank tea, stopped drinking tea, began to drink tea, and continued to drink tea. We also examined the association between tea and CVD among those men and women reporting a history of CVD at baseline, but with no history of cancer (n = 2188).


    Results
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 Methods
 Results
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The mean (standard deviation) age of the 17 228 men and women at baseline was 59.5 (8.6) years. The majority of subjects were men (n = 16 477; 95.6% of subjects), thus the overall results largely reflect population averages and effects in men. There was a fair amount of tea consumption in this population of middle-aged and older Americans, with a median tea intake of 1 cup/day. The proportions of subjects reporting tea intake of none, <1 cup/day, 1 cup/day, 2 cups/day, 3 cups/day, and >=4 cups/day were 42.7%, 10.6%, 22.9%, 14.7%, 3.9%, and 5.2%, respectively. Only a few subjects reported tea intake >4 cups/day, with 142 (0.8%), 136 (0.8%), and 113 (0.7%) subjects reporting corresponding intake of 5, 6, and >=7 cups/ day. Table 1Go compares baseline characteristics according to levels of baseline tea intake. Age-adjustment for continuous variables did not change their cross-sectional association with tea intake. Those who consumed greater amounts of tea were marginally younger, had higher physical activity levels, consumed less alcohol, and were less likely to currently smoke. There were no other clear differences in baseline risk factors according to tea intake.

During a median follow-up of 15 years, there were 3372 incident cases of CVD, including 2615 cases of CHD and 757 cases of stroke. Table 2Go provides the results for the association between tea and the risk of CVD. There was minimal net confounding by age, lifestyle, and clinical risk factors in each of the models. In sensitivity analyses, the inclusion or exclusion of history of hypertension or diabetes, which may be considered possible intermediate factors, did not appreciably alter the RR for tea and CVD. Further, other potential confounders such as coffee intake, multivitamin use, and blood pressure had a nominal impact on the RR. Finally, the exclusion of men with CVD during the first 2 years of follow-up resulted in no difference for the RR (data not shown).


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Table 2 Relative risks (RR) and 95% CI of cardiovascular disease, coronary heart disease, and stroke according to level of tea consumption among 17 228 Harvard and University of Pennsylvania alumni free of baseline cardiovascular disease
 
Compared with men and women consuming no tea, the multivariate RR of CVD for those drinking <1, 1, 2, 3, and >=4 cups/day of tea were 0.99, 0.96, 0.95, 0.91, and 0.95, respectively (P, linear trend = 0.19). The consideration of tea intake at levels higher than >=4 cups/day revealed no departure in the RR from the null. Adding coffee intake to multivariate models, the multivariate RR of CVD were virtually identical at 1.00, 0.96, 0.94, 0.89, and 0.95, respectively (P, linear trend = 0.16). The lack of an association for tea intake was seen for both CHD and stroke. Although subjects consuming >=4 cups/day of tea versus none had a non-significant multivariate RR of 0.83 (95% CI: 0.57–1.20) for stroke, the lack of a clear dose–response trend makes the interpretation of these findings less clear. The relation between tea and CVD death (1797 cases) closely paralleled the results for total CVD. Tea intake of none, <1, 1, 2, 3, and >=4 cups/day was associated with multivariate RR of CVD death of 1.00 (ref.), 0.98 (95% CI: 0.84–1.15), 0.95 (95% CI: 0.81–1.08), 0.96 (95% CI: 0.84–1.11), 0.92 (95% CI: 0.71–1.18), and 0.91 (95% CI: 0.72–1.15) (P, linear trend = 0.29).

The next step was to examine whether the association between tea and the risk of CVD may differ in various subgroups of subjects. All tests for interaction between levels of tea intake and each modifier of interest, including gender (P, interaction = 0.25), age (categorized as <60 and >=60 years; P, interaction = 0.56), hypertension (P, interaction = 0.22), and diabetes (P, interaction = 0.50), were non-significant (Table 3Go). A comparison of the RR of CVD in men versus women revealed that women had non-significant reductions in the risk of CVD, but with only 751 women in the present study power was limited. Older or normotensive subjects had modest non-significant reductions in the RR of CVD but only among those drinking 3 or >=4 cups/ day. These multivariate RR were comparable to both crude and age, sex-adjusted RR. The risks of CHD and stroke were generally similar to the overall results for CVD.


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Table 3 Does the multivariatea association between tea consumption and the risk of cardiovascular disease differ according to various subgroups among 17 228 Harvard and University of Pennsylvania alumni free of baseline cardiovascular disease?
 
There were 7730 male Harvard alumni who provided follow-up information on tea intake in 1988 who remained free of CVD until 1988. Using data from 1977 and 1988, men were classified as those who never drank tea (n = 2119), stopped drinking tea (n = 938), began to drink tea (n = 1177), and continued to drink tea (n = 3396) (Table 4Go). In Cox proportional hazards models, compared with men who never drank tea on both the 1977 and 1988 questionnaires, there was no increased risk of CVD, CHD, or stroke for men who stopped drinking tea, with corresponding multivariate RR of 1.09, 1.03, and 1.24. On the other hand, those who began to drink tea by 1988 had no significant decreases in the risk of CVD, CHD, and stroke compared with those who never drank tea. Only men who continued to drink tea throughout follow-up had a significant 36% reduction in the risk of stroke compared with men who never drank tea in age-adjusted models; that was modestly confounded enough in multivariate models to become a non-significant 33% reduction in the risk of stroke. Non-hypertensive Harvard men with updated tea information during follow-up had non-significant RR that were not different from the overall results in Table 4Go.


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Table 4 Pattern of tea consumption from 1977 to 1988 and subsequent relative risks (RR) and 95% CI of cardiovascular disease among 7730 male Harvard alumni free of cardiovascular disease through 1988
 
Finally, although some studies suggest that tea may have an inverse association with the risk of CVD among those with pre-existing CVD,10,18 an analysis of 2188 men and women with baseline CVD not included in the primary analyses above revealed no multivariate associations between tea and the risk of CVD (1115 cases; P, linear trend = 0.84), CHD (975 cases; P, linear trend = 0.95), or stroke (140 cases; P, linear trend = 0.65).


    Discussion
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 Abstract
 Methods
 Results
 Discussion
 References
 
Considerable attention has been drawn to tea in recent years as a potential cardioprotective beverage,19 with a growing body of laboratory and clinical evidence to support this claim.20 However, these prospective data in college alumni do not support an association between tea intake and CVD risk. This finding persisted despite a higher range of tea consumption than seen in most other US studies to date, with median intakes <1 cup/day and limited power to assess the higher levels of intake examined in this study. The observed risk reductions were small and non-significant despite ample power to detect 11–20%, 13–23%, and 23–39% reductions in the risk of CVD, CHD, and stroke, respectively. Men who continued to drink tea throughout follow-up had a non-significant 33% reduction in the risk of stroke versus those never drinking tea, providing preliminary evidence that long-term tea consumption may be necessary to confer benefits. The differences in results for stroke versus CHD, while interesting, are neither strong nor consistent enough. There were only modest differences in lifestyle factors comparing subjects drinking large amounts of tea versus no tea, suggesting that tea drinkers in the CAHS did not possess a substantially different coronary risk factor profile as noted in some previous reports.9

A comprehensive meta-analysis recently summarized epidemiological data on tea and the primary prevention of CVD.21 Subjects who increased their tea consumption by 3 cups/day had an 11% decrease in the risk of myocardial infarction that was not significant, while the results for CHD and stroke were too heterogeneous to be summarized. Previous studies on tea and CVD illustrate a wide range of both promising and discouraging findings. Initial investigations on tea and CVD were in the form of case-control studies in the US that examined the effects of low overall tea consumption levels on CVD, usually represented as myocardial infarction,22–25 and provided generally null findings. More recent studies have reported a wide range of results for tea and CVD, largely focusing on CHD death and with fewer events than in the present study.3,6,10,26 Our finding that men who continued to drink any amount of tea over long-term follow-up had a non-significant 33% reduction in the risk of stroke suggests that the cumulative dose of tea may be more important. Repeated assessment of tea also may have reduced measurement error versus a single measurement, particularly in populations with low levels of intake. Hertog et al.6 reported a significant RR of CHD death for 43 cases of 0.45, comparing >500 versus <=250 ml of daily tea intake. In contrast, data from the Health Professionals Follow-up Study indicated a RR of 1.59 (95% CI: 0.98–2.28) in men drinking >=2 cups/day of tea versus non-drinkers.10 A cross-sectional analysis of 10 359 subjects as part of the Scottish Heart Health Study found no association between tea intake of <=5 cups/day and the risk of CHD,26 which was maintained when these individuals were followed prospectively.3 The Caerphilly Study also found that tea was associated with a potentially higher risk of ischaemic heart disease mortality in Welsh men, independent of social class.27 Two reports among men and women from the Rotterdam study found strong inverse associations between tea intake of >=1 cup/day and the risk of severe aortic atherosclerosis and myocardial infarction.4,5

Tea has also been observed to play a possible role in secondary CVD prevention. Prospective studies have reported an inverse association between increasing tea intake and mortality after the diagnosis of myocardial infarction or coronary artery disease,10,18 not through platelet aggregation28 but rather through the mitigation of endothelial dysfunction.29 In subjects with baseline CVD in the CAHS, we found no association between tea and the risk of subsequent CVD events, suggesting no role for tea in the secondary prevention of CVD. Further long-term studies are necessary to understand the role of tea in the primary versus secondary prevention of CVD.

The potential cardiovascular benefits of tea are most commonly attributed to its flavonoid content, which includes the antioxidant polyphenols, catechins, flavonols, theaflavins, and thearubigins. These constituents in tea provide high levels of antioxidant activity30 but there are mixed views on its ability to inhibit low-density lipoprotein oxidation31–33 or reduce platelet aggregation.28,34–36 The antioxidant mechanisms of tea in vivo may be hindered by the reduced bioavailability of tea flavonoids.37 Data from short-term supplementation trials have shown that tea likely has a marginal clinical impact on lipid levels and other coronary risk factors.33,38–41 Yet studies of dietary flavonoids commonly assume that tea, which varies considerably in its flavonoid content and depends on cultural circumstances, may be responsible for the inverse association found with CVD in several studies.5–8,10,11,27,42–45 Without knowing whether tea was the single largest dietary source of flavonoids in the present study, our results for tea may or may not reflect a mechanism involving flavonoids and CVD. The flavonoid hypothesis as a specific mechanism for tea in reducing the risk of CVD remains unresolved, as evidence also points to tea as a surrogate for a healthier coronary risk factor profile. This is a common conundrum in nutritional epidemiology, and additional studies must extend to bench research and short-term feeding trials to shed light on these or other potential mechanisms, with causality ultimately inferred from randomized clinical trials.

Several issues need to be considered in our ability to examine the association between tea and CVD. First, we lacked a comprehensive semiquantitative food frequency questionnaire by which to examine the potential confounding effects of specific nutrients. However, controlling for coffee, alcohol, and other lifestyle and clinical factors had little effects on the RR. We therefore suspect that residual confounding by nutrient factors related to tea intake may have modestly but not greatly biased our results. Second, with a single baseline assessment of tea intake, measurement error may be an alternative explanation for the lack of an association with CVD. The incorporation of a second tea measurement in 1988 among a subgroup of men may reduce measurement error assuming tea measurement was valid and reliable. As an open-ended question, subjects had greater flexibility in their response, in which tea intake in the US in the 1970s and 1980s would be predominantly black tea. For these reasons we expect little measurement error for tea intake in this population of college alumni, but we lacked the ability to differentiate the effects of hot, iced, black, green, oolong, and herbal teas. Third, we relied upon self-reported CVD morbidity as part of our CVD definition, though these self-reports in the CAHS have been shown to have high validation rates.15 Further, the non-significant association was consistent whether we considered total CVD, fatal CVD, or non-fatal CVD.

The lack of an association between tea intake and CVD in this large prospective study of middle-aged and older college alumni largely reflected results in men. Women comprised only 4.4% of subjects with limited power in those subgroup analyses of tea and CVD. Had we combined higher categories of tea intake among women, results still did not suggest any dose–response effects with the risk of CVD. Our study population also consisted of highly educated, Caucasian men and women, whose homogeneity presents little confounding by education, race, or socioeconomic status but may raise concerns about the generalizability of these results. Biologically there are no a priori reasons to believe that the association between tea intake and CVD would differ in these groups; however, it is plausible that the amounts and types of tea consumed may differ markedly as evidenced by previous studies in Europe and Asia.21

In conclusion, these data on tea intake and the risk of CVD in middle-aged and older college alumni provide no compelling reasons for individuals to initiate black tea consumption. Until more observational and trial data allow for the simultaneous consideration of tea and flavonoid intake in CVD prevention, widespread consumption of black tea should be viewed as neither beneficial nor harmful.


KEY MESSAGES

  • Considerable attention has been drawn to tea in recent years as a potential cardioprotective beverage, with a growing body of laboratory, clinical, and epidemiological evidence to support this claim.
  • Tea intake, likely consumed as black tea, was not strongly associated with a reduced risk of cardiovascular disease, coronary heart disease, and stroke in this large population of middle-aged and older US college alumni.
  • However, men drinking tea throughout follow-up had a non-significant 33% reduction in stroke risk versus those never drinking tea, providing preliminary evidence that long-term tea consumption may be necessary to confer benefits.
  • These data provide no compelling reasons for individuals to initiate black tea consumption, which should be viewed as neither beneficial nor harmful.

 


    Acknowledgments
 
Supported by a grant from the Robert Wood Johnson Foundation, and CA-91213 and HL-67429 from the National Cancer Institute and the National Heart, Lung, and Blood Institute, Bethesda, MD. This is report No. LXXVIII in a series on chronic disease in former college students.


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