Coffee and caffeine consumption and the risk of hypertension in postmenopausal women1,2 Jinnie J Rhee,3* FeiFei Qin,4 Haley K Hedlin,4 Tara I Chang,3 Chloe E Bird,6 Oleg Zaslavsky,7 JoAnn E Manson,8 Marcia L Stefanick,5 and Wolfgang C Winkelmayer9 3 Divisions of Nephrology and 4Biomedical Informatics Research, Department of Medicine and 5Stanford Prevention Research Center, Stanford University School of Medicine, Palo Alto, CA; 6RAND Corporation, Santa Monica, CA; 7Faculty of Health Sciences and Social Welfare, University of Haifa, Haifa, Israel; 8Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; and 9Selzman Institute for Kidney Health, Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, TX

ABSTRACT Background: The associations of coffee and caffeine intakes with the risk of incident hypertension remain controversial. Objective: We sought to assess longitudinal relations of caffeinated coffee, decaffeinated coffee, and total caffeine intakes with mean blood pressure and incident hypertension in postmenopausal women in the Women’s Health Initiative Observational Study. Design: In a large prospective study, type and amount of coffee and total caffeine intakes were assessed by using self-reported questionnaires. Hypertension status was ascertained by using measured blood pressure and self-reported drug-treated hypertension. The mean intakes of caffeinated coffee, decaffeinated coffee, and caffeine were 2–3 cups/d, 1 cup/d, and 196 mg/d, respectively. Using multivariable linear regression, we examined the associations of baseline intakes of caffeinated coffee, decaffeinated coffee, and caffeine with measured systolic and diastolic blood pressures at annual visit 3 in 29,985 postmenopausal women who were not hypertensive at baseline. We used Cox proportional hazards models to estimate HRs and their 95% CIs for time to incident hypertension. Results: During 112,935 person-years of follow-up, 5566 cases of incident hypertension were reported. Neither caffeinated coffee nor caffeine intake was associated with mean systolic or diastolic blood pressure, but decaffeinated coffee intake was associated with a small but clinically irrelevant decrease in mean diastolic blood pressure. Decaffeinated coffee intake was not associated with mean systolic blood pressure. Intakes of caffeinated coffee, decaffeinated coffee, and caffeine were not associated with the risk of incident hypertension (P-trend . 0.05 for all). Conclusion: In summary, these findings suggest that caffeinated coffee, decaffeinated coffee, and caffeine are not risk factors for hypertension in postmenopausal women. Am J Clin Nutr 2016; 103:210–7. Keywords: blood pressure, caffeinated coffee, caffeine, decaffeinated coffee, hypertension INTRODUCTION

Hypertension is an established risk factor for many chronic diseases, including coronary artery disease, stroke, heart failure, and kidney disease and shortens life expectancy (1–4), and even

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a small decrease in blood pressure may have a significant effect on these health outcomes (5). Approximately 1 in 3 (78 million) adults in the United States have hypertension; however, only w50% of patients have their blood pressure controlled (6). Although blood pressure is generally lower in premenopausal women than in men, postmenopausal women have a higher prevalence of hypertension than do men of a similar age (7). Various dietary and other lifestyle factors play an important role in blood pressure control and hypertension prevention, one of which is coffee and caffeine consumption (8). Coffee is a popular beverage that is heavily consumed in the United States and worldwide. Approximately 89% of American adults consume caffeine on any given day, with beverages providing 98% of the caffeine consumed and coffee being the most predominant source (9). Previous studies of the associations of coffee and caffeine consumption with blood pressure have reported mixed results. In randomized controlled trials (RCTs),10 short-term caffeine or coffee intake caused an acute rise in systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 2/1 mm Hg compared with decaffeinated coffee use or abstinence (10, 11). Prospective observational studies have generally reported a lower risk of hypertension in coffee abstainers than in coffee consumers and 1

JJR was supported by NIH–National Institute for Diabetes and Digestive and Kidney Diseases grants T32 DK007357 and F32 DK103473. The WHI program is funded by the National Heart, Lung, and Blood Institute, NIH, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. 2 Supplemental Tables 1 and 2 are available from the “Online Supporting Material” link in the online posting of the article and from the same link in the online table of contents at http://ajcn.nutrition.org. *To whom correspondence should be addressed. E-mail: rheej@stanford. edu. 10 Abbreviations used: DBP, diastolic blood pressure; EFSA, European Food Safety Authority; FFQ, food frequency questionnaire; RCT, randomized controlled trial; SBP, systolic blood pressure; WHI, Women’s Health Initiative. Received July 29, 2015. Accepted for publication October 13, 2015. First published online December 9, 2015; doi: 10.3945/ajcn.115.120147.

Am J Clin Nutr 2016;103:210–7. Printed in USA. Ó 2016 American Society for Nutrition

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a slightly higher risk in moderate coffee consumers, but a lower risk of hypertension in individuals with extremely high coffee intakes, even after adjustment for BMI (5, 12–16). Similarly, data from cross-sectional studies and a meta-analysis also suggest an inverse linear or U-shaped association between coffee consumption and blood pressure (17); higher blood pressures were observed at lower levels of coffee consumption (5). Conflicting results regarding the association of coffee consumption and hypertension could be attributed at least in part to the use of self-reported cases of hypertension rather than to measured blood pressure and to the lack of differentiation between caffeinated and decaffeinated coffee consumption. In this prospective study, we examined the relations of caffeinated coffee, decaffeinated coffee, and caffeine intakes with mean blood pressure and the incidence of hypertension in a large cohort of postmenopausal women in the Women’s Health Initiative (WHI) Observational Study.

METHODS

Study design and population This prospective study used data obtained from the WHI Observational Study cohort, which included 93,676 postmenopausal women aged 50–79 y who enrolled in the study at 40 clinical centers nationwide from September 1993 to December 1998. Eligibility included postmenopausal status at enrollment, defined as no menstrual cycles for $12 mo before enrollment if aged #54 y and $6 mo if aged $55 y, and the ability to reside in the community for $3 y after enrollment. Women with any medical condition that had a predicted survival rate of ,3 y or any condition that could limit the ability to comply or stay within the study were excluded. Details of the study cohort and methods were reported elsewhere (18). In this study, we excluded women with hypertension at baseline (SBP or DBP $140 mm Hg or $90 mm Hg, respectively, and women being treated for hypertension) (n = 39,962) and women with missing data on baseline blood pressure (n = 182) or blood pressure at the year 3 visit (n = 8054). We also excluded women with missing data on primary exposures of interest, including caffeinated coffee, decaffeinated coffee, and/or caffeine intakes (n = 14,347). After further exclusion of women with missing data on the main covariate variables (n = 1146), the analytic sample comprised 29,985 participants (Figure 1). The WHI study protocol was reviewed and approved by human subjects review committees at all clinics, and written informed consent was obtained from the study participants. All procedures followed were in accordance with institutional guidelines and the Helsinki Declaration of 1975, as revised in 1983. Exposure assessment The primary exposures of interest were baseline intakes of caffeinated coffee, decaffeinated coffee, and total caffeine. All women in the study completed a questionnaire at baseline, on which they were asked about different types of coffee drinking habits. The question for caffeinated coffee was phrased as follows: “How many cups of regular coffee (not decaf) do you usually drink each day?” Intake of decaffeinated coffee was assessed by using responses to the question: “How many cups of

FIGURE 1 Study population selection from the Women’s Health Initiative Observational Study. Of 93,676 postmenopausal women in the Women’s Health Initiative Observational Study cohort, we excluded 182 women with missing data on baseline blood pressure and 39,962 women with hypertension at baseline (systolic blood pressure or diastolic blood pressure $140 or $90 mm Hg and women being treated for hypertension). We then excluded 8054 women with missing systolic and diastolic blood pressure measurements at the year 3 visit. We also excluded 14,347 women with missing data on primary exposures of interest, including caffeinated coffee, decaffeinated coffee, and/or caffeine intakes. After further exclusion of 1146 women with missing data on the main covariate variables, the analytic sample comprised 29,985 participants.

decaf coffee do you usually drink each day?” Women were able to select from the following categories: 1 cup/d (1 cup = 6 oz or w177 mL), 2–3 cups/d, 4–5 cups/d, and $6 cups/d. Tall cups (defined as $12 oz) and espresso drinks made with double shots of espresso were counted as 2 cups. In this study, the number of women in the last category was small (n = 981 for caffeinated coffee, n = 271 for decaffeinated coffee), so we collapsed the 4– 5 cups/d and $6 cups/d categories into a single category. In models in which we treated the number of cups of coffee as continuous, we assigned women to the middle value of their response category. Women who drank 2–3 cups/d were assigned to 2.5 cups/d, and women who drank $4 cups/d were assigned

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to 5.5 cups/d. Women were instructed not to drink coffee before their clinic visit. Dietary caffeine was assessed by using a standardized foodfrequency questionnaire (FFQ), which was developed to estimate average daily nutrient intakes over the previous 3-mo period, and was administered as part of baseline enrollment screening for the WHI (19). This self-administered FFQ includes questions, summary questions, and 122 items for individual foods and food groups (19). The WHI FFQ nutrient database was derived from the Nutrition Data Systems for Research (University of Minnesota, Minneapolis; version 2005) food and nutrient databases (20). This FFQ has been shown to perform well in this cohort and showed strong correlations with 24-h dietary recall interviews and food records in the WHI (19). Total caffeine intake was calculated by using FFQ-based intakes of soda (all types), coffee, and tea. Information on the caffeine content of other dietary sources, such as chocolate, or the caffeine content of medications was not available in the WHI. We decided a priori to categorize women into quintiles of dietary caffeine intake. Blood pressure measurements and hypertension assessment The primary outcomes of interest were SBP and DBP and the time to incident hypertension. Trained personnel measured seated SBP and DBP in the right arm after 5 min of rest using a conventional mercury sphygmomanometer with an appropriate cuff size based on measured arm circumference. Two blood pressure measurements were taken $30 s apart (21). For the current analyses, the mean of 2 readings from the year 3 visit (i.e., 3 y after enrollment) was used. Incident hypertension was defined by using an average SBP $ 140 mm Hg or an average DBP $90 mm Hg and/or a self-reported response of “yes” to the question “Pills for hypertension now?” Women who responded “yes” provided the date they began taking the pills. We followed the participants for incident hypertension until their first instance of hypertension (days since enrollment to blood pressure measurement collection at the year 3 visit when there was a reading of average SBP $140 mm Hg or average DBP $90 mm Hg or days since enrollment to when they started taking pills for hypertension), loss to follow-up (last visit used as last date of follow-up), death due to any cause, or the end of the study period, which was defined as the end of year 3/start of year 4, whichever occurred first. Assessment of covariates Covariate information was assessed from baseline questionnaires and physical measures. Details of baseline self- or interviewadministered questionnaires and physical measures were described previously (22, 23). Briefly, standardized questionnaires administered at baseline queried information on sociodemographic variables, including age, race-ethnicity (non-Hispanic white, black/ African American, Hispanic/Latino, and other), smoking status (never, former, and current), and years of hormone replacement therapy (categorized as none, ,5 y, 5 to ,10 y, 10 to ,15 y, and $15 y). Physical activity was assessed as the metabolic equivalent of task hours per week at baseline by using a validated 9-item measure of physical activity (Personal Habits Questionnaire) at baseline (24). Data on alcohol consumption (servings/ wk) were also abstracted from the Personal Habits Questionnaire.

Trained staff at the clinical center obtained anthropometric measurements at the baseline clinic visit. Weight was measured to the nearest 0.1 kg on a balance beam scale while the participant was wearing light clothing and no shoes, and height was measured to the nearest 0.1 cm by using a wall-mounted stadiometer. BMI was calculated as weight (in kg) divided by height squared (in m). Information on total energy intake and intakes of sodium, magnesium, calcium, potassium, and phosphorus was assessed from the FFQ. Statistical analysis Linear regression models were used to assess associations of caffeinated coffee, decaffeinated coffee, and caffeine intake with blood pressure measurements at annual visit 3. Predicted population marginal mean SBP and DBP and 95% CIs were estimated for each level of coffee and caffeine intake in the linear regression model. Cox proportional hazards models were used to estimate HRs and 95% CIs for time to incident hypertension in relation to caffeinated coffee, decaffeinated coffee, and caffeine intakes. Violations of the proportional hazards assumption were assessed through Schoenfeld residuals. Schoenfeld residuals were generated for the Cox proportional hazards models for time to incident hypertension as a function of caffeinated coffee, decaffeinated coffee, or caffeine intake. Plots of the residuals over time along with the lowess fit for the residuals were used to assess whether the main predictor variables changed over the study period. A nonzero slope of the lowess fit would indicate a violation against the proportional hazards assumption. For both sets of models, age-adjusted and multivariable-adjusted models were fit separately for each type of coffee intake. In the multivariable-adjusted linear models, covariates included age, baseline blood pressure measurements, BMI, physical activity, years of hormone replacement therapy, alcohol consumption, smoking status, and sodium, magnesium, calcium, potassium, and phosphorus intakes at baseline. However, because data on nutrient intake were collected at baseline and during follow-up, intakes of sodium, magnesium, calcium, potassium, and phosphorus were included as time-varying covariates in the Cox proportional hazards models. Tests for linear trend were conducted by treating the middle value for each category of caffeinated coffee and decaffeinated coffee or median value for each quintile of caffeine intake as a continuous variable in the model. All analyses were done by using SAS version 9.4 (SAS Institute). All statistical tests were evaluated at an alpha level of 0.05. RESULTS

The 29,985 women who were included in this study were followed for a total of 112,935 person-years, during which we identified 5566 cases of incident hypertension. Of 39,962 women who were excluded at baseline for hypertension, 79.2% were white, 12.2% were black/African American, 3.6% were Hispanic/ Latino, and 4.9% were of other race-ethnicity. Of 29,985 women who were in the analytic cohort, 89.8% were white, 3.2% were black/African American, 3.3% were Hispanic/Latino, and 3.7% were of other race-ethnicity. The mean intakes of caffeinated coffee, decaffeinated coffee, and caffeine were 2–3 cups/d, 1 cup/d, and 196 mg/d, respectively. Women who drank more caffeinated coffee were younger, were less physically active, had a higher

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BMI, were more often current smokers, and had higher intakes of total calories, alcohol, and other nutrients (Table 1). The proportion of non-Hispanic white women was largest in the highest caffeinated coffee intake category, and the proportion of black/African American and Hispanic/Latino women and women of other racial and ethnic groups decreased with increasing consumption of caffeinated coffee. No clinically meaningful differences in baseline SBP and DBP across frequency categories of caffeinated coffee intake were observed. Women who drank more decaffeinated coffee had slightly lower BMIs, were more physically active, and had lower total calorie intakes, alcohol intakes, and baseline SBP and DBP (Supplemental Table 1). The patterns observed in women with higher intakes of caffeinated coffee were also found in women with higher caffeine intakes (Supplemental Table 2). We found no statistically significant association between caffeinated coffee intake and mean SBP or DBP in either of our models (Table 2; P-trend . 0.05 for both). Higher decaffeinated coffee consumption, however, was associated with significantly lower DBP readings at follow-up (P-trend = 0.01) but not with mean SBP (P-trend = 0.06). In age-adjusted models, a higher total caffeine intake was associated with a lower mean SBP (P-trend = 0.03) (Table 3).

However, this association was no longer statistically significant after adjustment for other confounding variables (P-trend = 0.10). The association between caffeine intake and mean DBP was not significant in both age- and multivariable-adjusted models (P-trend . 0.05 for both). In an age-adjusted model, we found a slightly lower risk of incident hypertension for increased consumption of decaffeinated coffee (P-trend = 0.03) (Table 4). Overall, however, we found no significant association between either caffeinated or decaffeinated coffee intake and incident hypertension in multivariable-adjusted models. Similarly, we found no association across caffeine intake categories and incident hypertension in either of our models, with the exception of women in the third quintile of caffeine intake, who had an 18% (95% CI: 11%, 25%) lower risk of incident hypertension than nondrinkers in the age-adjusted model (Table 5; P-trend . 0.05 for all).

DISCUSSION

In the large prospective WHI Observational Study cohort of postmenopausal women, neither caffeinated nor decaffeinated coffee consumption was associated with an increased risk of

TABLE 1 Baseline characteristics of the study population by frequency of caffeinated coffee intake: Women’s Health Initiative Observational Study (n = 29,985)1 Intake of caffeinated coffee

Characteristics Age, y Race-ethnicity, % Non-Hispanic white Black/African American Hispanic/Latino Other BMI, kg/m2 Physical activity, MET-h/wk Duration of HRT, % None ,5 y 5 to ,10 y 10 to ,15 y $15 y Alcohol intake, servings/wk Smoking status, % Never Former Current Sodium intake, mg Magnesium intake, mg Calcium intake, mg Potassium intake, mg Phosphorus intake, mg Total calorie intake, kcal Blood pressure, mm Hg Systolic Diastolic

0 cups/d (n = 6150)

1 cup/d (n = 6865)

2–3 cups/d (n = 12,473)

$4 cups/d (n = 4497)

63.1 6 7.13

62.7 6 7.2

62.2 6 7.1

62.0 6 6.9

91.3 3.4 2.4 2.9 25.8 6 4.9 15.8 6 14.4

84.8 5.0 4.6 5.7 25.8 6 5.1 14.9 6 14.4

90.1 2.9 3.6 3.5 26.1 6 5.0 14.9 6 14.7

94.5 1.5 1.9 2.2 26.1 6 5.0 14.0 6 14.6

36.7 22.5 15.7 11.4 13.7 2.6 6 4.8

35.9 22.8 15.4 12.0 13.9 2.7 6 5.0

37.5 23.3 15.3 11.1 12.9 3.6 6 5.9

41.8 22.4 14.7 9.8 11.4 3.4 6 5.8

48.5 47.3 4.2 2555 6 1049 258 6 93 838 6 447 2677 6 932 1143 6 485 1495 6 574

53.0 43.1 4.0 2565 6 1179 254 6 99 826 6 463 2603 6 991 1131 6 519 1531 6 647

44.4 48.5 7.1 2609 6 1175 259 6 99 834 6 461 2667 6 992 1146 6 516 1564 6 643

37.1 47.4 15.6 2770 6 1191 274 6 100 871 6 478 2867 6 1011 1202 6 529 1653 6 667

,0.0001 ,0.0001 ,0.0001 ,0.0001 ,0.0001 ,0.0001

117.9 6 11.6 71.6 6 7.8

118.2 6 11.8 71.9 6 7.6

118.1 6 11.8 72.0 6 7.7

117.3 6 11.9 71.5 6 8.0

0.0005 ,0.0001

P value2 ,0.0001 ,0.0001

,0.0001 ,0.0001 ,0.0001

,0.0001 ,0.0001

1 cup = 6 oz or w177 mL. HRT, hormone replacement therapy; MET, metabolic equivalent of task. Data were analyzed by using ANOVA and chi-square tests for continuous variables and categorical variables, respectively. 3 Mean 6 SD (all such values). 1 2

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TABLE 2 Age- and multivariable-adjusted mean systolic and diastolic blood pressures (and 95% CIs) at year 3 according to the frequency of caffeinated and decaffeinated coffee intakes: Women’s Health Initiative Observational Study (n = 29,985)1 Intake of caffeinated coffee 0 cups/d (n = 6150) Systolic blood pressure Model 12 Mean 95% CI Model 23 Mean 95% CI Diastolic blood pressure Model 12 Mean 95% CI Model 23 Mean 95% CI

1 cup/d (n = 6865)

2–3 cups/d (n = 12,473)

Intake of decaffeinated coffee $4 cups/d (n = 4497)

0 cups/d P-trend (n = 16,634)

1 cup/d (n = 6331)

2–3 cups/d (n = 5555)

$4 cups/d (n = 1465)

P-trend

119.8 120.1 120.5 119.9 (119.5, 120.2) (119.8, 120.5) (120.2, 120.7) (119.5, 120.3)

0.60

120.5 119.8 119.8 119.4 ,0.001 (120.3, 120.7) (119.4, 120.1) (119.4, 120.2) (118.7, 120.2)

120.9 120.9 121.2 121.0 (120.5, 121.4) (120.5, 121.4) (120.8, 121.6) (120.5, 121.5)

0.45

121.1 121.0 120.9 120.9 (120.7, 121.5) (120.5, 121.4) (120.5, 121.4) (120.1, 121.6)

71.2 (71.0, 71.4)

71.6 (71.4, 71.8)

71.8 (71.7, 72.0)

71.3 (71.1, 71.6)

0.40

71.8 (71.7, 71.9)

71.2 (71.2, 71.6)

71.1 (71.1, 71.5)

70.9 (70.6, 71.5)

,0.001

71.5 (71.2, 71.8)

71.8 (71.6, 72.1)

72.0 (71.7, 72.2)

71.4 (71.4, 72.0)

0.13

71.9 (71.7, 72.1)

71.7 (71.5, 72.0)

71.7 (71.4, 71.9)

71.5 (71.1, 72.0)

0.01

0.06

1

Predicted population marginal mean systolic and diastolic blood pressures and 95% CIs were estimated for each level of caffeine intake by using linear regression models. 1 cup = 6 oz or w177 mL. 2 Adjusted for age. 3 Adjusted for age, baseline blood pressure, BMI, physical activity, hormone replacement therapy, alcohol consumption, smoking, total caloric intake, and intakes of sodium, magnesium, calcium, potassium, and phosphorus as time-varying covariates.

CI: 21.52, 0.61) (25). In the current study, we observed a small difference in DBP of similar magnitude (a difference of 20.4 mm Hg of uncertain clinical significance) between women who drank $4 cups decaffeinated coffee/d and nondrinkers. Most of these previous RCTs were conducted in participants whose mean age was lower than that of the postmenopausal women in the current study. Therefore, the data presented herein add to the literature on the lack of evidence of the association between chronic coffee consumption and blood pressure by showing that these findings are also applicable to older women, in whom the prevalence of hypertension is higher than in men of similar age (7).

incident hypertension. After adjustment for other risk factors, a higher intake of decaffeinated coffee was associated with slight decreases in mean DBP. We also found that total caffeine intake was not associated with incident hypertension or mean SBP and DBP in postmenopausal women. Our finding that caffeinated coffee intake was not associated with increases in mean blood pressure measurements is consistent with the findings of a recent meta-analysis of RCTs which showed that chronic coffee consumption was not associated with significant changes in SBP or DBP (25). The authors reported a pooled weighted difference in mean change in SBP of 20.55 mm Hg (95% CI: 22.46, 1.36) and of DBP of 20.45 mm Hg (95%

TABLE 3 Age- and multivariable-adjusted mean systolic and diastolic blood pressures (and 95% CIs) at year 3 according to quintile of caffeine intake: Women’s Health Initiative Observational Study (n = 29,985)1 Quintile of caffeine intake

Caffeine intake, mg Systolic blood pressure, mm Hg Age-adjusted Multivariable-adjusted2 Diastolic blood pressure, mm Hg Age-adjusted Multivariable-adjusted2

1 (n = 5997)

2 (n = 5997)

3 (n = 5997)

4 (n = 5971)

5 (n = 6023)

0–83

83–177

177–179

179–315

315–794

119.7 (119.3, 120.0) 120.8 (120.3, 121.3)

120.5 (120.1, 120.9) 121.2 (120.7, 121.7)

119.9 (119.6, 120.3) 120.8 (120.3, 121.3)

120.6 (120.2, 121.0) 121.2 (120.8, 121.7) 71.8 (71.6, 72.0) 72.0 (71.7, 72.2)

120.2 (119.8, 120.6) 121.1 (120.6, 121.6) 71.5 (71.3, 71.7) 71.8 (71.5, 72.1)

71.3 (71.1, 71.5) 71.7 (71.4, 72.0)

71.8 (71.6, 72.0) 71.9 (71.6, 72.2)

71.4 (71.2, 71.6) 71.7 (71.4, 72.0)

P-trend

0.03 0.10

0.08 0.11

1 Predicted population marginal mean systolic and diastolic blood pressures and 95% CIs were estimated for each level of caffeine intake by using linear regression models. 2 Adjusted for age, baseline blood pressure, BMI, physical activity, hormone replacement therapy, alcohol consumption, smoking, total caloric intake, and intakes of sodium, magnesium, calcium, potassium, and phosphorus as time-varying covariates.

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TABLE 4 HRs (95% CIs) of incident hypertension according to frequency of caffeinated and decaffeinated coffee intakes: Women’s Health Initiative Observational Study (n = 29,985)1 Intake of caffeinated coffee

No. of cases Person-years Model 12 HR 95% CI Model 23 HR 95% CI

Intake of decaffeinated coffee

0 cups/d

1 cup/d

2–3 cups/d

$4 cups/d

1162 23,177

1326 25,759

2273 47,029

805 16,970

1.00

1.05 (0.97, 1.13)

1.00 (0.94, 1.08)

1.00 (0.91, 1.09)

1.00

1.00 (0.93, 1.08)

0.95 (0.89, 1.02)

0.99 (0.90, 1.08)

0 cups/d

1 cup/d

2–3 cups/d

$4 cups/d

3147 62,520

1128 23,918

1047 20,920

244 5577

0.59

1.00

0.92 (0.86, 0.98)

0.98 (0.91, 1.05)

0.85 (0.75, 0.97)

0.03

0.51

1.00

0.98 (0.92, 1.05)

1.05 (0.98, 1.13)

0.92 (0.81, 1.05)

0.92

P-trend

P-trend

Cox proportional hazards models were used to estimate HRs and 95% CIs for time to incident hypertension. 1 cup = 6 oz or w177 mL. Adjusted for age. 3 Adjusted for age, baseline blood pressure, BMI, physical activity, hormone replacement therapy, alcohol consumption, smoking, total caloric intake, and intakes of sodium, magnesium, calcium, potassium, and phosphorus as time-varying covariates. 1 2

We found no association between caffeinated and decaffeinated coffee intakes and risk of hypertension, and these results are consistent with the results of a recent meta-analysis of 10 RCTs and 5 cohort studies, which did not show an association between coffee intake and the risk of hypertension (25). In a meta-analysis of cohort studies, Steffen et al. (25) found a pooled risk ratio of 1.03 (95% CI: 0.98, 1.08) for the risk of hypertension. Individual observational studies have generally found inverse J-shaped associations between caffeinated coffee intake and hypertension risk, with the risk increasing with up to 3 cups coffee/d compared with ,1 cup/d and then decreasing at higher intakes (5). Winkelmayer et al. (16) reported that intake of caffeinated coffee was weakly and inversely related to incident hypertension from participants’ self-report. Women who drank $4–5 cups coffee/d in this study had a 9% lower risk of incident hypertension than women who drank ,1 cup/d (16). Similarly, Uiterwaal et al. (15) found that women who drank .6 cups/d had a 33% lower risk than did women who drank .0–3 cups/d, but no associations were found in women who were coffee abstainers or drank .3– 6 cups/d. In the current study, we had very few women at higher intakes ($6 cups/d) of coffee, which could explain why we did

not observe a decreased risk of hypertension in participants who drank $4 cups/d of either type of coffee. In the current study, we found that caffeine intake was not associated with mean SBP, DBP, or incident hypertension. It has been suggested that the human body rapidly adapts to the effects of caffeine (13). Progressive physiological adaptation may blunt the acute pressor response in chronic coffee consumers in as little as 3–5 d (26, 27), which could partly explain why coffee and caffeine intakes do not influence blood pressure over a longer follow-up period in chronic consumers. Such pharmacokinetics of caffeine are in line with those in a recent report by the European Food Safety Authority (EFSA) (28). The EFSA recently published a scientific opinion on the safety of caffeine and noted that caffeine consumption, at single doses ranging from 80 to 300 mg, acutely increases blood pressure, which reaches a peak 30 min after consumption and then returns to baseline after 2– 4 h in the adult population (28). In this study of postmenopausal women, we found no increased risk of incident hypertension in women who consumed caffeine at levels that far exceeded the doses evaluated by the EFSA. Women in the highest quintile of intake, among whom the range of intake varied from 315 to

TABLE 5 HRs (95% CIs) of incident hypertension according to quintile of caffeine intake: Women’s Health Initiative Observational Study (n = 29,985)1 Quintile of caffeine intake

Caffeine intake, mg No. of cases Person-years Model 12 HR 95% CI Model 23 HR 95% CI 1

1

2

3

4

5

P-trend

0–83 1230 22,393

83–177 1131 22,571

177–179 982 22,783

179–315 1137 22,437

315–794 1086 22,751

1.00

0.94 (0.87, 1.02)

0.82 (0.75, 0.89)

0.98 (0.90, 1.06)

0.92 (0.85, 1.00)

0.11

1.00

0.97 (0.90, 1.05)

0.88 (0.81, 1.06)

1.00 (0.92, 1.09)

0.97 (0.89, 1.06)

0.66

Cox proportional hazards models were used to estimate HRs and 95% CIs for time to incident hypertension. Adjusted for age. 3 Adjusted for age, baseline blood pressure, BMI, physical activity, hormone replacement therapy, alcohol consumption, smoking, total caloric intake, and intakes of sodium, magnesium, calcium, potassium, and phosphorus as time-varying covariates. 2

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794 mg/d, were not at an increased risk of incident hypertension. The panel concluded that single doses of caffeine up to 200 mg do not give rise to safety concerns and that habitual caffeine consumption up to 400 mg/d does not give rise to safety concerns for nonpregnant adults. Further research is needed to fully elucidate the role of chronic caffeine intake in hypertension. A limitation of our study was the lack of information on different brewing methods, which can change the concentrations of active chemicals in coffee (29, 30). Genetic differences in the individual’s ability to metabolize caffeine may vary greatly, but information on metabolizer status was not available in the WHI to account for this source of variation in the associations examined. Moreover, we only had a single assessment of coffee and caffeine intakes at baseline. This could fail to capture cumulative intake or changes in intake during long-term follow-up, making it subject to random error of self-report and underestimation of true associations. Generalizability of our findings may be limited because the study consisted of only relatively healthy postmenopausal women who were willing to be followed up for up to 9 y in the WHI Observational Study. Similarly, our study findings may not be generalizable to racial and ethnic minorities because most participants in our study were non-Hispanic white postmenopausal women. On the basis of these findings, it is also not possible to assess whether coffee and caffeine intake is associated with blood pressure in women with a prior diagnosis of hypertension. The FFQ did not account for caffeine-containing over-the-counter products and/or dietary supplements, energy drinks, and chocolate, so we were unable to consider these sources of caffeine intake. In addition, the FFQ is limited by the assumption that it represents an average diet. The FFQ may also misclassify individuals with unusual culture-specific diets, but we expected this to have a minimal effect on our findings because most of the study participants were non-Hispanic white postmenopausal women. For the purpose of accounting for covariates, the analytic cohort differed from the eligible participants in that participants excluded from the analysis were more likely to be black/African American, which introduced potential selection bias. Finally, we cannot rule out the possibility of residual confounding as a result of the observational nature of the study. The strengths of our study included the large overall sample size, prospective study design, validated dietary data, available information on a large range of covariates, and adequate outcome ascertainment, for which we used both measured blood pressure and self-reported drug-treated hypertension to capture treated and untreated hypertension cases. We also had information on both caffeinated and decaffeinated coffee consumption. Currently, there is no clear epidemiological evidence on whether chronic coffee and caffeine intake increases the risk of hypertension. Findings from the current study provide no evidence of a relation between coffee and caffeine intake and elevated blood pressure in normotensive postmenopausal US women. This study is innovative because, unlike previous prospective studies, we differentiated between caffeinated and decaffeinated coffee and used measured rather than self-reported blood pressure and self-reported drug-treated hypertension to identify incident cases. Future prospective studies should assess the associations between coffee, caffeine, and hypertension in other age groups to capture the effect of varying levels of coffee consumption in the general population. More research is needed

before recommendations can be made in favor of or against coffee and caffeine consumption as it relates to blood pressure and hypertension in high-risk groups that consist of individuals with prehypertension or resistant hypertension. The authors’ responsibilities were as follows—JJR and WCW: designed the research; FQ and HKH: performed the statistical analysis; JJR, FQ, HKH, and WCW: contributed to the interpretation of the data; JJR, FQ, and HKH: drafted the manuscript; JJR, FQ, HKH, TIC, CEB, OZ, JEM, MLS, and WCW: made critical revisions to the manuscript for intellectual content; JJR: had primary responsibility for the final content; and all authors: read and approved the final manuscript. None of the authors reported any conflicts of interest.

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