Discussion

To quantitatively assess the association between coffee consumption and total mortality, we conducted a meta-analysis of twenty prospective cohort studies, consisting of 129 538 cases of death among the 973 904 participants. The results support a significant inverse association between coffee consumption and risk of death. Overall, the risk of death decreased by 14 % for high (median of the highest categories: 5–6 cups/d) v. no or low (mostly less than 1 cup/d) coffee consumption. The reduced risk of death was similar for participants who drank ≥ 2–4 cups of coffee per d and those who drank ≥ 5–9 cups/d. Even consumption of one or two cups of coffee daily was associated with a lower risk of death (reduced by 8 %). Similar inverse associations were found for men and women, and limited data also suggested an inverse association between decaffeinated coffee consumption and mortality.

There was some evidence of heterogeneity among the studies overall, but the observed heterogeneity seemed to be explained, partly by one study, which was targeted on a unique population of Adventist religious adherents in the USA⁽ Reference Kahn, Phillips and Snowdon ^{16 )}. This was the only study that showed a significant positive association between coffee consumption and total mortality among the studies included in the meta-analysis. The reason for the observed positive association is unclear, but it may be due to confounding from unhealthy lifestyles among subjects consuming high amounts of coffee based on the previous literature⁽ Reference Je, Liu and Giovannucci ^{46 )}. The study was adjusted for smoking status, but was not adjusted for other potential confounders such as alcohol consumption and BMI. In addition, some residual confounding may also have existed, since coffee consumption has been considered a bad behaviour by the Adventists, and thus they were less likely to follow other prescripts of the church as well, resulting in increased mortality among coffee drinkers.

The mechanisms of the long-term effects of coffee are unclear. Coffee is a complex mixture of biologically active substances that may have both beneficial and harmful effects on the health of humans. Studies have shown some negative health consequences of caffeine consumption, particularly in relation to CVD risk, including increased blood pressure⁽ Reference Noordzij, Uiterwaal and Arends ^{2 ,} Reference Hartley, Lovallo and Whitsett ^{3 )}. However, these effects seem to be acute, and habitual coffee drinkers develop partial tolerance to the effects of caffeine in coffee. For the long-term effects of coffee, coffee components other than caffeine may become more relevant to affect health outcomes. Coffee is one of the major sources of antioxidants in the diet⁽ Reference Svilaas, Sakhi and Andersen ^{47 )}. Phenolic compounds in coffee (e.g. chlorogenic, ferulic and p-coumaric acids) have strong antioxidant activities⁽ Reference Gómez-Ruiz, Leake and Ames ^{13 )}. Several studies have also found an inverse association between coffee consumption and blood concentrations of some inflammatory markers⁽ Reference Lopez-Garcia, van Dam and Qi ^{48 )}. Prolonged inflammation may contribute to atherosclerosis and IHD as well as cancers. In addition, the chlorogenic acid in coffee may decrease blood pressure by increasing NO levels⁽ Reference Watanabe, Arai and Mitsui ^{49 )} and reduce the risk of diabetes mellitus by slowing the release of glucose into the blood stream after consumption of a meal and improving insulin sensitivity, along with other components in coffee including Mg, trigonelline and quinides⁽ Reference van Dam and Hu ^{50 –} Reference Tunnicliffe and Shearer ^{52 )}. Long-term hyperinsulinaemia is related to an increased risk of tumorigenesis due to increased cell proliferation and reduced apoptosis and thus enhances cancer progression⁽ Reference Giovannucci, Harlan and Archer ^{53 ,} Reference Inoue and Tsugane ^{54 )}. Hypertension, diabetes, CVD, inflammatory diseases and cancers are important causes of mortality. Thus, the net long-term impact of coffee consumption may favour a decreased risk of death by delaying the progression of disease through the beneficial properties of coffee components.

Of the twenty studies included in the meta-analysis, some studies also reported risk estimates of deaths from CVD⁽ Reference Leitzmann, Stampfer and Willett ^{12 –} Reference Kleemola, Jousilahti and Pietinen ^{23 ,} Reference Jazbec, Simić and Corović ^{25 –} Reference Happonen, Läärä and Hiltunen ^{27 ,} Reference Lopez-Garcia, van Dam and Li ^{29 –} Reference de Koning Gans, Uiterwaal and van der Schouw ^{31 ,} Reference Freedman, Park and Abnet ^{33 ,} Reference Gardener, Rundek and Wright ^{34 )}, which showed an inverse trend of coffee consumption overall, while one study that was conducted early in men showed an increased risk of CVD-specific deaths⁽ Reference LeGrady, Dyer and Shekelle ^{19 )}. Several studies also reported risk estimates of deaths from total cancer⁽ Reference LeGrady, Dyer and Shekelle ^{19 ,} Reference Rosengren and Wilhelmsen ^{20 ,} Reference Klatsky, Armstrong and Friedman ^{21 ,} Reference Iwai, Ohshiro and Kurozawa ^{24 ,} Reference Andersen, Jacobs and Carlsen ^{26 ,} Reference Happonen, Läärä and Hiltunen ^{27 ,} Reference Lopez-Garcia, van Dam and Li ^{29 ,} Reference Sugiyama, Kuriyama and Akhter ^{30 ,} Reference Tamakoshi, Lin and Kawado ^{32 –} Reference Gardener, Rundek and Wright ^{34 )} in addition to total mortality. Unlike for deaths from CVD, many of the studies showed no association between cancer deaths and coffee consumption overall, while some studies showed a non-significant inverse trend⁽ Reference Happonen, Läärä and Hiltunen ^{27 )} or significant inverse associations, but in only women⁽ Reference Sugiyama, Kuriyama and Akhter ^{30 ,} Reference Tamakoshi, Lin and Kawado ^{32 )}. Interestingly, a study conducted in Japan showed a reduced risk of death in women only for colorectal cancer, but not for other cancers. The inverse association for total mortality that we found in the meta-analysis seems to be influenced mostly by the reduced risk of deaths from CVD. It seems possible that coffee consumption protects against death from specific types of cancers, but not against total cancer deaths. This may be attributed to the aetiological heterogeneity of cancers when all types are grouped together, suggesting that the effect of coffee varies by cancer site. For example, recent epidemiological studies have shown stronger inverse associations of coffee consumption with the risk of liver cancer⁽ Reference Sang, Chang and Li ^{55 )}, endometrial cancer⁽ Reference Je and Giovannucci ^{43 )} and colorectal cancer⁽ Reference Tian, Wang and Hong ^{56 )}, while no significant association with coffee consumption has been found for breast cancer⁽ Reference Li, Ren and Qin ^{57 )}. Thus, the overall effect may depend on the population rates for these specific cancers. The recent largest prospective US cohort study of the National Institutes of Health–American Association of Retired Persons (NIH-AARP) Diet and Health Study⁽ Reference Lopez-Garcia, van Dam and Li ^{29 )} included in the present meta-analysis has shown inverse associations of coffee consumption with total and disease-specific deaths (including those from heart disease, respiratory diseases, diabetes and infections), but not with deaths due to cancers. In that study, inverse associations for total mortality were similar regardless of the predominant type of coffee consumed (caffeinated or decaffeinated) or across many subgroups. For cancer deaths, it is also possible that the residual confounding effects of smoking, alcohol or other unhealthy lifestyle factors related to coffee consumption may still exist, which are likely to obscure the beneficial effects of coffee consumption.

On the other hand, some factors related to health status may confound the association between coffee consumption and total mortality more inversely than the true association. There is a possibility that subclinical diseases lead to a reduction in coffee consumption, i.e. those in the lowest category of coffee consumption had more past disease history than those who were in the higher categories of coffee consumption, causing an elevation in risk among low/non-coffee drinkers. However, the risk estimate from the present meta-analysis limited to studies that had adjusted for health status⁽ Reference Kahn, Phillips and Snowdon ^{16 ,} Reference Vandenbroucke, Kok and van 't Bosch ^{18 –} Reference Rosengren and Wilhelmsen ^{20 ,} Reference Woodward and Tunstall-Pedoe ^{22 –} Reference Jazbec, Simić and Corović ^{25 ,} Reference Happonen, Läärä and Hiltunen ^{27 –} Reference Sugiyama, Kuriyama and Akhter ^{30 ,} Reference Tamakoshi, Lin and Kawado ^{32 –} Reference Gardener, Rundek and Wright ^{34 )} was not attenuated, but remained essentially the same. A study conducted in Japan attempted to examine the reverse causation with exclusion of death that occurred within 2–8 years from baseline and did not alter the relationship between coffee consumption and all-cause mortality⁽ Reference Tamakoshi, Lin and Kawado ^{32 )}. Similarly, the large US cohort studies of NHS and HPFS conducted sensitivity analyses to evaluate the robustness of their inverse findings⁽ Reference Lopez-Garcia, van Dam and Li29a,b ⁾. They carried out several analyses by excluding individuals in the lowest category of coffee consumption, excluding those who reduced their coffee consumption in the 10 years preceding the study or excluding those who died within the first 4 years of follow-up. As a result of the analyses, all the estimates remained similar to those in the main analyses. The observed findings seem to suggest that the difference in health at baseline did not explain the observed inverse association.

We attempted to conduct an exploratory meta-analysis of total mortality in relation to decaffeinated coffee consumption, and the results showed similar inverse associations with no heterogeneity. The largest US cohort study indicated a significant inverse association for high coffee consumption ( ≥ 4 cups/d) v. no coffee consumption, but it was not included in the meta-analysis due to insufficient data⁽ Reference Freedman, Park and Abnet ^{33 )}. Another recent study carried out by Gardener et al. ⁽ Reference Gardener, Rundek and Wright ^{34 )} reported a hazard ratio of 0·88 (95 % CI 0·88, 0·97) for consumption of one cup of decaffeinated coffee per day.

The present meta-analysis has several strengths. First, to the best of our knowledge, this is the first meta-analysis to investigate the long-term effect of coffee consumption on mortality. Second, all the studies included in the meta-analysis had a prospective design excluding recall and selection bias, which could be of concern in case–control studies. For practical and ethical reasons, the prospective design may be the best study design to investigate varying amounts of coffee consumption for a long period of time until many subjects die. Third, a large number of total cases were included in the meta-analysis, which increased statistical power to quantitatively assess the association of total mortality with coffee consumption. In addition, a relatively large number of studies allowed us to conduct subgroup analyses by geographical region, follow-up time, sex and confounder adjustment. Fourth, in addition to the large sample size, many of the studies had relatively long follow-up durations, which allowed observing the long-term effects of coffee consumption on mortality. Lastly, we found little evidence of publication bias, which could be of concern in a meta-analysis of published literature.

The present meta-analysis also has several potential limitations. First, a meta-analysis itself cannot solve confounding problems that could be inherent in the original studies, which may, in part, explain the observed findings. Usually, known and measured factors such as smoking status or alcohol consumption can be removed through statistical methods, as most of the studies included in the present meta-analysis did. All the studies adjusted for a strong confounder, smoking status, and the additional analysis carried out in the present meta-analysis limited to studies that had adjusted for at least alcohol consumption and BMI showed similar results. Nevertheless, we cannot rule out the possibility that unmeasured factors such as psychosocial factors associated with coffee drinking might have affected the inverse associations of coffee consumption and mortality. Since many people tend to use coffee shops as meeting places, those who report consuming coffee frequently are more likely to have a good social network. Thus, the effect of psychosocial factors related to coffee consumption should be assessed. Second, misclassification of coffee consumption categories may have occurred in the original analysis of each study and thus the meta-analysis, given that coffee consumption was assessed by self-report and, moreover, assessed at a single time point for most of the studies. Among the studies, two studies carried out in the USA for men (HPFS) and women (NHS) updated information on coffee consumption every 4 years during 18 and 24 years of follow-up, respectively⁽ Reference Lopez-Garcia, van Dam and Li29a,b ⁾. Except for the two studies, the others assessed coffee consumption at baseline only. However, misclassification of coffee consumption categories would have probably led to the underestimation, rather than to overestimation, of results, and thus the association between coffee consumption and risk of death may be even stronger. We found a slightly stronger inverse association in studies with relatively short follow-up durations. This may be related to less exposure misclassification in studies with short follow-up durations, which reduces the possibility of subjects altering their coffee consumption during follow-up. Third, the cut-offs for high exposure categories varied among the studies included in the meta-analysis, ranging from 2 to 9 cups/d. Even in the same geographical region, each country used different highest categories. For the highest categories of coffee consumption, studies carried out in Europe used >2–9 cups/d, those in the USA used 3–6 cups/d and those in Japan used 2–4 cups/d. We found no significant difference in the pooled RR stratified by cut-offs for the highest category (2–4 v. 5–9 cups/d), which might suggest that heavy coffee consumption ( ≥ 5 cups/d) seems not to provide further benefits against death compared with moderately high coffee consumption (2–4 cups/d). Of the studies included in the meta-analysis, two used 1 or 2 cups/d as a reference⁽ Reference Jacobsen, Bjelke and Kvale ^{17 ,} Reference LeGrady, Dyer and Shekelle ^{19 )}, and the other studies used 0 or < 1 cup/d as a reference. After the exclusion of the two studies, the pooled RR remained similar (RR 0·85, 95 % CI 0·79, 0·91). Finally, different brewing methods and varying cup sizes might have attenuated the results.