Results Over 18.1 years of follow-up, 2820 cases of ischaemic heart disease and 1072 cases of total stroke (519 ischaemic stroke and 300 haemorrhagic stroke) were recorded. After adjusting for sociodemographic and lifestyle confounders, fish eaters and vegetarians had 13% (hazard ratio 0.87, 95% confidence interval 0.77 to 0.99) and 22% (0.78, 0.70 to 0.87) lower rates of ischaemic heart disease than meat eaters, respectively (P<0.001 for heterogeneity). This difference was equivalent to 10 fewer cases of ischaemic heart disease (95% confidence interval 6.7 to 13.1 fewer) in vegetarians than in meat eaters per 1000 population over 10 years. The associations for ischaemic heart disease were partly attenuated after adjustment for self reported high blood cholesterol, high blood pressure, diabetes, and body mass index (hazard ratio 0.90, 95% confidence interval 0.81 to 1.00 in vegetarians with all adjustments). By contrast, vegetarians had 20% higher rates of total stroke (hazard ratio 1.20, 95% confidence interval 1.02 to 1.40) than meat eaters, equivalent to three more cases of total stroke (95% confidence interval 0.8 to 5.4 more) per 1000 population over 10 years, mostly due to a higher rate of haemorrhagic stroke. The associations for stroke did not attenuate after further adjustment of disease risk factors.

Participants 48 188 participants with no history of ischaemic heart disease, stroke, or angina (or cardiovascular disease) were classified into three distinct diet groups: meat eaters (participants who consumed meat, regardless of whether they consumed fish, dairy, or eggs; n=24 428), fish eaters (consumed fish but no meat; n=7506), and vegetarians including vegans (n=16 254), based on dietary information collected at baseline, and subsequently around 2010 (n=28 364).

For stroke, two previous reports, 5 6 including one that included EPIC-Oxford data, 6 found no significant differences in risk of total stroke deaths between vegetarians and non-vegetarians. However, no previous studies have examined the incidence of stroke in relation to vegetarian diets, or have examined the main stroke types.

For ischaemic heart disease, some but not all previous studies reported significantly lower risks of mortality from ischaemic heart disease in vegetarians than in non-vegetarians. 5 6 7 In terms of incidence, the only previous study (the European Prospective Investigation into Cancer (EPIC)-Oxford) reported that vegetarians had a lower risk of ischaemic heart disease than non-vegetarians, 8 but at the time of publication the study had an insufficient duration of follow-up to separately examine the risks in other diet groups (fish eaters and vegans).

Vegetarian and vegan diets have become increasingly popular in recent years, partly due to perceived health benefits, as well as concerns about the environment and animal welfare. 1 In the United Kingdom, both the representative National Diet and Nutrition Survey 2008-12 and a 2016 Ipsos MORI survey estimated about 1.7 million vegetarians and vegans living in the country. 2 3 Evidence suggests that vegetarians might have different disease risks compared with non-vegetarians, 4 but data from large scale prospective studies are limited, because few studies have recruited sufficient numbers of vegetarian participants.

Methods

Study population and design EPIC-Oxford is a prospective cohort study of about 65 000 men and women who were recruited across the UK between 1993 and 2001. Details of the recruitment process have been described previously.9 Individuals were recruited from either general practices or by postal questionnaire. The general practice recruitment method recruited 7421 men and women aged 35 to 59 who were registered with participating general practices, all of whom completed a full questionnaire on their diet, lifestyle, health characteristics, and medical history. The postal recruitment preferentially targeted vegetarians, vegans, and other people interested in diet and health, and recruited 57 990 participants aged 20 or older. A full questionnaire was mailed to all members of the Vegetarian Society and all surviving participants of the Oxford Vegetarian Study,10 and respondents were invited to provide names and addresses of relatives and friends who were also interested in receiving a questionnaire. A short questionnaire was also distributed to all members of the Vegan Society, enclosed in vegetarian and health food magazines, and displayed in health food shops; and a full questionnaire was subsequently mailed to all those who returned the short questionnaire. Despite the targeted recruitment of the postal method, about 80% of meat eaters in the cohort were recruited by post. Subsequently, a follow-up questionnaire was sent to participants in 2010, which asked similar questions on their diet and lifestyle, and participants returned the questionnaires between 2010 and 2013. A participant flowchart of the recruitment process and inclusion into this study is shown as supplementary figure 1. The study protocol was approved by a multicentre research ethics committee (Scotland A Research Ethics Committee) and all participants provided written informed consent.

Assessment of diet group and diet The full baseline questionnaire collected responses to four questions about consumption of meat, fish, dairy products, and eggs, in the form of “Do you eat any meat (including bacon, ham, poultry, game, meat pies, sausages)?” or similar for the other three food groups. These four questions were used to classify participants into meat eaters (participants who reported eating meat, regardless of whether they ate fish, dairy, or eggs), fish eaters (participants who did not eat meat but did eat fish), vegetarians (participants who did not eat meat or fish, but did eat one or both of dairy products and eggs), and vegans (participants who did not eat meat, fish, dairy products, or eggs). The follow-up questionnaire sent in 2010 included identical questions on consumption of meat, fish, dairy products, and eggs (yes/no). Therefore, at both baseline and follow-up, participants were classified into one of four diet groups: meat eaters, fish eaters, vegetarians, and vegans. Owing to the small number of vegans, vegetarians and vegans were combined as one diet group in the main analyses, but the two groups were examined separately for each outcome in secondary analyses. The baseline questionnaire also included a semiquantitative food frequency section containing 130 items, which asked about dietary intake over the past year, and which was previously validated using 16 days (in four sets of four days) of weighed dietary records and selected recovery and concentration biomarkers.111213 For calculation of food and nutrient intakes, the frequency of consumption of each food or beverage was multiplied by a standard portion size (mostly based on data from the UK Ministry of Agriculture, Fisheries, and Food)14 and nutrient content of each food or beverage (based on McCance and Widdowson’s food composition tables).15 Because our prespecified analysis plan was to examine disease risks associated with distinct dietary groups, the associations of individual foods and nutrients with risks were not assessed in this study, but information on intakes of foods and nutrients were used in descriptive and secondary analyses.

Assessment of other characteristics In addition to diet, the baseline questionnaire also asked questions on sociodemographic characteristics, lifestyle, and medical history, including questions on education level, smoking, physical activity, use of dietary supplements, and use of oral contraceptives or hormone replacement therapy in women. Socioeconomic status was categorised by use of the Townsend deprivation index,16 based on the participants’ postcodes. For physical activity, based on their responses to questions asked about their occupation and their time spent participating in activities including walking, cycling, and other physical exercises, participants were categorised by a validated physical activity index with four levels.17 Alcohol consumption was determined from responses to five items on the food frequency questionnaire. Questions relating to smoking and alcohol consumption were also asked on the follow-up questionnaire in 2010. For biological measurements, body mass index was calculated from participants’ self reported height and weight at recruitment, which was previously found to be accurate compared with measured height and weight in a validation study of about 4800 participants.18 All participants were also asked at recruitment whether they were willing to have their blood pressure measured at their general practice and to provide a blood sample. Details of the procedures for blood pressure measurement and blood sample collection, which were conducted in subsets of the cohort, have been previously reported.81920

Outcome ascertainment Participants were followed up via record linkage to records from the UK’s health service up to 31 March 2016. Outcomes of interest were ischaemic heart disease (codes 410-414 from ICD-9 (international classification of diseases, 9th revision) or codes I20-I25 from ICD-10), including acute myocardial infarction (ICD-9 410 or ICD-10 I21); and total stroke (ICD-9 430-431, 433-434, 436; or ICD-10 I60-I61, I63-I64), including ischaemic stroke (ICD-9 433-434 or ICD-10 I63) and haemorrhagic stroke (ICD-9 430-431 or ICD-10 I60-I61). Details of events, using the relevant ICD-9 or ICD-10 codes, were obtained from hospital records or death certificates.

Exclusion criteria Participants who were not resident in England, Wales, or Scotland (n=945) were excluded, as were those with no Hospital Episode Statistics data or NHS number (n=20). We also excluded participants who completed the short questionnaire only (n=7619); were younger than 20 (n=1) or older than 90 at recruitment (n=58); had no follow-up (were censored at or before the date of recruitment (eg, if they were living abroad), n=364); could not be traced by the NHS (n=14); had an unknown diet group (if they did not answer the relevant questions to be classified, n=132); had unreliable nutrient data (≥20% of food frequencies missing, or daily energy intakes <500 kcal or >3500 kcal for women or <800 kcal or >4000 kcal for men (1 kcal=4.18 kJ=0.00418 MJ), n=1219); had a self reported history of acute myocardial infarction, stroke, or angina at recruitment (n=6837); or had a date of diagnosis that preceded or equalled the date of recruitment (n=14).

Statistical analyses Baseline characteristics and food and nutrient intakes of the EPIC-Oxford participants were summarised by diet group. For self reported body mass index, and measures of blood pressure (systolic and diastolic blood pressure) and blood lipids (total cholesterol, high density lipoprotein cholesterol (HDL-C), non-HDL-C), the means and 95% confidence intervals are presented, after adjustment for sex and age at entry (in 5-year age groups), alcohol consumption (<1, 1-7, 8-15, ≥16 g/day), and physical activity (inactive, low activity, moderately active, very active, unknown).17 Cox proportional hazards regression models were used to estimate the hazard ratios and 95% confidence intervals for the associations between diet group (meat eaters, fish eaters, vegetarians including vegans) and each outcome of interest, with meat eaters as the reference group. For participants who completed both the baseline and follow-up questionnaire, diet group and relevant time varying covariates (smoking and alcohol consumption) were updated at follow-up. The underlying time variable was the age at recruitment to the age at diagnosis, death, or administrative censoring, whichever occurred first. For acute myocardial infarction or ischaemic heart disease, events were censored on the respective outcomes of interest. For total stroke, ischaemic stroke, and haemorrhagic stroke, events were censored on any stroke. All analyses were stratified by sex, method of recruitment (general practice or postal), and region (seven regions across the UK), and adjusted for year of recruitment (per year from 1994 to 1999), education (no qualifications, basic secondary (eg, O level), higher secondary (eg, A level), degree, unknown), Townsend deprivation index (quarters, unknown),16 smoking (never, former, light, heavy, unknown), alcohol consumption (<1, 1-7, 8-15, ≥16 g/day), physical activity (inactive, low activity, moderately active, very active, unknown), dietary supplement use (no, yes, unknown), and oral contraceptive use (no, yes ever, unknown) and hormone replacement therapy use (no, yes ever, unknown) in women. We used Wald tests to test for heterogeneity of risk between diet groups. The proportional hazards assumption was assessed on the basis of Schoenfeld residuals, and was not violated for the variables of interest in the adjusted model for either ischaemic heart disease or stroke (P>0.05 for all categories). Self reported history of high blood pressure (no, yes, unknown), high blood cholesterol (no, yes, unknown), diabetes (no, yes, unknown), and body mass index (<20, 20-22.5, 22.5-25, 25-27.5, ≥27.5, unknown) were assessed as potential physiological mediators, since these factors were known to be associated with vegetarian diets,1920212223 as well as being established cardiovascular risk factors.24 Total fruit and vegetable intake, total dietary fibre, and total energy intake (each continuous) were assessed as possible relevant dietary factors. We assessed the effects of potential physiological mediators and possible relevant dietary factors by adding each variable one at a time to the previous model. An additional model was also fitted including all potential physiological mediators. To estimate the population impact of vegetarian diets on cardiovascular health, we assessed the absolute risk difference for each outcome between meat eaters, fish eaters, and vegetarians. Predicted incidence and absolute risk differences were presented as per 1000 population over 10 years, and were estimated by use of hazard ratios and 95% confidence intervals expressed as floating absolute risks,2526 which do not alter the value of the hazard ratios but assign an appropriate 95% confidence interval to all groups, including the reference group (thereby allowing an estimation of the uncertainty in the effect size in the reference group). In meat eaters, predicted incidence over this time period of each outcome was calculated as (1−S r )×1000, where S r =(1−observed incidence in meat eaters)10, and represents the predicted 10 year survival (that is, non-incidence) in meat eaters. By subtracting this estimate of survival from 1, and multiplying by 1000, the resulting estimate represents incidence per 1000 population over 10 years. For all other diet groups, predicted incidence was calculated as (1−S r HR)×1000, where HR represents the hazard ratio or confidence intervals for each outcome in that diet group. By applying HR or confidence interval estimates in each diet group as an exponential to survival in the reference group, S r HR represents the predicted 10 year survival rate in the each of the other diet groups. Absolute risk differences were then calculated as the crude differences between the predicted incidence per 1000 population over 10 years between each diet group and the meat eaters. Additional sensitivity analyses included analyses using baseline diet group only, excluding participants with less than five years of follow-up, including participants recruited via the postal method only, censoring at age 70 or setting entry time at age 70 to evaluate possible differences by age at event, and performing multiple imputation (with 10 imputations) for missing covariates. The percentages of missing values in the covariates were 12.7% for the Townsend deprivation index, 10.9% for physical activity, 6.3% for education level, and less than 2% for each of the other covariates. We assessed heterogeneity in the associations between diet group and risk of ischaemic heart disease or stroke by sex, age at recruitment (<60 or ≥60 years), smoking status (never, former, or current), body mass index (<25 or ≥25), presence of risk factors (one or more of self reported history of high blood pressure, high blood cholesterol, or diabetes), and any long term treatment for any illness or condition (no, yes) by adding appropriate interaction terms to the Cox models and testing for statistical significance of interaction across strata using likelihood ratio tests. All analyses were performed with Stata version 14.1 or 15.1 (Stata Corp, TX, United States) and P values less than 0.05 were considered significant.