Summary Background Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. Methods We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose–response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th–95th percentile 1·04–13·5]) from 71 011 participants from 37 studies. Findings In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10–1·17), coronary disease excluding myocardial infarction (1·06, 1·00–1·11), heart failure (1·09, 1·03–1·15), fatal hypertensive disease (1·24, 1·15–1·33); and fatal aortic aneurysm (1·15, 1·03–1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91–0·97). In comparison to those who reported drinking >0–≤100 g per week, those who reported drinking >100–≤200 g per week, >200–≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1–2 years, or 4–5 years, respectively. Interpretation In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines. Funding UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

Introduction 1 Department of Health

Alcohol Guidelines Review: Report from the guidelines development group to the UK Chief Medical Officers. , 2 Kalinowski A

Humphreys K Governmental standard drink definitions and low-risk alcohol consumption guidelines in 37 countries. 1 Department of Health

Alcohol Guidelines Review: Report from the guidelines development group to the UK Chief Medical Officers. 2 Kalinowski A

Humphreys K Governmental standard drink definitions and low-risk alcohol consumption guidelines in 37 countries. 1 Department of Health

Alcohol Guidelines Review: Report from the guidelines development group to the UK Chief Medical Officers. , 2 Kalinowski A

Humphreys K Governmental standard drink definitions and low-risk alcohol consumption guidelines in 37 countries. 1 Department of Health

Alcohol Guidelines Review: Report from the guidelines development group to the UK Chief Medical Officers. , 2 Kalinowski A

Humphreys K Governmental standard drink definitions and low-risk alcohol consumption guidelines in 37 countries. Alcohol consumption guidelines vary substantially across the globe.In the USA, for example, an upper limit of 196 g per week (about 11 standard UK glasses of wine or pints of beer per week) is recommended for men, and an upper limit of 98 g per week is recommended for women.Similar recommendations apply in Canada and Sweden.By contrast, guidelines in Italy, Portugal, and Spain recommend low-risk limits almost 50% higher than these.At the other extreme, UK guidelines recommend low-risk limits for men almost half that recommended by US guidelines. 3 Stampfer MJ

Colditz GA

Willett WC

Speizer FE

Hennekens CH A prospective study of moderate alcohol consumption and the risk of coronary disease and stroke in women. , 4 Boffetta P

Garfinkel L Alcohol drinking and mortality among men enrolled in an American Cancer Society prospective study. , 5 Thun MJ

Peto R

Lopez AD

et al. Alcohol consumption and mortality among middle-aged and elderly U.S. adults. , 6 Mukamal K

Conigrave K

Mittleman M

et al. Roles of drinking pattern and type of alcohol consumed in coronary heart disease in men. , 7 Corrao G

Bagnardi V

Zambon A

La Vecchia C A meta-analysis of alcohol consumption and the risk of 15 diseases. , 8 Hvidtfeldt UA

Tolstrup JS

Jakobsen MU

et al. Alcohol intake and risk of coronary heart disease in younger, middle-aged, and older adults. , 9 Patra J

Taylor B

Irving H

et al. Alcohol consumption and the risk of morbidity and mortality for different stroke types—a systematic review and meta-analysis. , 10 Ronksley PE

Brien SE

Turner BJ

Mukamal KJ

Ghali WA Association of alcohol consumption with selected cardiovascular disease outcomes: a systematic review and meta-analysis. , 11 Roerecke M

Rehm J The cardioprotective association of average alcohol consumption and ischaemic heart disease: a systematic review and meta-analysis. , 12 Bergmann MM

Rehm J

Klipstein-Grobusch K

et al. The association of pattern of lifetime alcohol use and cause of death in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. , 13 Leong DP

Smyth A

Teo KK

et al. Patterns of alcohol consumption and myocardial infarction risk: observations from 52 countries in the INTERHEART case-control study. , 14 Ferrari P

Licaj I

Muller DC

et al. Lifetime alcohol use and overall and cause-specific mortality in the European Prospective Investigation into Cancer and nutrition (EPIC) study. , 15 Xi B

Veeranki SP

Zhao M

Ma C

Yan Y

Mi J Relationship of alcohol consumption to all-cause, cardiovascular, and cancer-related mortality in U.S. adults. 16 Smyth A

Teo KK

Rangarajan S

et al. Alcohol consumption and cardiovascular disease, cancer, injury, admission to hospital, and mortality: a prospective cohort study. , 17 Bell S

Daskalopoulou M

Rapsomaniki E

et al. Association between clinically recorded alcohol consumption and initial presentation of 12 cardiovascular diseases: population based cohort study using linked health records. Such variation in policy might reflect ambiguity about drinking risk thresholds associated with the lowest risk of mortality,as well as uncertainty about the specific consequences of alcohol consumption, including those related to cardiovascular disease subtypes. For example, recent studies have challenged the concept that moderate alcohol consumption is universally associated with lower cardiovascular disease risk,but the dose–response associations of alcohol consumption with cardiovascular disease subtypes remain poorly understood. Therefore, to help in the formulation of evidence-based alcohol policy, we analysed individual-participant data from 83 long-term prospective studies in 19 high-income countries. Our aim was to characterise risk thresholds for all-cause mortality and cardiovascular disease subtypes in current drinkers of alcohol.

Methods Study design, data sources, and participants 18 Jackson R

Broad J

Connor J

Wells S Alcohol and ischaemic heart disease: probably no free lunch. , 19 Knott CS

Coombs N

Stamatakis E

Biddulph JP All cause mortality and the case for age specific alcohol consumption guidelines: pooled analyses of up to 10 population based cohorts. , 20 Emberson JR

Bennett DA Effect of alcohol on risk of coronary heart disease and stroke: causality, bias, or a bit of both?. 21 Ng Fat L

Cable N

Marmot MG

Shelton N Persistent long-standing illness and non-drinking over time, implications for the use of lifetime abstainers as a control group. We focused our study on current alcohol drinkers for three main reasons. First, alcohol guidelines provide recommendations about low-risk limits only for drinkers (we are unaware of any guidelines that encourage non-drinkers to consume alcohol). Second, a focus on current drinkers should limit potential biases that are difficult to control in observational studies (eg, reverse causality, residual confounding, and unmeasured effect modification) because ex-drinkers include people who might have abstained from alcohol owing to poor health itself,as well as those who have changed their habits to achieve a healthier lifestyle. Third, never-drinkers might differ systematically from drinkers in ways that are difficult to measure, but which might be relevant to disease causation. 22 Danesh J

Erqou S

Walker M

et al. The Emerging Risk Factors Collaboration: Analysis of individual data on lipid, inflammatory and other markers in over 1.1 million participants in 104 prospective studies of cardiovascular diseases. 23 Danesh J

Saracci R

Berglund G

et al. EPIC-Heart: The cardiovascular component of a prospective study of nutritional, lifestyle and biological factors in 520,000 middle-aged participants from 10 European countries. 24 Sudlow C

Gallacher J

Allen N

et al. UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. We did a combined analysis of individual-participant data from three large-scale data sources available to our consortium, each constituting purpose-designed prospective cohort studies with quantitative information about alcohol consumption ( appendix p 21 ). First, the Emerging Risk Factors Collaboration (ERFC) is a collaboration of prospective cohort studies with information about a variety of risk factors, cardiovascular disease outcomes, and mortality.Of the 102 studies in the ERFC with information about alcohol status, 81 contained information about the quantity of consumption. Second, EPIC-CVD, a ten-country case-cohort study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) prospective cohort study, had quantitative alcohol information from 22 of its 23 contributing centres.Third, UK Biobank—a single large prospective study—had cohort-wide data about quantitative alcohol consumption.Therefore, our combined analysis included information from a total of 83 prospective studies that each used broadly similar methods to quantify alcohol consumption, record risk factors, and ascertain cause-specific death and cardiovascular disease events. We harmonised records of alcohol consumption across the contributing studies using a conversion of 1 unit=8 g of pure alcohol to a standard scale of grams per week ( appendix pp 1–2 ), enabling a common analytical approach despite variation in the methods used (eg, self-administered vs interview-led questionnaires; food frequency questionnaires vs dietary recall surveys), and in consumption scales over different periods of ascertainment. Details of contributing studies are in appendix pp 3–4, 10–11 Research in context Evidence before this study We searched for prospective epidemiological studies of alcohol consumption investigating disease risk thresholds published in any language up until March 1, 2017 (with no specified earliest date), in PubMed, Scientific Citation Index Expanded, and Embase using relevant terms (“alcohol”, “mortality”, “survival”, “cardiovascular disease”, “cohort”, and “prospective”). We found many primary reports and literature-based reviews. However, no study had combined the following key features required to achieve reliable estimates of dose–response associations: availability of individual-participant data; quantitative assessment of alcohol consumption levels using validated instruments; periodic re-surveys of alcohol consumption levels; recording of large numbers of deaths (eg, >20 000 deaths); and sufficient detail and power to disaggregate incident cardiovascular disease outcomes into subtypes (eg, >20 000 incident total cardiovascular disease outcomes). Added value of this study The current study combined all the key study design features mentioned above, and afforded several additional advantages. First, it reduced the potentially distorting effects of reverse causality by focusing on current drinkers without previous cardiovascular disease who survived at least 12 months of follow-up. Second, it enhanced generalisability by including individual-participant data from 83 prospective studies in 19 different high-income countries. Third, it used a variety of established and emerging risk factors, enabling investigation of potential confounders and mediators. Implications of all the available evidence The chief implication of this study for public policy is to support reductions of alcohol consumption limits in existing guidelines, suggesting that the threshold for lowest risk for all-cause mortality is about 100 g per week (about 5–6 standard UK glasses of wine or pints of beer per week). The chief implication for scientific understanding is the strengthening of evidence that the association between alcohol consumption and total cardiovascular disease risk is actually comprised of several distinct and opposite dose–response curves rather than a single J-shaped association. 7 Corrao G

Bagnardi V

Zambon A

La Vecchia C A meta-analysis of alcohol consumption and the risk of 15 diseases. , 17 Bell S

Daskalopoulou M

Rapsomaniki E

et al. Association between clinically recorded alcohol consumption and initial presentation of 12 cardiovascular diseases: population based cohort study using linked health records. , 25 Conen D Alcohol consumption and incident cardiovascular disease: not just one unifying hypothesis. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no known baseline history of cardiovascular disease (defined as coronary heart disease, other heart disease, stroke, transient ischaemic attack, peripheral arterial disease, or cardiovascular surgery); appendix p 21 . The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week: >0–≤25, >25–≤50, >50–≤75, >75–≤100, >100–≤150, >150–≤250, >250–≤350, and >350 g per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and the following cardiovascular disease subtypes (defined in appendix p 5 ): fatal and non-fatal myocardial infarction; fatal and non-fatal coronary disease excluding myocardial infarction; fatal and non-fatal stroke (including ischaemic, haemorrhagic, subarachnoid, and unclassified subtypes of stroke); fatal and non-fatal heart failure; and mortality from other cardiovascular causes, including cardiac dysrhythmia, hypertensive disease, sudden death, and aortic aneurysm.In analyses of cardiovascular disease subtypes, participants contributed follow-up time until the first outcome recorded (ie, cardiovascular deaths preceded by non-fatal outcomes were not included). Event times were censored at the end of follow-up or death from non-cardiovascular causes. Statistical analysis 26 Prentice RL A case-cohort design for epidemiologic cohort studies and disease prevention trials. 27 Thompson S

Kaptoge S

White I

et al. Statistical methods for the time-to-event analysis of individual participant data from multiple epidemiological studies. Hazard ratios (HRs) for alcohol consumption were calculated separately within each study using Cox regression models, stratified by sex and with adjustment for known confounders: age, smoking status (current vs non-current) and history of diabetes. To account for EPIC-CVD's case-cohort design (which was used because lipids and other cardiovascular disease biomarkers were measured only in the case-cohort subset and not the full EPIC cohort), the Cox models for cardiovascular disease events were adapted using Prentice weights and stratified by centre.For the four case-control studies nested within prospective cohorts of the ERFC, odds ratios were calculated using, as appropriate, conditional or unconditional logistic regression models, taking into account relevant matching factors. Study-specific estimates were then pooled across studies by random-effects meta-analysis.We tested for violation of the proportional hazards assumption by including time interactions with alcohol consumption. To avoid model overfitting, studies with fewer than five incident cases of a particular outcome were excluded from analyses of that particular outcome. 28 Wood AM

White I

Thompson SG

Lewington S

Danesh J Fibrinogen Studies Collaboration

Regression dilution methods for meta-analysis: assessing long-term variability in plasma fibrinogen among 27,247 adults in 15 prospective studies. , 29 Wood AM

Thompson SG

Kostis JB

et al. Correcting for multivariate measurement error by regression calibration in meta-analyses of epidemiological studies. 28 Wood AM

White I

Thompson SG

Lewington S

Danesh J Fibrinogen Studies Collaboration

Regression dilution methods for meta-analysis: assessing long-term variability in plasma fibrinogen among 27,247 adults in 15 prospective studies. To correct for measurement error and within-person variability in alcohol consumption over time, we estimated long-term average (henceforth, “usual”) alcohol consumption using multi-level regression calibration and information from 152 640 serial assessments in 71 011 individuals from 37 studies. This calculation was achieved either by regressing re-survey measurements (for the repeat alcohol assessments available in the ERFC studies and UK Biobank) or lifetime alcohol consumption measurements (for calculated lifetime alcohol consumption measurements available in EPIC-CVD) on baseline alcohol consumption, adjusted for duration of follow-up and baseline age, sex, smoking status, history of diabetes, other relevant covariate(s), and with random effects for study and re-survey.The regression dilution ratio (ie, the calibration slope), which measures the extent of within-person variability,was extracted from the calibration model. HRs in this paper relate to usual alcohol consumption levels unless specified otherwise. 30 Easton DF

Peto J

Babiker AG Floating absolute risk: an alternative to relative risk in survival and case-control analysis avoiding an arbitrary reference group. , 31 Plummer M Improved estimates of floating absolute risk. 32 Royston P

Ambler G

Sauerbrei W The use of fractional polynomials to model continuous risk variables in epidemiology. We assessed the shapes of associations for all-cause mortality and cardiovascular disease outcomes by calculating study-specific HRs within the predefined groups of baseline alcohol consumption, pooled them by multivariate random-effects meta-analysis, and plotted them against mean usual (and baseline) alcohol consumption within each group. We estimated 95% CIs for each group (including the reference group) that corresponded to the amount of information underlying each group.For each major outcome, we determined the best fitting first or second order fractional polynomialto describe the association with baseline alcohol consumption (using a 1% significance level as evidence for a second order fractional polynomial over a first order fractional polynomial) using Cox regression models stratified by sex, study, and centre. Further analyses assumed a linear association with alcohol consumption, expressing results per 100 g per week (12·5 units/week) in usual alcohol consumption. To assess the effect of excluding known current drinkers with missing alcohol consumption data, we did a sensitivity analysis using multiple imputation within studies, before combining the data in a meta-analysis. We investigated associations with alcohol type (wine, beer, and spirits), consumption frequency (dichotomised as drinkers who consumed alcohol on ≤2 days per week or those who consumed alcohol on >2 days per week) and episodic heavy drinking (dichotomised as binge drinkers who consumed ≥100 g per drinking occasion or non-binge drinkers who consumed <100 g per drinking occasion). 2 statistic. 33 Higgins JPT

Thompson SG Quantifying heterogeneity in a meta-analysis. 34 Begg CB

Mazumdar M Operating characteristics of a rank correlation test for publication bias. 35 Egger M

Davey Smith G

Schneider M

et al. Bias in meta-analysis detected by a simple, graphical test. We used regression calibration methods similar to those described above to estimate and adjust for long-term levels of potential confounding factors or mediators in individuals with available information. HRs were adjusted for usual levels of available potential confounders or mediators, including body-mass index (BMI), systolic blood pressure, high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), total cholesterol, fibrinogen, and baseline measures for smoking amount (in pack-years), level of education reached (no schooling or primary education only vs secondary education vs university), occupation (not working vs manual vs office vs other), self-reported physical activity level (inactive vs moderately inactive vs moderately active vs active), self-reported general health (scaled 0–1 where low scores indicate poorer health), self-reported red meat consumption, and self-reported use of anti-hypertensive drugs. We investigated effect modification with formal tests for interaction, using a 0·1% significance threshold to make some allowance for multiple testing. Heterogeneity was investigated by grouping studies according to recorded characteristics and through meta-regression, assessed by the Istatistic.Evidence of small study effects was assessed visually with funnel plots and by Begg and Mazumdar's testand Egger's test. 36 Centers for Disease Control and Prevention National Center for Health Statistics

Underlying cause of death 1999–2015 on CDC WONDER Online Database (released Dec, 2016). 37 WHO

WHO Statistical Information System (WHOSIS). , 38 UN Population Division

World Population Prospects. 39 Di Angelantonio E

Kaptoge S

et al. Emerging Risk Factors Collaboration

Association of cardiometabolic multimorbidity with mortality. Methods we used to estimate reductions in life expectancy (years of life lost) are described in the appendix (pp 6–7) . Briefly, estimates of cumulative survival from 40 years of age onwards in different categories of baseline alcohol consumption were calculated by applying estimated HRs (specific to age-at-risk) for cause-specific mortality to the detailed mortality component of the US Centers for Disease Control and Prevention's WONDER database,which recorded 10 million deaths (from all causes) in more than 305 million individuals in the USA during 2007–10.Results were modelled from age 40 years and enabled estimation of years of life lost between light drinkers (defined as those consuming >0–≤100 g/week of alcohol) and pre-defined groups of >100–≤200, >200–≤350, and >350 g per week. This method does not make use of the survival estimates from the modelled data; instead, it makes inferences by estimating age-at-risk specific HRs, which are then combined with external population age-specific mortality rates. Analyses used Stata (version 14.2 and 15.1). All p values presented are for 2-sided tests. Role of the funding source The funders of the study did not have any role in the study design, data analysis, or reporting of this manuscript. AMW and SK had full access to the combined dataset, and, together with EDA and JD, had responsibility for the decision to submit the manuscript for publication.

Discussion The main finding of this analysis was that the threshold for lowest risk for all-cause mortality was about 100 g per week. For men, we estimated that long-term reduction of alcohol consumption from 196 g per week (the upper limit recommended in US guidelines) to 100 g per week or below was associated with about 1–2 years of longer life expectancy at age 40 years. Exploratory analyses suggested that drinkers of beer or spirits, as well as binge drinkers, had the highest risk for all-cause mortality. 41 Lazo M

Chen Y

McEvoy JW

et al. Alcohol consumption and cardiac biomarkers: The atherosclerosis risk in communities (ARIC) study. , 42 Kiechl S

Willeit J Complex association between alcohol consumption and myocardial infarction: always good for a new paradox. 16 Smyth A

Teo KK

Rangarajan S

et al. Alcohol consumption and cardiovascular disease, cancer, injury, admission to hospital, and mortality: a prospective cohort study. , 43 Holmes MV

Dale CE

Zuccolo L

et al. Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. , 44 Cho Y

Shin S-Y

Won S

Relton CL

Davey Smith G

Shin M-J Alcohol intake and cardiovascular risk factors: a Mendelian randomisation study. , 45 Au Yeung SL

Jiang C

Cheng KK

et al. Moderate alcohol use and cardiovascular disease from Mendelian randomization. , 46 Yun KE

Chang Y

Yun S-C

et al. Alcohol and coronary artery calcification: an investigation using alcohol flushing as an instrumental variable. Our study has highlighted the complex and diverse potential mechanisms by which alcohol consumption may exert cardiovascular effects.It has shown that the association between alcohol consumption and total cardiovascular disease risk comprises several distinct and opposite dose–response curves, rather than a single J-shaped association. In particular, whereas higher alcohol consumption was roughly linearly associated with a higher risk of all stroke subtypes, coronary disease excluding myocardial infarction, heart failure, and several less common cardiovascular disease subtypes, it was approximately log-linearly associated with a lower risk of myocardial infarction. Our results are concordant with recent observational data and Mendelian randomisation studies. 44 Cho Y

Shin S-Y

Won S

Relton CL

Davey Smith G

Shin M-J Alcohol intake and cardiovascular risk factors: a Mendelian randomisation study. , 47 Taylor AE

Lu F

Carslake D

et al. Exploring causal associations of alcohol with cardiovascular and metabolic risk factors in a Chinese population using Mendelian randomization analysis. , 48 Chen L

Smith GD

Harbord RM

Lewis SJ Alcohol intake and blood pressure: a systematic review implementing a Mendelian randomization approach. 49 Zanoni P

Khetarpal SA

Larach DB

et al. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. , 50 Brien SE

Ronksley PE

Turner BJ

Mukamal KJ

Ghali WA Effect of alcohol consumption on biological markers associated with risk of coronary heart disease: systematic review and meta-analysis of interventional studies. , 51 Voight BF

Peloso GM

Orho-Melander M

et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. , 52 HPS3/TIMI55-REVEAL Collaborative Group

Effects of anacetrapib in patients with atherosclerotic vascular disease. 50 Brien SE

Ronksley PE

Turner BJ

Mukamal KJ

Ghali WA Effect of alcohol consumption on biological markers associated with risk of coronary heart disease: systematic review and meta-analysis of interventional studies. 53 Di Angelantonio E

Sarwar N

et al. The Emerging Risk Factors Collaboration

Major lipids, apolipoproteins, and risk of vascular disease. , 54 Woodward M

Barzi F

Feigin V

et al. Associations between high-density lipoprotein cholesterol and both stroke and coronary heart disease in the Asia Pacific region. 55 MacMahon S

Peto R

Collins R

et al. Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Our results contribute toward understanding of the basis for these directionally divergent cardiovascular disease associations. For example, our data have suggested that elevated systolic blood pressure could mediate alcohol consumption's positive association with stroke and coronary disease excluding myocardial infarction.By contrast, pathways related to HDL-C (but not necessarily HDL-C itself) could mediate alcohol consumption's inverse association with myocardial infarction. Both blood pressure and HDL-C are known to increase in response to alcohol consumption.They have contrasting associations with cardiovascular disease outcomes: the inverse association of HDL-C with cardiovascular disease is substantially stronger for coronary disease than stroke,whereas the positive association of systolic blood with cardiovascular disease is considerably stronger for stroke than coronary disease.However, we did not find convincing evidence that other known risk factors were important mediators or confounders. 56 Ahmed I

Sutton AJ

Riley RD Assessment of publication bias, selection bias, and unavailable data in meta-analyses using individual participant data: a database survey. Our study's access to individual-participant data avoided limitations of previous literature-based reviews.To limit reverse causality, our study focused on current drinkers without baseline cardiovascular disease and omitted the initial period of follow-up. To limit confounding, our study adjusted for a variety of risk factors. To correct for misclassification in alcohol consumption and covariates, our study also used extensive information on serial assessments. Our results were robust to a variety of sensitivity analyses. Generalisability of the findings was enhanced by inclusion of data from 83 prospective studies based in many different high-income countries recruited between 1964 and 2010. Although alcohol consumption levels declined during this period, HRs were similar over calendar time. 20 Emberson JR

Bennett DA Effect of alcohol on risk of coronary heart disease and stroke: causality, bias, or a bit of both?. , 57 Del Boca FK

Darkes J The validity of self-reports of alcohol consumption: state of the science and challenges for research. 58 Mukamal KJ

Clowry CM

Murray MM

et al. Moderate alcohol consumption and chronic disease: the case for a long-term trial. Nevertheless, our study has some potential limitations. Self-reported alcohol consumption data are prone to bias and are challenging to harmonise across studies conducted over different time periods that used varying instruments and methods to record such data.We did not, however, identify major differences in results across studies that used differing alcohol measurement instruments. Despite our study's access to extensive serial alcohol re-surveys from mid-life, our study could not investigate alcohol consumption during the entire life course. Misclassification in outcomes would have diluted dose-response associations, suggesting that true underlying associations of alcohol consumption with cardiovascular disease subtypes are stronger and more divergent than we observed. Because we did not generally have access to additional alcohol-related adverse outcomes (eg, non-fatal liver disease, injuries, or psychiatric comorbidities), we probably under-estimated potential benefits associated with lowering alcohol consumption. Because some individuals who reduced, but did not cease, alcohol consumption due to health complications were probably included in our analysis, we cannot exclude the effects of reverse causation (especially since some contributing studies did not record baseline chronic disease other than cardiovascular disease). Therefore, alternative study designs including randomised trialsare needed, to control more completely for residual biases (including those related to studying ex-drinkers and never-drinkers). In conclusion, our study shows that among current drinkers, the threshold for lowest risk of all-cause mortality was about 100 g per week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear thresholds below which lower alcohol consumption stopped being associated with a lower disease risk. These data support adoption of lower limits of alcohol consumption than are recommended in most current guidelines. This online publication has been corrected. The corrected version first appeared at thelancet.com on May 31, 2018

Contributors

All the authors contributed to data collection, and to the design, analysis, interpretation, and re-drafting of this report. AMW and SK had full access to the combined data and did the statistical analysis. AMW, EDA, and JD drafted the manuscript and had responsibility for submission of the manuscript for publication.

Data management team

Thomas Bolton, Catherine Perry, Sarah Spackman, and Matthew Walker.

Coordinating centre

Thomas Bolton, Stephen Burgess, Adam S Butterworth, Emanuele Di Angelantonio, Stephen Kaptoge, Lisa Pennells, Catherine Perry, David Stevens, Sarah Spackman, Simon G Thompson, Matthew Walker, Angela M Wood, and John Danesh (principal investigator).

Declaration of interests

ASB reports grants from European Commission Framework 7 (HEALTH-F2-2012-279233), the European Research Council (268834), the British Heart Foundation (SP/09/002 and RG/08/014 and RG13/13/30194), the UK Medical Research Council (G0800270 and MR/L003120/1), from National Institute for Health Research (through the NIHR Cambridge Biomedical Research Centre), during the conduct of the study; and grants from Merck, Biogen, Bioverativ, Novartis, and Pfizer, outside the submitted work. BMP reports that he serves on the DSMB of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. MD reports grants from Japan Society for the Promotion of Science, during the conduct of the study. EDA reports grants from European Commission Framework 7, the European Research Council, the British Heart Foundation, the UK Medical Research Council, and the National Institute for Health Research, during the conduct of the study; and grants from NHS Blood and Transplant, outside the submitted work. EB reports grants from the National Health and Medical Research Council of Australia, during the conduct of the study. HMK reports a research agreement (through Yale) from Johnson & Johnson (Janssen) and Medtronic to develop methods of clinical trial data sharing; personal fees from UnitedHealth, IBM Watson, Element Science, and Aetna; a personal health information platform from Hugo; grants from the FDA and Medtronic; and contracts from Centers for Medicare & Medicaid Services to develop and maintain measures that are publicly reported, outside the submitted work. JD reports grants from the UK Medical Research Council, the British Heart Foundation, the UK National Institute of Health Research, and the European Commision, during the conduct of the study; personal fees and non-financial support from Merck Sharp and Dohme UK Atherosclerosis, personal fees and non-financial support from Novartis Cardiovascular and Metabolic Advisory Board, grants from the British Heart Foundation, European Research Council, Merck, the National Institute of Health Research, NHS Blood and Transplant, Novartis, Pfizer, the UK Medical Research Council, the Wellcome Trust, and AstraZeneca, and personal fees and non-financial support from Pfizer Population Research Advisory Panel, outside the submitted work. ML reports grants from National Institutes of Health, during the conduct of the study; grants from National Kidney Foundation, outside the submitted work; and Funding from the National Institutes of Health, Grant 5U10AA025286, to Johns Hopkins University. MS reports grants from the UK Medical Research Council, the British Heart Foundation, the National Institute for Health Research, European Commission Framework 7, and the European Research Council, during the conduct of the study. NvS reports grants from the Netherlands Ministry of Health Welfare and Sports, Directorate of Long-Term Care, during the conduct of the study. OHF reports grants from Nestle and Metagenics, outside the submitted work. PJN reports grants from the NIH, during the conduct of the study. SGT reports grants from the UK Medical Research Council and the British Heart Foundation, during the conduct of the study. SKi reports grants from FFG COMET program: “Research Center of Excellence in Vascular Ageing—Tyrol, VASCage” (K-Project No. 843536) funded by the BMVIT, BMWFW, Wirtschaftsagentur Wien and Standortagentur Tirol, outside the submitted work. SKa reports grants from the UK Medical Research Council and the British Heart Foundation, during the conduct of the study. WK reports personal fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, GSK, DalCor, Sanofi, Berlin-Chemie, Kowa, and Amgen; grants and non-financial support from Roche Diagnostics, Beckmann, Singulex, and Abbott, outside the submitted work. The other authors declare no competing interests.

Acknowledgments The study's coordinating centre (Emerging Risk Factors Collaboration and EPIC-CVD Coordinating Centres, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK) has been underpinned by grants from the UK Medical Research Council (G0800270 and MR/L003120/1), British Heart Foundation (SP/09/002, RG/08/014 and RG13/13/30194), National Institute for Health Research (through the National Institute for Health Research Cambridge Biomedical Research Centre), European Commission Framework 7 (through the EPIC-CVD award; HEALTH-F2-2012-279233), and the European Research Council (through an Advanced Investigator Award to JD; 268834). JD holds a BHF Professorship and NIHR Senior Investigator Award. A study website Funding for the EPIC-InterAct project was provided by the EU FP6 programme (grant number LSHM_CT_2006_037197). A study website includes a list that investigators have provided of funding agencies that have supported individual EPIC centres. A study website includes a list that investigators have provided of funding agencies that have supported individual cohorts of the ERFC contributing to the present consortium. This research has been conducted using the UK Biobank resource (application 21886). We thank Nicola Kerrison and Stephen Sharp (both from the University of Cambridge MRC Epidemiology Unit, Cambridge, UK) for the former's data management in the EPIC-InterAct subcohort and the latter's statistical input into development of the EPIC-CVD's analytical guidelines.