Naimi, Timothy S.

Abstract Aims Alcohol and its relationship with cardiovascular disease (CVD) remain contentious. Several observational studies have found cardioprotective associations, while Mendelian randomization studies have found null or harmful effects of moderate drinking. Biases, including abstainer misclassification and sick-quitter effects, may obscure true associations. It is widely understood that former drinkers are often sick quitters. However, removal of former drinkers from analyses addresses bias in the abstainer group but fails to account for induced survivorship among current drinkers. This study sought to determine whether adjusting for biases altered the association between alcohol and CVD by comparing conventional models with those using (i) occasional drinkers as the reference group instead of lifetime abstainers and (ii) ‘intention-to-treat’ reallocation of former drinkers based on past drinking patterns. Methods and results The Multi-Ethnic Study of Atherosclerosis is a prospective cohort study of 6814 participants aged 45–84 years between 2000 and 2002 without baseline CVD. A total of 6755 participants were included after excluding those with missing data. Alcohol consumption was self-reported and classified as lifetime abstainer, former, or current drinker [occasional (≤1 drink/week), light (2–7 drinks/week), moderate (8–14 drinks/week), heavy (>14 drinks/week)]. Outcomes included coronary artery calcium (CAC; 0, 1–100, 101–300, and >300) and clinical events [myocardial infarction (MI), stroke, cardiovascular mortality, composite major adverse cardiovascular events (MACEs), and heart failure]. Of 6755 participants, 20.6% were lifetime abstainers, 24.1% former drinkers, and 55.3% current drinkers. Adjusting for biases altered the observed relationship between alcohol and CVD, showing increased harm with light drinking, decreased protection with moderate drinking, and a dose–response relationship between alcohol and CAC, particularly CAC >300 in adjusted models. Protective associations between moderate drinking and MI [hazard ratio (HR): 0.64, 95% confidence interval (CI): 0.38–1.06] and cardiovascular mortality (HR: 0.81, 95% CI: 0.53–1.25) were attenuated and became non-significant. Light drinking shifted from null to increased risk for MI (HR: 1.46, 95% CI: 1.11–1.92), stroke (HR: 1.54, 95% CI: 1.17–2.03), MACE (HR: 1.33, 95% CI: 1.12–1.57), and heart failure (HR: 1.42, 95% CI: 1.10–1.84). Conclusion Associations between alcohol and CVD in observational studies are sensitive to methodologic variation. Results from models correcting for abstainer/sick-quitter biases may help explain discrepant results from previous studies.

Abstract Background Alcohol consumption and its relationship with cardiovascular disease (CVD) remains controversial. Observational studies have reported J-shaped associations suggesting cardioprotective effects of moderate drinking, while other observational and Mendelian Randomization studies have found dose-response harm. Biases such as abstainer misclassification, sick quitter effects, and residual confounding may obscure true associations. This study aimed to reassess alcohol’s impact on CVD using novel methods to minimize bias. Purpose We evaluated the relationship between alcohol and subclinical (coronary artery calcium [CAC]) and clinical (myocardial infarction [MI], stroke, cardiovascular death, major adverse cardiovascular events [MACE], and heart failure) outcomes in the Multi-Ethnic Study of Atherosclerosis (MESA). We compared conventional models with those using (1) occasional drinkers as the reference group instead of lifetime abstainers and (2) intention-to-treat (ITT) reallocation of former drinkers based on past drinking patterns. Methods MESA is a prospective cohort study of 6,814 participants aged 45-84 years without baseline CVD. Alcohol use was classified as lifetime abstainer, former drinker, or current drinker (occasional [≤1 drink/week], light [2-7 drinks/week], moderate [8-14 drinks/week], heavy [>14 drinks/week]). We used multinomial logistic regression for CAC and Cox proportional hazards models for clinical outcomes across four models: (1) non-drinker reference, (2) lifetime abstainer reference, (3) occasional drinker reference, and (4) occasional drinker reference with ITT reallocation of former drinkers to their previous drinking levels. Results Increasing alcohol consumption correlated with a dose-response increase in CAC. Heavy drinking was consistently associated with severe CAC (>300). In fully adjusted models, light (OR: 1.23, 95% CI: 1.02-1.48), moderate (OR: 1.27, 95% CI: 1.04-1.55), and heavy drinking (OR: 1.42, 95% CI: 1.12-1.78) were associated with higher CAC scores compared to occasional drinkers. Traditional models replicated protective effects of moderate drinking for MI and cardiovascular mortality. However, these associations attenuated in adjusted models. Moderate drinking showed an attenuated, non-significant benefit for MI (HR: 0.64, 95% CI: 0.38-1.06) and cardiovascular mortality (HR: 0.81, 95% CI: 0.53-1.25) in fully adjusted models. Light drinking shifted from null to increased risk for MI (HR: 1.46, 95% CI: 1.11-1.92), stroke (HR: 1.54, 95% CI: 1.17-2.03), MACE (HR: 1.33, 95% CI: 1.12-1.57), and heart failure (HR: 1.42, 95% CI: 1.10-1.84). Conclusion Adjusting for abstainer and sick quitter biases altered the observed relationship between alcohol and CVD, showing increased harm with light drinking, attenuated protective effects of moderate drinking, and a dose-response relationship for CAC in bias-adjusted models. These findings illustrate the importance of methodology in alcohol-CVD relationships.

Introduction Alcohol is consumed by an estimated 137.4 million people in the USA 12 years of age and older and, as a result, is estimated to have caused about 140 thousand deaths among people 20 to 64 years of age each year from 2015 up to and including 2019. Methods The proposed review of the evidence on alcohol’s impact on health aims to produce conclusions to inform the Dietary Guidelines for Americans, 2026–2030 . A multi-method approach will be utilised to formulate conclusions on (i) weekly (ie, average) thresholds to minimise long-term and short-term risks of morbidity and mortality, (ii) daily thresholds to minimise the short-term risk of injury or acute illness due to per occasion drinking, (iii) alcohol use among vulnerable populations (eg, pregnant women) and (iv) situations and circumstances that are hazardous for alcohol use. To inform expert decisions, this project will also include a systematic review of existing low-risk drinking guidelines, a systematic review of meta-analyses which examine alcohol’s impact on key attributable disease and mortality outcomes, and of estimates of the lifetime absolute risk of alcohol-attributable mortality and morbidity based on a person’s sex and average level of alcohol use. The systematic reviews were designed in accordance with the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P). The preliminary conclusions produced as a result of this project will undergo public consultation, and data from these consultations will be qualitatively analysed. The results of the public consultations will be used to further revise and refine the project’s conclusions. Ethics and registration The study was granted an ethics exemption as only secondary data sources and unidentifiable public consultation will be utilised. Systematic reviews are pre-registered with PROSPERO (registration numbers CRD42024584924 and CRD42024584948). Dissemination This project will establish a scientific consensus concerning alcohol’s impact on health. This consensus is imperative for informing the upcoming Dietary Guidelines for Americans, 2026–2030 , and for better informing individuals about the health risks associated with alcohol use.

Abstract Background Alcohol is consumed by an estimated 137.4 million people in the United States 12 years of age and older, and, as a result, is estimated to have caused about 140 thousand deaths among people 20 to 64 years of age each year from 2015 up to and including 2019. Methods The proposed proposed review of the evidence on alcohol’s impact to health aims to produce conclusions to inform the Dietary Guidelines for Americans, 2026–2030. A multi-method approach will be utilized to formulate conclusions on (i) weekly (i.e., average) thresholds to minimize long-term and short-term risks of morbidity and mortality, (ii) daily thresholds to minimize the short-term risk of injury or acute illness due to per occasion drinking, (iii) alcohol use among vulnerable populations (e.g., pregnant women), and (iv) situations and circumstances that are hazardous for alcohol use. To inform expert discussions, this project will also include a systematic review of existing low-risk drinking guidelines, a systematic review of meta-analyses which examine alcohol’s impact on key attributable disease and mortality outcomes, and of estimates of the lifetime absolute risk of alcohol-attributable mortality and morbidity based on a person’s sex and average level of alcohol use. The preliminary conclusions produced as a result of this project will undergo public consultation, and data from these consultations will be analyzed using both quantitative and qualitative methods. The results of the public consultations will be used to further revise and refine the project’s conclusions. Discussion This project will establish a scientific consensus concerning alcohol’s impact on health. This consensus is imperative for informing the upcoming Dietary Guidelines for Americans, 2026–2030, and for better informing individuals about the health risks associated with alcohol use.