The Moderate Alcohol and Cardiovascular Health Trial (MACH15): Design and methods for a randomized trial of moderate alcohol consumption and cardiometabolic risk
Restricted accessResearch articleFirst published online December, 2020
The Moderate Alcohol and Cardiovascular Health Trial (MACH15): Design and methods for a randomized trial of moderate alcohol consumption and cardiometabolic risk
Observational studies have documented lower risks of coronary heart disease and diabetes among moderate alcohol consumers relative to abstainers, but only a randomized clinical trial can provide conclusive evidence for or against these associations.
Aim
The purpose of this study was to describe the rationale and design of the Moderate Alcohol and Cardiovascular Health Trial, aimed to assess the cardiometabolic effects of one alcoholic drink daily over an average of six years among adults 50 years or older.
Methods
This multicenter, parallel-arm randomized trial was designed to compare the effects of one standard serving (∼11–15 g) daily of a preferred alcoholic beverage to abstention. The trial aimed to enroll 7800 people at high risk of cardiovascular disease. The primary composite endpoint comprised time to the first occurrence of non-fatal myocardial infarction, non-fatal ischemic stroke, hospitalized angina, coronary/carotid revascularization, or total mortality. The trial was designed to provide >80% power to detect a 15% reduction in the risk of the primary outcome. Secondary outcomes included diabetes. Adverse effects of special interest included injuries, congestive heart failure, alcohol use disorders, and cancer.
Results
We describe the design, governance, masking issues, and data handling. In three months of field center activity until termination by the funder, the trial randomized 32 participants, successfully screened another 70, and identified ∼400 additional interested individuals.
Conclusions
We describe a feasible design for a long-term randomized trial of moderate alcohol consumption. Such a study will provide the highest level of evidence for the effects of moderate alcohol consumption on cardiovascular disease and diabetes, and will directly inform clinical and public health guidelines.
GunzerathLFadenVZakhariS, et al.
National Institute on Alcohol Abuse and Alcoholism report on moderate drinking.Alcohol: Clin Exp Res2004;
28: 829–847.
2.
RonksleyPEBrienSETurnerBJ, et al.
Association of alcohol consumption with selected cardiovascular disease outcomes: a systematic review and meta-analysis. BMJ2011;
342: d671.
3.
WoodAMKaptogeSButterworthAS, et al.
Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies. Lancet2018;
391: 1513–1523.
4.
BrienSERonksleyPETurnerBJ, et al.
Effect of alcohol consumption on biological markers associated with risk of coronary heart disease: systematic review and meta-analysis of interventional studies.BMJ (Clinical research ed)2011;
342: d636.
5.
HolmesMVDaleCEZuccoloL, et al.
Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. BMJ (Clinical research ed)2014;
349: g4164.
6.
TakeuchiFYokotaMYamamotoK, et al.
Genome-wide association study of coronary artery disease in the Japanese. Eur J Hum Genet2012;
20: 333–340.
7.
MillwoodIYWaltersRGMeiXW, et al.
Conventional and genetic evidence on alcohol and vascular disease aetiology: a prospective study of 500 000 men and women in China. Lancet2019;
393: 1831–1842.
8.
HanHWangHYinZ, et al.
Association of genetic polymorphisms in ADH and ALDH2 with risk of coronary artery disease and myocardial infarction: a meta-analysis. Gene2013;
526: 134–141.
9.
CarlssonSHammarNGrillV.Alcohol consumption and type 2 diabetes. Diabetologia2005;
48: 1051–1054.
10.
JoostenMMChiuveSEMukamalKJ, et al.
Changes in alcohol consumption and subsequent risk of type 2 diabetes in men. Diabetes2011;
60: 74–79.
11.
Di CastelnuovoACostanzoSBagnardiV, et al.
Alcohol dosing and total mortality in men and women: an updated meta-analysis of 34 prospective studies. Arch Intern Med2006;
166: 2437–2445.
12.
Smith-WarnerSASpiegelmanDYaunS-S, et al.
Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA1998;
279: 535–540.
13.
CorraoGBagnardiVZambonA, et al.
Exploring the dose-response relationship between alcohol consumption and the risk of several alcohol-related conditions: a meta-analysis. Addiction1999;
94: 1551–1573.
14.
PrabhuAObiKORubensteinJH.The synergistic effects of alcohol and tobacco consumption on the risk of esophageal squamous cell carcinoma: a meta-analysis.Am J Gastroenterol2014;
109: 822.
15.
PianoMR.Alcoholic cardiomyopathy: incidence, clinical characteristics, and pathophysiology. Chest2002;
121: 1638–1650.
16.
LarssonSCWallinAWolkA.Alcohol consumption and risk of heart failure: meta-analysis of 13 prospective studies. Clin Nutr2018;
37: 1247–1251.
17.
CherpitelCJTamTMidanikL, et al.
Alcohol and non-fatal injury in the U.S. general population: a risk function analysis. Accid Anal Prev1995;
27: 651–661.
18.
DawsonDAGrantBF.The “gray area” of consumption between moderate and risk drinking. J Stud Alcohol Drugs2011;
72: 453–458.
19.
BeulensJWSierksmaASchaafsmaG, et al.
Kinetics of homocysteine metabolism after moderate alcohol consumption. Alcohol: Clin Exp Res2005;
29: 739–745.
20.
MukamalKJClowryCMMurrayMM, et al.
Moderate alcohol consumption and chronic disease: the case for a long-term trial. Alcohol Clin Exp Res2016;
40: 2283–2291.
21.
LeongDPSmythATeoKK, et al.
Patterns of alcohol consumption and myocardial infarction risk: observations from 52 countries in the INTERHEART case-control study. Circulation2014;
130: 390–398.
22.
SmythATeoKKRangarajanS, et al.
Alcohol consumption and cardiovascular disease, cancer, injury, admission to hospital, and mortality: a prospective cohort study. Lancet2015;
386: 1945–1954.
23.
FreibergMSSametJH.Alcohol and coronary heart disease: the answer awaits a randomized controlled trial. Circulation2005;
112: 1379–1381.
24.
KlonerRARezkallaSH.To drink or not to drink? That is the question. Circulation2007;
116: 1306–1317.
25.
CohenJEZellerMEissenbergT, et al.
Criteria for evaluating tobacco control research funding programs and their application to models that include financial support from the tobacco industry. Tob Control2009;
18: 228–234.
26.
US Department of Health and Human Services. Subpart A – Basic HHS Policy for Protection of Human Subjects. Maryland: US Department of Health and Human Services, 2018.
27.
MukamalKJNaBMuL, et al.
Lessons and challenges from a 6-month randomized pilot study of daily ethanol consumption: research methodology and study design. Curr Dev Nutr2017;
1: e000505.
28.
US Department of Health and Human Services and US Department of Agriculture (USDA). 2015-2020 dietary guidelines for Americans (Appendix 9: Alcohol). 8th ed. Washington D.C.: USDA, 2015.
29.
US Department of Health and Human Services and US Department of Agriculture (USDA). 2015-2020 dietary guidelines for Americans. 8th ed. Washington D.C.: USDA, 2015.
30.
RimmEBKlatskyAGrobbeeD, et al.
Review of moderate alcohol consumption and reduced risk of coronary heart disease: is the effect due to beer, wine, or spirits?BMJ (Clinical research ed)1996;
312: 731–736.
31.
CleophasT.Wine, beer and spirits and the risk of myocardial infarction: a systematic review. Biomed Pharmacother1999;
53: 417–423.
32.
van der GaagMSvan TolAScheekLM, et al.
Daily moderate alcohol consumption increases serum paraoxonase activity; a diet-controlled, randomised intervention study in middle-aged men. Atherosclerosis1999;
147: 405–410.
33.
ShaiIWainsteinJHarman-BoehmI, et al.
Glycemic effects of moderate alcohol intake among patients with type 2 diabetes. Diabetes Care2007;
30: 3011–3016.
34.
KimSHAbbasiFLamendolaC, et al.
Effect of moderate alcoholic beverage consumption on insulin sensitivity in insulin-resistant, nondiabetic individuals. Metab Clin Exp2009;
58: 387–392.
35.
EstruchRSacanellaEMotaF, et al.
Moderate consumption of red wine, but not gin, decreases erythrocyte superoxide dismutase activity: a randomised cross-over trial. Nutr Metab Cardiovasc Dis2011;
21: 46–53.
36.
Sobell LC and Sobell MB. Timeline follow-back. In: Litten RZ and Allen JP (eds) Measuring Alcohol Consumption. Totowa, NJ: Humana Press, 1992, pp. 41–72.
37.
GoodmanWKPriceLHRasmussenSA, et al.
The Yale-Brown obsessive compulsive scale: I. Development, use, and reliability. Arch Gen Psychiatry1989;
46: 1006–1011.
38.
CarrollKM.Enhancing retention in clinical trials of psychosocial treatments: practical strategies.NIDA Res Monogr1997;
165: 4–24.
39.
EstruchRRosESalas-SalvadóJ, et al.
Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med2013;
368: 1279–1290.
40.
SvetkeyLPStevensVJBrantleyPJ, et al.
Comparison of strategies for sustaining weight loss: the weight loss maintenance randomized controlled trial. JAMA2008;
299: 1139–1148.
41.
PaulRTsanaclisLMurrayC, et al.
Ethyl glucuronide as a long-term alcohol biomarker in fingernail and hair. Matrix comparison and evaluation of gender bias.Alcohol Alcohol2019;
54: 402–407.
42.
KintzP.2014 consensus for the use of alcohol markers in hair for assessment of both abstinence and chronic excessive alcohol consumption. Forensic Sci Int2015;
249: A1–A2.
43.
KentDMAlsheikh-AliAHaywardRA.Competing risk and heterogeneity of treatment effect in clinical trials. Trials2008;
9: 30.
44.
AmbrosiusWTSinkKMFoyCG, et al.
The design and rationale of a multicenter clinical trial comparing two strategies for control of systolic blood pressure: the Systolic Blood Pressure Intervention Trial (SPRINT). Clinical Trials2014;
11: 532–546.
45.
DahlöfBDevereuxRBKjeldsenSE, et al.
Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet2002;
359: 995–1003.
46.
MantelN.Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 11966;
50: 163–170.
47.
PetoRPetoJ.Asymptotically efficient rank invariant test procedures. J R Stat Soc Ser A1972: 185–207.
48.
JungS-HJeongJ-H.Rank tests for clustered survival data.Lifetime data Anal2003;
9: 21–33.
49.
CoxDR.Regression models and life-tables. J R Stat Soc Series B Stat Methodol1972;
34: 187–220.
50.
GliddenDVVittinghoffE.Modelling clustered survival data from multicentre clinical trials. Stat Med2004;
23: 369–388.
51.
GangnonREKosorokMR.Sample-size formula for clustered survival data using weighted log-rank statistics. Biometrika2004;
91: 263–275.
52.
SheinerLBRubinDB.Intention-to-treat analysis and the goals of clinical trials. Clin Pharm Ther1995;
57: 6–15.
53.
DunnGMaracyMTomensonB.Estimating treatment effects from randomized clinical trials with noncompliance and loss to follow-up: the role of instrumental variable methods. Stat Methods Med Res2005;
14: 369–395.
54.
SussmanJBHaywardRA.An IV for the RCT: using instrumental variables to adjust for treatment contamination in randomised controlled trials.BMJ (Clinical research ed)2010;
340: c2073.
55.
FrangakisCERubinDB.Addressing complications of intention-to-treat analysis in the combined presence of all-or-none treatment-noncompliance and subsequent missing outcomes. Biometrika1999;
86: 365–379.
56.
MarkSDRobinsJM.A method for the analysis of randomized trials with compliance information: an application to the Multiple Risk Factor Intervention Trial. Control Clin Trials1993;
14: 79–97.
57.
SchoenfeldD.The asymptotic properties of nonparametric tests for comparing survival distributions. Biometrika1981;
68: 316–319.
58.
RimmEBWilliamsPFosherK, et al.
Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors. BMJ (Clinical research ed)1999;
319: 1523–1528.
59.
PraudDRotaMRehmJ, et al.
Cancer incidence and mortality attributable to alcohol consumption. Int J Cancer2016;
138: 1380–1387.
60.
MillerSIKreekKMLieberCS, et al. Recommended council guidelines on ethyl alcohol administration in human experimentation.
Bethesda:
National Institute on Alcohol Abuse and Alcoholism, 1989.
61.
RegenscheidAScarfoneK.Recommendations of the National Institute of Standards and Technology. NIST Special Publication2011;
800: 155.
62.
Regulation 2016/679 of the European Parliament and of the Council of 27 April. Brussels,2016, pp.1–88.
63.
Marques-VidalPDuclmetièrePEvansA, et al.
Alcohol consumption and myocardial infarction: a case-control study in France and Northern Ireland. Am J Epidemiol1996;
143: 1089–1093.
64.
BriasoulisAAgarwalVMesserliFH.Alcohol consumption and the risk of hypertension in men and women: a systematic review and met-analysis. J Clin Hypertens2012;
14: 792–798.
65.
GepnerYGolanRHarman-BoehmI, et al.
Effects of initiating moderate alcohol intake on cardiometabolic risk in adults with type 2 diabetes: a 2-year randomized, controlled trial. Ann Intern Med2015;
163: 569–579.
66.
MukamalKJPhillipsRSMittlemanMA.Beliefs, motivations, and opinions about moderate drinking: a cross-sectional survey.Fam Med2008;
40: 188.
67.
KanerEHeatherNBrodieJ, et al.
Patient and practitioner characteristics predict brief alcohol intervention in primary care. Br J Gen Pract2001;
51: 822–827.
68.
AbergFPuukkaPSalomaaV, et al. Risks of light and moderate alcohol use in fatty liver disease: follow-up of population cohorts. Hepatology (Baltimore, Md). Epub ahead of print 20 July 2019. DOI: 10.1002/hep.30864.
69.
PoynardTBedossaPOpolonP.Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet1997;
349: 825–832.
70.
RoereckeMVafaeiAHasanOSM, et al.
Alcohol consumption and risk of liver cirrhosis: a systematic review and meta-analysis. Am J Gastroenterol2019;
114: 1574–1586.
71.
KongFLiHXuG, et al.
Association of dietary behaviors and sleep quality: results from the adults chronic diseases and risk factors survey of 2015 in Ningbo, China. Int J Environ Res Public Health2018;
15: 1823.
72.
Urbano-MarquezAEstruchRNavarro-LopezF, et al.
The effects of alcoholism on skeletal and cardiac muscle.N Engl J Med1989;
320: 409–415.
73.
MarfellaRCacciapuotiFSiniscalchiM, et al.
Effect of moderate red wine intake on cardiac prognosis after recent acute myocardial infarction of subjects with type 2 diabetes mellitus. Biabet Med2006;
23: 974–981.
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