Time to rethink the ischaemic heart disease effects of low to moderate alcohol consumption?
In a recent study reported in the British Medical Journal, Holmes and colleagues [1] challenged the traditional view that light to moderate intake of alcohol is causally linked to reductions of risk for ischaemic disease, in particular to reductions of risk of ischaemic heart disease (IHD) [2]. The authors used a Mendelian randomization analysis based on a large data set of more than 260 000 subjects and 20 000 IHD events. Their conclusions are based mainly on the results of their analyses stratified by alcohol consumption, which are not compatible with a protective effect on IHD (see Table 1). This leaves us with a situation, where different analyses, based on different assumptions, yield different results (see Table 1). To pick the methodologically strongest kinds of evidence: randomized controlled experimental studies on the pathophysiological pathway of alcohol intake on biomarkers for IHD lead to different conclusions than the Mendelian randomization analysis. Concretely, the fact that alcohol intake causes more favorable biomarker profiles for IHD in short-term experimental case-crossover and/or before-after designs [3] supports a beneficial effect on IHD, while the Mendelian randomization analysis, showing that reductions in alcohol intake are always linked to favourable IHD risk, even at moderate levels, points to the opposite.
Based on the current data, no clear decision between the two types of evidence seems possible. The results clearly indicate that more research with innovative design is necessary to solve the mysteries of a potential beneficial effect of light to moderate alcohol consumption without irregular heavy drinking occasions on IHD risk. Four aspects seem to deserve most attention: a) the fact that one result of the Mendelian randomization analyses was that the ADH1B rs1229984 A-allele was indiscriminately associated with all alcohol indicators from average volume of alcohol consumed over heavy drinking occasions to gamma-glutamyltransferase, whereas these indicators seem to be associated with different forms of harm with respect to IHD and with respect to mortality in general (see Table 1 for details); b) the fact, that epidemiological and experimental evidence indicate that heavy drinking also seems to be associated with some favourable biomarkers for IHD, such as increased HDL or lower levels of fibrinogen (e.g., [3, 4]), even though heavy drinking is not associated with lower IHD risk [5, 6]; c) the lack of distinguishing irregular and regular heavy drinking in most of the literature [7] and d) whether we find good ways to empirically test the key assumptions of Mendelian randomization analysis [8].
Until we answer the seeming contradictions between results from different types of studies, we should be very cautious in placing too much weight on the IHD effects in policy formulation.
References
1. Holmes MV, Dale CE, Zuccolo L, Silverwood RJ, Guo Y, Ye Z, et al. Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. BMJ. 2014;349:g4164.
2. 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. BMJ. 2011;342:d671.
3. 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. BMJ. 2011;342:d636.
4. Galán I, Valencia-Martín JL, Guallar-Castillón P, Rodríguez-Artalejo F. Alcohol drinking patterns and biomarkers of coronary risk in the Spanish population. Nutr Metab Cardiovasc Dis. 2014;24:189-97.
5. Roerecke M, Rehm J. The cardioprotective association of average alcohol consumption and ischaemic heart disease: a systematic review and meta-analysis. Addiction. 2012;107:1246-60.
6. Roerecke M, Rehm J. Cause-specific mortality risk in alcohol use disorder treatment patients: a systematic review and meta-analysis. Int J Epidemiol. 2014;43:906-19.
7. Gmel G, Kuntsche E, Rehm J. Risky single occasion drinking: bingeing is not bingeing. Addiction. 2011;106:1037-45.
8. Glymour MM. Alcohol and cardiovascular disease. BMJ. 2014;349:g4334.
9. Roerecke M, Rehm J. Irregular heavy drinking occasions and risk of ischemic heart disease: a systematic review and meta-analysis. Am J Epidemiol. 2010;171:633-44.
10. Bagnardi V, Zatonski W, Scotti L, La Vecchia C, Corrao G. Does drinking pattern modify the effect of alcohol on the risk of coronary heart disease? Evidence from a meta-analysis. J Epidemiol Community Health. 2008;62:615-19.
11. Grønbaek M. The positive and negative health effects of alcohol- and the public health implications. J Intern Med. 2009;265:407-20.
12. Di Castelnuovo A, Costanzo S, Donati MB, Iacoviello L, de Gaetano G. Prevention of cardiovascular risk by moderate alcohol consumption: epidemiologic evidence and plausible mechanisms. Intern Emerg Med. 2010;5:291-7.
13. Murray RP, Barnes GE, Ekuma O. Does personality mediate the relation between alcohol consumption and cardiovascular disease morbidity and mortality? Addict Behav. 2005;30:475-88.
14. Naimi T, Xuan Z, Brown D, Saitz R. Confounding and studies of ‘moderate’ alcohol consumption: the case of drinking frequency and implications for Low-Risk Drinking Guidelines. Addiction. 2013;108:1534-43.
15. Grønbaek M. Alcohol and cardiovascular disease--more than one paradox to consider. Type of alcoholic beverage and cardiovascular disease--does it matter? J Cardiovasc Risk. 2003;10:5-10.
16. Klatsky AL. Alcohol and cardiovascular mortality: common sense and scientific truth. J Am Coll Cardiol. 2010;55:1336-8.
17. Poikolainen K, Vahtera J, Virtanen M, Linna A, Kivimäki i M. Alcohol and coronary heart disease risk--is there an unknown confounder? Addiction. 2005;100:1150-57.
18. Ferrence R, Kozlowski LT. Moderate drinking and health: being confounded by confounders. Addiction. 1995;90:485-8.
19. Skog OJ. Public health consequences of the J-curve hypothesis of alcohol problems. Addiction. 1996;91:325-37.
20. Romelsjö A, Branting M, Hallqvist J, Alfredsson L, Hammar N, Leifman A, et al. Abstention, alcohol use and risk of myocardial infarction in men and women taking account of social support and working conditions: the SHEEP case-control study. Addiction. 2003;98:1453-62.
21. Chikritzhs T, Liang W. Fishy curves: a case of bias and confounding? Addiction. 2013;108:1548-49.
22. Chikritzhs T, Fillmore K, Stockwell T. A healthy dose of scepticism: four good reasons to think again about protective effects of alcohol on coronary heart disease. Drug Alcohol Rev. 2009;28:441-44.
23. Grønbaek M. Factors influencing the relation between alcohol and cardiovascular disease. Curr Opin Lipidol. 2006;17:17-21.
24. Naimi TS, Brown DW, Brewer RD, Giles WH, Mensah G, Serdula MK, et al. Cardiovascular risk factors and confounders among nondrinking and moderate-drinking U.S. adults. Am J Prev Med. 2005;28:369-73.
25. Jackson R, Broad J, Connor J, Wells S. Alcohol and ischaemic heart disease: probably no free lunch. Lancet 2005;366:1911-12.
26. Shaper A, Wannamethee G, Walker M. Alcohol and mortality in British men: explaining the U-shaped curve. Lancet. 1988;2:1267-73.
27. Fillmore KM, Stockwell T, Chikritzhs T, Bostrom A, Kerr W. Moderate alcohol use and reduced mortality risk: systematic error in prospective studies and new hypotheses. Ann Epidemiol. 2007;17:S16-S23.
28. Rimm EB, Williams P, Fosher K, Criqui MH, Stampfer MJ. Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors. BMJ. 1999;19:1523-28.
29. Rehm J. On the limitations of observational studies. Addict Res Theory. 2007;15:20-22.
30. McKee M, Britton A. The positive relationship between alcohol and heart disease in Eastern Europe: potential physiological mechanisms. J R Soc Med. 1998;91:402-07.
31. Puddey IB, Rakic V, Dimmitt SB, Beilin LJ. Influence of pattern of drinking on cardiovascular disease and cardiovascular risk factors - a review. Addiction. 1999;94:649-63.
32. George A, Figueredo VM. Alcohol and arrhythmias: a comprehensive review. J Cardiovasc Med. 2010;11:221-28.
33. Norström T, Ramstedt M. Mortality and population drinking: a review of the literature. Drug Alcohol Rev. 2005;24:537-47.
34. Leon DA, Chenet L, Shkolnikov V, Zakharov S, Shapiro J, Rakhmanova G, et al. Huge variation in Russian mortality rates 1984-1994: artefact, alcohol, or what? Lancet. 1997;350:383-88.
35. Gmel G, Rehm J, Frick U. Methodological approaches to conducting pooled cross-sectional time series analysis: the example of the association between all-cause mortality and per capita alcohol consumption for men in 15 European states. Eur Addict Res. 2001;7:128-37.
36. Gmel G, Rehm J, Frick U. Trinkmuster, Pro-Kopf-Konsum von Alkohol und koronare Mortalität. Sucht. 2003;49:95-104.
37. Rehm J, Room R, Monteiro M, Gmel G, Graham K, Rehn N, et al. Alcohol Use. In: Ezzati M, Lopez AD, Rodgers A, et al., eds. Comparative quantification of health risks: global and regional burden of disease attributable to selected major risk factors. Geneva, Switzerland: World Health Organization; 2004. p. 959-1109.
38. Morgenstern H. Ecological studies. In: Rothman K, Greenland S, Lash T, eds. Modern Epidemiology. 3rd Edition.: Lippincott, Williams and Wilkins; 2008. p. 511-31.
39. Morgenstern H. Ecologic studies in epidemiology: concepts, principles, and methods. Annu Rev Public Health. 1995;16:61-81.
40. Davey Smith G. Mendelian randomization for strengthening causal inference in observational studies: application to gene by environment interaction. Perspect Psychol Sci. 2010;5:527-46.
41. Didelez V, Sheehan N. Mendelian randomization as an instrumental variable approach to causal inference. Stat Methods Med Res. 2007;16:309-30.
Competing interests:
No conflict of interest declared with respect to this letter. In the past 5 years, unrelated to the work submitted, JR has received honoraria, travel support and grants from Lundbeck. MR reports no financial relationships with commercial interests.
In a recent study reported in the British Medical Journal, Holmes and colleagues [1] challenged the traditional view that light to moderate intake of alcohol is causally linked to reductions of risk for ischaemic disease, in particular to reductions of risk of ischaemic heart disease (IHD) [2]. The authors used a Mendelian randomization analysis based on a large data set of more than 260 000 subjects and 20 000 IHD events. Their conclusions are based mainly on the results of their analyses stratified by alcohol consumption, which are not compatible with a protective effect on IHD (see Table 1). This leaves us with a situation, where different analyses, based on different assumptions, yield different results (see Table 1). To pick the methodologically strongest kinds of evidence: randomized controlled experimental studies on the pathophysiological pathway of alcohol intake on biomarkers for IHD lead to different conclusions than the Mendelian randomization analysis. Concretely, the fact that alcohol intake causes more favorable biomarker profiles for IHD in short-term experimental case-crossover and/or before-after designs [3] supports a beneficial effect on IHD, while the Mendelian randomization analysis, showing that reductions in alcohol intake are always linked to favourable IHD risk, even at moderate levels, points to the opposite.
Based on the current data, no clear decision between the two types of evidence seems possible. The results clearly indicate that more research with innovative design is necessary to solve the mysteries of a potential beneficial effect of light to moderate alcohol consumption without irregular heavy drinking occasions on IHD risk. Four aspects seem to deserve most attention: a) the fact that one result of the Mendelian randomization analyses was that the ADH1B rs1229984 A-allele was indiscriminately associated with all alcohol indicators from average volume of alcohol consumed over heavy drinking occasions to gamma-glutamyltransferase, whereas these indicators seem to be associated with different forms of harm with respect to IHD and with respect to mortality in general (see Table 1 for details); b) the fact, that epidemiological and experimental evidence indicate that heavy drinking also seems to be associated with some favourable biomarkers for IHD, such as increased HDL or lower levels of fibrinogen (e.g., [3, 4]), even though heavy drinking is not associated with lower IHD risk [5, 6]; c) the lack of distinguishing irregular and regular heavy drinking in most of the literature [7] and d) whether we find good ways to empirically test the key assumptions of Mendelian randomization analysis [8].
Until we answer the seeming contradictions between results from different types of studies, we should be very cautious in placing too much weight on the IHD effects in policy formulation.
References
1. Holmes MV, Dale CE, Zuccolo L, Silverwood RJ, Guo Y, Ye Z, et al. Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. BMJ. 2014;349:g4164.
2. 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. BMJ. 2011;342:d671.
3. 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. BMJ. 2011;342:d636.
4. Galán I, Valencia-Martín JL, Guallar-Castillón P, Rodríguez-Artalejo F. Alcohol drinking patterns and biomarkers of coronary risk in the Spanish population. Nutr Metab Cardiovasc Dis. 2014;24:189-97.
5. Roerecke M, Rehm J. The cardioprotective association of average alcohol consumption and ischaemic heart disease: a systematic review and meta-analysis. Addiction. 2012;107:1246-60.
6. Roerecke M, Rehm J. Cause-specific mortality risk in alcohol use disorder treatment patients: a systematic review and meta-analysis. Int J Epidemiol. 2014;43:906-19.
7. Gmel G, Kuntsche E, Rehm J. Risky single occasion drinking: bingeing is not bingeing. Addiction. 2011;106:1037-45.
8. Glymour MM. Alcohol and cardiovascular disease. BMJ. 2014;349:g4334.
9. Roerecke M, Rehm J. Irregular heavy drinking occasions and risk of ischemic heart disease: a systematic review and meta-analysis. Am J Epidemiol. 2010;171:633-44.
10. Bagnardi V, Zatonski W, Scotti L, La Vecchia C, Corrao G. Does drinking pattern modify the effect of alcohol on the risk of coronary heart disease? Evidence from a meta-analysis. J Epidemiol Community Health. 2008;62:615-19.
11. Grønbaek M. The positive and negative health effects of alcohol- and the public health implications. J Intern Med. 2009;265:407-20.
12. Di Castelnuovo A, Costanzo S, Donati MB, Iacoviello L, de Gaetano G. Prevention of cardiovascular risk by moderate alcohol consumption: epidemiologic evidence and plausible mechanisms. Intern Emerg Med. 2010;5:291-7.
13. Murray RP, Barnes GE, Ekuma O. Does personality mediate the relation between alcohol consumption and cardiovascular disease morbidity and mortality? Addict Behav. 2005;30:475-88.
14. Naimi T, Xuan Z, Brown D, Saitz R. Confounding and studies of ‘moderate’ alcohol consumption: the case of drinking frequency and implications for Low-Risk Drinking Guidelines. Addiction. 2013;108:1534-43.
15. Grønbaek M. Alcohol and cardiovascular disease--more than one paradox to consider. Type of alcoholic beverage and cardiovascular disease--does it matter? J Cardiovasc Risk. 2003;10:5-10.
16. Klatsky AL. Alcohol and cardiovascular mortality: common sense and scientific truth. J Am Coll Cardiol. 2010;55:1336-8.
17. Poikolainen K, Vahtera J, Virtanen M, Linna A, Kivimäki i M. Alcohol and coronary heart disease risk--is there an unknown confounder? Addiction. 2005;100:1150-57.
18. Ferrence R, Kozlowski LT. Moderate drinking and health: being confounded by confounders. Addiction. 1995;90:485-8.
19. Skog OJ. Public health consequences of the J-curve hypothesis of alcohol problems. Addiction. 1996;91:325-37.
20. Romelsjö A, Branting M, Hallqvist J, Alfredsson L, Hammar N, Leifman A, et al. Abstention, alcohol use and risk of myocardial infarction in men and women taking account of social support and working conditions: the SHEEP case-control study. Addiction. 2003;98:1453-62.
21. Chikritzhs T, Liang W. Fishy curves: a case of bias and confounding? Addiction. 2013;108:1548-49.
22. Chikritzhs T, Fillmore K, Stockwell T. A healthy dose of scepticism: four good reasons to think again about protective effects of alcohol on coronary heart disease. Drug Alcohol Rev. 2009;28:441-44.
23. Grønbaek M. Factors influencing the relation between alcohol and cardiovascular disease. Curr Opin Lipidol. 2006;17:17-21.
24. Naimi TS, Brown DW, Brewer RD, Giles WH, Mensah G, Serdula MK, et al. Cardiovascular risk factors and confounders among nondrinking and moderate-drinking U.S. adults. Am J Prev Med. 2005;28:369-73.
25. Jackson R, Broad J, Connor J, Wells S. Alcohol and ischaemic heart disease: probably no free lunch. Lancet 2005;366:1911-12.
26. Shaper A, Wannamethee G, Walker M. Alcohol and mortality in British men: explaining the U-shaped curve. Lancet. 1988;2:1267-73.
27. Fillmore KM, Stockwell T, Chikritzhs T, Bostrom A, Kerr W. Moderate alcohol use and reduced mortality risk: systematic error in prospective studies and new hypotheses. Ann Epidemiol. 2007;17:S16-S23.
28. Rimm EB, Williams P, Fosher K, Criqui MH, Stampfer MJ. Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors. BMJ. 1999;19:1523-28.
29. Rehm J. On the limitations of observational studies. Addict Res Theory. 2007;15:20-22.
30. McKee M, Britton A. The positive relationship between alcohol and heart disease in Eastern Europe: potential physiological mechanisms. J R Soc Med. 1998;91:402-07.
31. Puddey IB, Rakic V, Dimmitt SB, Beilin LJ. Influence of pattern of drinking on cardiovascular disease and cardiovascular risk factors - a review. Addiction. 1999;94:649-63.
32. George A, Figueredo VM. Alcohol and arrhythmias: a comprehensive review. J Cardiovasc Med. 2010;11:221-28.
33. Norström T, Ramstedt M. Mortality and population drinking: a review of the literature. Drug Alcohol Rev. 2005;24:537-47.
34. Leon DA, Chenet L, Shkolnikov V, Zakharov S, Shapiro J, Rakhmanova G, et al. Huge variation in Russian mortality rates 1984-1994: artefact, alcohol, or what? Lancet. 1997;350:383-88.
35. Gmel G, Rehm J, Frick U. Methodological approaches to conducting pooled cross-sectional time series analysis: the example of the association between all-cause mortality and per capita alcohol consumption for men in 15 European states. Eur Addict Res. 2001;7:128-37.
36. Gmel G, Rehm J, Frick U. Trinkmuster, Pro-Kopf-Konsum von Alkohol und koronare Mortalität. Sucht. 2003;49:95-104.
37. Rehm J, Room R, Monteiro M, Gmel G, Graham K, Rehn N, et al. Alcohol Use. In: Ezzati M, Lopez AD, Rodgers A, et al., eds. Comparative quantification of health risks: global and regional burden of disease attributable to selected major risk factors. Geneva, Switzerland: World Health Organization; 2004. p. 959-1109.
38. Morgenstern H. Ecological studies. In: Rothman K, Greenland S, Lash T, eds. Modern Epidemiology. 3rd Edition.: Lippincott, Williams and Wilkins; 2008. p. 511-31.
39. Morgenstern H. Ecologic studies in epidemiology: concepts, principles, and methods. Annu Rev Public Health. 1995;16:61-81.
40. Davey Smith G. Mendelian randomization for strengthening causal inference in observational studies: application to gene by environment interaction. Perspect Psychol Sci. 2010;5:527-46.
41. Didelez V, Sheehan N. Mendelian randomization as an instrumental variable approach to causal inference. Stat Methods Med Res. 2007;16:309-30.
Competing interests: No conflict of interest declared with respect to this letter. In the past 5 years, unrelated to the work submitted, JR has received honoraria, travel support and grants from Lundbeck. MR reports no financial relationships with commercial interests.