stroke risk lowest if zero alcohol

Another article came out suggesting there was no cardiovascular benefit from moderate alcohol consumption (see alcohol and stroke Lancet2019 in dropbox, or doi.org/10.1016/ S0140-6736(18)32214-1).

Details:

-- 512,715 adults in the prospective China Kadoorie Biobank, from 2004-2008, with recorded alcohol use and other demographics; they chose 10 areas in China that had very different levels of alcohol consumption

    -- people were followed for 10 years, monitoring cardiovascular disease (including ischemic stroke, intracerebral hemorrhage, and myocardial infarction) by linking with morbidity and mortality registries and electronic records

-- 161,498 were genotyped for 2 variants that alter alcohol metabolism (ALDH2-rs671 and ADH1B-rs1229984); rs671 is only in east Asia

    -- both of these variants increase effective acetaldehyde accumulation, creating severe discomfort with drinking, and thereby reducing alcohol intake. The former one (rs671) is the most important in this regard and strongly reduces alcohol intake

    -- male alcohol intake was divided into whether they were homozygous or heterozygous for these variants

    -- and in general, comparing those with the AA variant of rs671 (homozygous for this more severe variant) vs heterozygotes vs normal, there was respectively essentially no alcohol intake (3 g/week), 37 g/week , and 157 g/week; and the proportion of current drinkers (defined as some alcohol use in most weeks in the past year) was 1% vs 16% vs 45%; those with the rs1229984 variant had 98 g/week vs 106 g/week vs 157 g/week of alcohol and current drinkers were 32%, 33%, and 43% respectively (ie, in the latter case, not much difference if homozygous vs heterozygous)

-- no difference in smoking/other self-reported baseline characteristics by the genotypes

-- they compared the reported conventional epidemiology: the individual drinking patterns with the cardiovascular outcomes vs the genotype-predicted mean alcohol intake, which ignored the drinking pattern but compared the different genetic variants, and whether homo vs heterozygous, with the outcomes

-- they effectively used those with genetic variants who drank little or no alcohol as a control group

Results:

-- 33% of men (69,897/210,205) reported drinking alcohol in most weeks (mainly spirits) vs only 2% of women (6245/302,510)

-- by conventional epidemiology, they found the relationship between self-reported alcohol intake had a U-shaped association with the incidence of ischemic stroke (n= 14,930), intracerebral hemorrhage (n= 3496) and acute myocardial infarction (n= 2958)

    -- men who reported drinking 100 g of alcohol per week (1 to 2 drinks per day) had a lower risk for all of these conditions than nondrinkers or heavy drinkers

-- genotype-predicted mean male alcohol intake, which varied from 4 to 256 g per week (0 to 4 drinks per day), did not have any U-shaped association with risk

    --10,470 people in this analysis had a stroke or coronary heart disease

    -- for stroke: there was a continuously positive log-linear association with risk

        -- intracerebral hemorrhage: for 280 g of alcohol per week, 58% increased risk, RR 1.58 (1.36-1.84) p <0.0001)

        -- ischemic stroke, 27% increased risk, RR 1.27 (1.13-1.43), p=0.0001

    -- myocardial infarction: no significant association with risk, RR 0.96 (0.78-1.18), p=0.69

-- for women, few drank and none of these associations held. For men only, the surrogate markers of systolic blood pressure or HDL levels were associated with drinking (ie, these findings support the direct effect of alcohol on these nonclinical outcomes in men)

Commentary:

-- over the years there’ve been many article suggesting that there’s a lower incidence of stroke and myocardial infarction in those with moderate alcohol intake (1 to 2 drinks a day). There have been several studies questioning this, suggesting that this represents reverse causality: those abstaining or drinking small amounts of alcohol may be doing so because they are sicker, and that that is the reason there is higher mortality in this group. In particular, some studies have found that former drinkers may be at even higher risk. See http://gmodestmedblogs.blogspot.com/2015/02/moderate-alcohol-and-cardioprotection.html

 --mendelian randomization is a technique that tends to eliminate reverse causation. Basically it assumes that genetic variants are distributed randomly in the population (ie one does not choose one's mate by their genetic SNPs...), so that a variant that is associated with a significant difference in some attribute (eg, drinking) can be compared with a desired outcome (eg cardiovascular disease), and mimic the undoable study of having some group randomized to no drinking and another to drinking various amounts of alcohol and looking at outcomes 10 years from now (ie, mendelian randomization acts like a quick and doable RCT-type analysis). The assumptions include: the genetic variants are well-categorized, they are specific to the condition (ie, the variant does not affect both blood pressure as well as tendency to drink, both of which could affect the outcome), or that the variant is not linked to other unmeasured but causal variants

--of interest, there was a U-shaped curve with stroke incidence in the conventional epidemiology group, with higher incidence in non-drinkers and especially so in ex-drinkers, though the U-shaped curve did persist when excluding ex-smokers and those who self-reported poor health. But there was no relationship in the genetic analysis, no evidence of a protective effect of moderate alcohol (ie: “stroke risk increased steadily across the whole range of genotype-predicted mean male alcohol intake (4-256 g/week)”

--there was still a significant U-shaped curve for cardiac outcomes in the conventional epidemiology group, but there was no statistically significant relationship in the genetic analysis. other studies have found a more profound effect of alcohol on strokes (esp hemorrhagic) than heart disease, and the incidence of acute MIs in the Chinese study above was relatively low, perhaps explaining at least part of the lack of statistical association in the genetic analysis

 -- both the conventional and the genetic analyses came to the same conclusion that 280g of alcohol/week was associated with about 5 mmHg increase in systolic blood pressure, and is associated with a 15% increase ischemic heart disease and ischemic stroke, and a 30% increase in intracerebral hemorrhage

--in the genetic analysis, the excess risks of ischemic stroke and intracerebral hemorrhage were 27% and 58% per 280 g alcohol/week, suggesting that alcohol was responsible for 8% of all ischemic strokes and 16% of intracerebral hemorrhages. And this is twice as much as would be expected just by the increases in systolic blood pressure

--limitations of this study include the accuracy of self-reported alcohol intake, and the fact that drinking patterns are variable and change over time. Also most drinkers had spirits and not wine, so not able to extrapolate these findings to wine drinkers. And these genetic variants are not really so specific; they are involved in many biochemical pathways and changes in those other pathways could have other physiological effects and perhaps interfere some with their conclusions.

So, this study also suggests that there really is no protective effect of moderate alcohol drinking in for risk of stroke or heart disease. other mandelian randomization studies (eg, see alcohol mandelian randomization addiction2015 in dropbox, or doi:10.1111/add.12828) and some that excluded former drinkers in the non-drinker category have come to similar conclusions. The bottom line is that we clinicians should try to debunk the popular perception that moderate alcohol is beneficial, and instead focus on its clear toxic effects (cancer risk, cirrhosis, and the myriad of bad social outcomes)

http://gmodestmedblogs.blogspot.com/2018/10/alcohol-as-leading-risk-facor-for-death.html highlights alcohol as the leading risk factor for death in those 15-49 yo

http://gmodestmedblogs.blogspot.com/2019/04/a-bottle-of-wine-week-and-cancer-risk.html mathematically models wine consumption, suggesting that 1 bottle of wine a week has the same cancer risk as smoking 5-10 cigarettes a week

http://gmodestmedblogs.blogspot.com/2019/05/increasing-alcoholic-liver-disease.html noted the increasing incidence of alcoholic liver disease

http://gmodestmedblogs.blogspot.com/2014/08/alcohol-consumption-and-atrial.html prospectively associated the level of alcohol consumption with atrial fibrillation

geoff

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