CONTINUING MEDICAL EDUCATION

“What Are the Effects of Moderate Drinking on Stroke Risk?”

Pembimbing:
dr. Wahyu Djatmiko, Sp.PD (K)HOM

Disusun oleh:
Bunga Octavia 1820221112

UNIVERSITAS PEMBANGUNAN NASIONAL “VETERAN” JAKARTA

FAKULTAS KEDOKTERAN
SMF ILMU PENYAKIT DALAM
RSUD PROF. DR. MARGONO SOEKARJO
PURWOKERTO
2019
 LEMBAR PENGESAHAN

CONTINUING MEDICAL EDUCATION

“What Are the Effects of Moderate Drinking on Stroke Risk?”

Disusun Oleh:
Bunga Octavia 1820221112

Diajukan untuk memenuhi syarat mengikuti Kepaniteraan Klinik di bagian

Ilmu Penyakit Dalam RSUD Prof. Dr. Margono Soekarjo

Telah disetujui dan dipresentasikan

Pada tanggal : Juni 2019

Dokter Pembimbing:

dr. Wahyu Djatmiko, Sp.PD (K)HOM

Clinical Context

Compared with alcohol abstinence or with heavy drinking, moderate alcohol intake
has been linked to reduced cardiovascular risk in many studies, but whether or not
this association is causal has been unclear. In East Asia, 2 common genetic variants
markedly affect alcohol drinking patterns: the ALDH2-rs671 variant greatly slows
acetaldehyde breakdown, so that alcohol consumption leads to severe discomfort
from acetaldehyde accumulation, which strongly reduces alcohol drinking, and the
ADH1B-rs1229984 variant reduces alcohol drinking to a lesser extent by
accelerating alcohol conversion to acetaldehyde.

Analysis of data from the nationwide China Kadoorie Biobank prospective study
allowed comparison of the findings from conventional epidemiology (classifying
people by self-reported intake) and from genetic epidemiology (using these 2
variants to classify people by genotype-predicted mean alcohol intake). Because
few Chinese women drink, these genetic variants can predict large absolute
differences in mean alcohol intake in men, but not in women. If alcohol itself
substantially affects the incidence of stroke or myocardial infarction, then these 2
genetic variants should affect disease incidence differently in men and in women.

Study Synopsis and Perspective

Blood pressure and stroke risk steadily rise as alcohol intake increases, results from
a large, population-based study show.

In findings that contradict some previous research that suggests moderate drinking
may protect against stroke, an innovative study that compared conventional
epidemiologic analyses and genetic analyses shows this is not the case.

The study included more than 500,000 individuals in China and showed that alcohol
was responsible for approximately 8% of ischemic stroke and 16% of intracerebral
hemorrhage in men.

"There are no protective effects of moderate alcohol intake against stroke. Even
moderate alcohol consumption increases the chances of having a stroke. The
findings for heart attack were less clear-cut, so we plan to collect more evidence,"
study coauthor Zhengming Chen, DPhil, Nuffield Department of Public Health,
University of Oxford, United Kingdom, said in a release.
The study, by Iona Y Millwood, DPhil, from the Medical Research Council
Population Health Research Unit, Nuffield Department of Population Health,
University of Oxford, United Kingdom, was published online April 4 in the
Lancet.[1]

Mixed Findings

"It's always been uncertain whether the apparent protection from moderate alcohol
intake influences stroke and heart attack," study coauthor Richard Peto, FRS,
professor of Medical Statistics and Epidemiology at the Clinical Trial Service Unit
and Epidemiological Studies Unit, Nuffield Department of Population Health, told
Medscape Medical News.

In other words, although results of previous epidemiologic studies were reassuring

for moderate drinkers, such study designs could not completely rule out other
factors lowering the risk for stroke or cardiovascular disease.

One observational study, published in Stroke and reported by Medscape Medical

News at the time,[2] suggested moderate drinking was associated with lower stroke
risk among women in the Nurses' Health Study.

In contrast, researchers conducting another study looked at 600,000 individuals and

found that even moderate drinking may increase mortality risk.[3]

"Moderate alcohol intake has been associated with reduced cardiovascular risk in
many studies, in comparison with abstinence or with heavier drinking," the current
researchers note.

Prospective epidemiologic studies typically yield a U-shaped curve of association

between alcohol intake and stroke risk, where moderate drinking of about 1 to 2
drinks per day is linked to the lowest risk, Sir Peto said. However, these findings
on moderate drinking may be clouded by other, confounding factors.

To get a clearer picture, the investigators prospectively studied 512,715 men and
women from the China Kadoorie Biobank and followed them for about 10 years.

Participants were recruited between June 2004 and July 2008 from 10 diverse rural
and urban areas of China. At baseline, interviewers recorded socioeconomic status,
medical history, smoking, drinking, diet, and physical activity.
Investigators also monitored cardiovascular disease, including ischemic stroke,
intracerebral hemorrhage, and myocardial infarction, by linking morbidity and
mortality registries and electronic hospital records. The cohort's mean age was 52
years.

Genetic Alcohol Intolerance

Based on self-reported current and past drinking patterns, the researchers classified
participants as nondrinkers, occasional drinkers, current drinkers, or ex-drinkers.

The investigators performed both traditional epidemiologic and genetic

epidemiologic analyses, which used Mendelian randomization to detect differences.

A total of 161,498 participants were genotyped for the 2 common genetic variants,
rs671 for the ALDH2 gene and rs1229984 for the ADH1B gene, which together
substantially reduce alcohol intake.

East Asians who feature genotypes associated with these variants can experience
Alcohol Flushing Syndrome. The build-up of the alcohol metabolite acetaldehyde
in this syndrome can cause uncomfortable facial flushing, nausea, and tachycardia.

Among men, these genetic variants caused a 50-fold difference in average alcohol
intake, from near zero to about 4 drinks per day.

"Those affected cannot drink much or don't drink at all," Sir Peto said. In a research
sense, "it's a randomly allocated inability to drink."

Men with these genetic variants drink 10-fold less than unaffected men, Sir Peto
estimated. In addition, women in China drink about 20 times less alcohol than men,
making them an ideal control group to rule out other factors that may reduce, or
increase, stroke risk.

At baseline, 33% (69,897) of men and 2% (6245) of women reported drinking some
alcohol in most weeks, mainly spirits. But there was wide variation in the
prevalence of drinking across geographic areas.
Consistent with previous studies, the conventional analyses in men revealed U-
shaped associations among self-reported alcohol intake, stroke, and myocardial
infarction, with moderate alcohol use associated with the lowest risk.

No U-Curve

However, the genetic analyses showed that among men who drank an average of 4
drinks per day, the relative risk for ischemic stroke was 1.27 (95% confidence
interval [CI], 1.13-1.43; P=.0001), 1.58 for intracerebral hemorrhage (95% CI,
1.36-1.84; P<.0001), and 1.38 for total stroke (95% CI, 1.26-1.51; P<.0001).

Consuming about 4 drinks daily also was also associated with a mean systolic blood
pressure increase of 4.3 mm Hg in the genetic analyses.

The mean intake of alcohol in all men was about 100 g per week. The relative risk
for ischemic stroke at this consumption level was 1.09 (95% CI, 1.04-1.14). The
relative risk for intracerebral hemorrhage was 1.18 (95% CI, 1.12-1.24), and for
total stroke it was 1.12 (95% CI, 1.09-1.16). Adjusting for potential confounders
did not significantly alter the results.

Among men, both conventional and genetic analyses showed that increasing
alcohol intake was associated with elevated blood pressure, concentrations of high-
density lipoprotein cholesterol, and γ-glutamyl transferase, a serum marker for
alcohol-related liver disease (all P<.0001).

The genetic findings suggest the "apparently protective effects of moderate alcohol
intake against stroke are not mainly caused by alcohol itself, and are largely artifacts
of reverse causation and confounding," the researchers note.

Because participants reported drinking mainly spirits, the effects of other drinks,
such as red wine, could not be evaluated.

In terms of future research, the investigators would like to conduct a study with a
larger cohort and longer follow-up that combines findings from their group and
others, said Sir Peto.

"What we would really like to do is answer the question about heart attacks. It's not
as easy, however, because they experience more stroke in China, Korea, and Japan
than heart attacks," he added.
More Research Warranted

In an accompanying editorial, Shiu Lun Au Yeung, PhD, and Tai Hing Lam, MD,
praised the study for its prospective design.[4]

The authors "showed that, at least for stroke, the apparently protective effects of
moderate alcohol consumption were largely non-causal using [M]endelian
randomisation, which is the optimal non-experimental design to minimise
confounding,"

Future research comparing alcohol consumption and abstinence should take the
time-varying nature of alcohol use into account and incorporate longer-term follow-
up, added Dr Yeung and Dr Lam, who are both affiliated with School of Public
Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong
Kong Special Administrative Region, China.

More information on the potential benefits of quitting alcohol for people at different
consumption levels would be "ethical, informative, and warranted," they add.

In terms of addressing alcohol-attributable diseases on a global scale, the

editorialists call for a global initiative to address alcohol use similar to the
successful World Health Organization Framework Convention on Tobacco Control.

"The lag between the peak of alcohol prevalence and alcohol-induced diseases,
which could be several decades, might confuse policy makers, and be used by the
alcohol industry and related interests to argue against more stringent control
measures by claiming that moderate drinkers should not be deprived of the
supposed health benefits. We need to learn from tobacco control and unite to
advocate for a [Framework Convention for Alcohol Control]," they write.

Professor Sir Peto and some coauthors report receiving grants from the Hong Kong
Kadoorie Charitable Foundation, Wellcome Trust, UK Medical Research Council,
GlaxoSmithKline, the British Heart Foundation, and Cancer Research UK during
the conduct of the study. Dr Yeung and Dr Lam have disclosed no relevant financial
relationships.

Lancet. Published online April 4, 2019.

 Study Highlights

 Between June 25, 2004, and July 15, 2008, 512,715 adults, mean age 52 years, from
10 diverse rural and urban areas of China were enrolled in the prospective China
Kadoorie Biobank and provided information about alcohol use, socioeconomic
status, medical history, smoking, diet, and physical activity.
 During follow-up for about 10 years, until January 1, 2017, linkage with morbidity
and mortality registries and electronic hospital records allowed determination of
incident cardiovascular disease, including ischemic stroke, intracerebral
hemorrhage, and myocardial infarction.
 A subset of 161,498 participants underwent genotyping for ALDH2-rs671 and
ADH1B-rs1229984, 2 variants that alter alcohol metabolism.
 Relative risks (RRs) associating cardiovascular disease incidence with self-reported
drinking patterns (conventional epidemiology) or with genotype-predicted mean
alcohol intake in men (genetic epidemiology Mendelian randomization) were
determined from adjusted Cox regression.
 Stratification by study area controlled for variation between areas in disease rates
and in genotype-predicted alcohol intake.
 Alcohol intake differed markedly across the 10 study areas, mostly because of
cultural rather than genetic reasons.
 One third (33%; 69,897/210,205) of men reported drinking alcohol in most weeks,
mostly spirits, as did only 2% (6245/302,510) of women.
 All possible combinations of genotype and study area were grouped into 6
categories according to mean male alcohol intake.
 Among men, these 6 categories varied widely in mean intake, from almost no
alcohol to a mean of ~25 drinks per week, whereas mean alcohol intake was low
among women in all 6 categories.
 Using conventional epidemiology in men, self-reported alcohol intake had U-
shaped associations with incidence of ischemic stroke (n=14,930), intracerebral
hemorrhage (n=3496), and acute myocardial infarction (n=2958).
 Compared with abstainers or heavier drinkers, men who reported drinking about
100 g of alcohol per week (1-2 drinks/day) had lower risks for all 3 diseases.
 Genotype-predicted mean male alcohol intake varied widely, from 4 to 256 g per
week (near zero to ~4 drinks/day), but had no U-shaped associations with risk.
 Genotype-predicted mean alcohol intake had a continuously positive log-linear
association with stroke risk, particularly for intracerebral hemorrhage (RR for 280
g/week [~4 drinks/day], 1.58; 95% CI, 1.36-1.84; P<.0001), more so than for
ischemic stroke (RR, 1.27; 95% CI, 1.13-1.43; P=.0001).
 Even at ~100 g/week, which was the mean intake of alcohol among men, RR was
1.09 (95% CI, 1.04-1.14) for ischemic stroke, 1.18 (95% CI, 1.12-1.24) for
intracerebral hemorrhage, and 1.12 (95% CI, 1.09-1.16) for total stroke.
 Adjustment for potential confounders did not significantly affect the findings.
 In contrast, genotype-predicted mean alcohol intake was not significantly
associated with risk for myocardial infarction.
 Reported usual alcohol intake in current drinkers and genotype-predicted alcohol
intake in all men were similarly and strongly directly associated with systolic blood
pressure and concentrations of HDL cholesterol and γ-glutamyl transferase, a serum
marker for alcohol-related liver damage (each P<.0001).
 Drinking ~4 drinks daily was associated with a mean systolic blood pressure
increase of 4.3 mm Hg in the genetic analyses.
 Few women drank, and the studied genetic variants did not predict high mean
alcohol intake and were not significantly associated with blood pressure, stroke, or
myocardial infarction.
 On the basis of their genetic epidemiology findings, the investigators concluded
that the apparently protective effects of moderate alcohol intake against stroke are
largely noncausal.
 Alcohol drinking uniformly increases blood pressure and stroke risk in a dose-
dependent fashion, with little net effect on myocardial infarction risk in this study
population.
 The findings in women primarily showed that alcohol, rather than any other effects
of genotype, mediated the genotypic findings in men.
 Genotypic studies in China can provide generally relevant evidence about causal
effects of alcohol intake.
 However, populations of European descent have only the rs1229984 variant, which
is less important, so genetic studies cannot directly compare the effects of negligible
and moderate alcohol intake levels.
 A meta-analysis of findings from conventional epidemiological analyses of
prospective studies conducted mostly in populations of European descent excluded
nondrinkers and showed that, among drinkers, stroke incidence increased steadily
with the amount of alcohol consumed.
 Alcohol increases blood pressure and high-density lipoprotein cholesterol; in this
study, 280 g per week of alcohol increased systolic blood pressure by approximately
5 mm Hg, which translates to increases of approximately 15% for ischemic heart
disease and ischemic stroke, and of approximately 30% for intracerebral
hemorrhage.
 In the present study, alcohol was responsible for approximately 8% of ischemic
stroke and 16% of intracerebral hemorrhage in men.
 The genetic epidemiological comparisons across 6 categories of alcohol intake
showed that risk increased continuously across the whole range, from negligible to
high genotype-predicted mean intake.
 There was no excess risk in the category of lowest intake, in which two-thirds of
individuals drank no alcohol and most others drank only occasionally.
 The positive association of stroke risk with genetically predicted mean alcohol
intake was comparable to that with usual alcohol intake among current drinkers.
 These findings contradict the hypothesis that, in comparison with abstinence,
moderate drinking is protective, and indicate that the lower stroke risks in moderate
drinkers than in nondrinkers that were suggested by conventional epidemiological
analyses were not mainly caused by protective effects of moderate drinking, but
rather reflected biases of reverse causation or confounding.
 Study limitations include uncertain alcohol exposure, as drinking patterns are
variable and intake may be underreported, alcohol intake was mostly limited to
spirits rather than wine or other drinks, and possible failure of measured biomarkers
to capture some important mechanisms by which alcohol could affect myocardial
infarction risk.
 An accompanying editorial agreed that at least for stroke, the apparently protective
effects of moderate alcohol drinking were largely noncausal, using Mendelian
randomization, which is the optimal nonexperimental design to reduce
confounding.
 The editorial recommends that future research examine the time-varying nature of
alcohol use and have longer-term follow-up to help determine the potential benefits
of stopping alcohol use for people at different levels of drinking.
 In addition, the editorial calls for a global initiative regarding alcohol drinking,
modeled on the World Health Organization Framework Convention on Tobacco
Control.

Clinical Implications

 Alcohol intake was linked to increased blood pressure and stroke risk in a dose-
dependent fashion, with little net effect on risk for myocardial infarction, in a large,
prospective Chinese population-based study using genetic epidemiology as well as
conventional ewww.amapidemiology analysis.
 The genetic epidemiology findings suggest that the apparently protective effects of
moderate alcohol intake against stroke, reported in previous studies, are largely
noncausal and likely reflect biases of reverse causation or confounding.
 Implications for the Healthcare Team: An accompanying editorial calls for a global
initiative regarding alcohol drinking, modeled on the World Health Organization
Framework Convention on Tobacco Control.