Alcohol and Immediate Risk of Cardiovascular Events
A Systematic Review and Dose–Response Meta-Analysis
Elizabeth Mostofsky, ScD; Harpreet S. Chahal, BMSc; Kenneth J. Mukamal, MD, MPH;
Eric B. Rimm, ScD; Murray A. Mittleman, MD, DrPH
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Background—Although considerable research describes the cardiovascular effects of habitual moderate and heavy alcohol
consumption, the immediate risks following alcohol intake have not been well characterized. Based on its physiological
effects, alcohol may have markedly different effects on immediate and long-term risk.
Methods and Results—We searched CINAHL, Embase, and PubMed from inception to March 12, 2015, supplemented with
manual screening for observational studies assessing the association between alcohol intake and cardiovascular events
in the following hours and days. We calculated pooled relative risks and 95% confidence intervals for the association
between alcohol intake and myocardial infarction, ischemic stroke, and hemorrhagic stroke using DerSimonian and Laird
random-effects models to model any alcohol intake or dose–response relationships of alcohol intake and cardiovascular
events. Among 1056 citations and 37 full-text articles reviewed, 23 studies (29 457 participants) were included. Moderate
alcohol consumption was associated with an immediately higher cardiovascular risk that was attenuated after 24 hours,
and even protective for myocardial infarction and hemorrhagic stroke (≈2–4 drinks: relative risk=30% lower risk) and
protective against ischemic stroke within 1 week (≈6 drinks: 19% lower risk). In contrast, heavy alcohol drinking was
associated with higher cardiovascular risk in the following day (≈6–9 drinks: relative risk=1.3–2.3) and week (≈19–30
drinks: relative risk=2.25–6.2).
Conclusions—There appears to be a consistent finding of an immediately higher cardiovascular risk following any alcohol
consumption, but, by 24 hours, only heavy alcohol intake conferred continued risk. (Circulation. 2016;133:979-987.
DOI: 10.1161/CIRCULATIONAHA.115.019743.)
Key Words: alcohol drinking ◼ cardiovascular diseases ◼ dose-response relationship, drug ◼ epidemiology
◼ meta-analysis
I
t is well-recognized that moderate alcohol intake has longterm cardiovascular benefits, but even protective exposures
can lead to acutely increased risk. Alcohol has biphasic and
complex physiological effects that result in both higher and
lower cardiovascular risk depending on the amount consumed,
drinking frequency, and the outcome under study.1,2 For
instance, moderate and high alcohol intake is associated with
increased heart rate,3 electromechanical delay,4 and impaired
fibrinolysis5 within hours of intake, but there are long-term
improvements in blood pressure6 and coagulation.7 In addition, the risk of cardiovascular events triggered by alcohol
may be modified by usual drinking patterns.1 There has been
no comprehensive study to investigate the acute cardiovascular risk following alcohol intake. Therefore, we conducted
a systematic review and dose–response meta-analysis of the
evidence on the risk of myocardial infarction (MI), ischemic
stroke (IS), and hemorrhagic stroke (HS) in the hours and days
after alcohol intake. The primary hypothesis defined before
initiation of the literature review was that, in comparison with
no alcohol consumption, moderate alcohol consumption is
associated with an immediately higher risk of cardiovascular
events that becomes protective after 24 hours, whereas heavy
alcohol drinking is associated with higher cardiovascular risk
both immediately and in the following days.
Clinical Perspective on p 987
Methods
We performed a systematic review, meta-analysis, and dose–response
meta-analysis in accordance with the Meta-Analysis of Observational
Received October 2, 2015; accepted January 19, 2016.
From Cardiovascular Epidemiology Research Unit, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (E.M., H.S.C.,
M.A.M.); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA (E.M., E.B.R., M.A.M.); Department of Epidemiology
and Biostatistics, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada (H.S.C.); Division of General Medicine and Primary
Care, Beth Israel Deaconess Medical Center, Boston, MA (K.J.M.); Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA
(E.B.R.); and Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston,
MA (E.B.R.).
Guest Editor for this article was Mercedes R. Carnethon, PhD.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.
115.019743/-/DC1.
Correspondence to Elizabeth Mostofsky, ScD, Harvard T.H. Chan School of Public Health, Kresge Bldg Rm 505B, 677 Huntington Ave, Boston MA
02115. E-mail [email protected]
© 2016 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.115.019743
979
980 Circulation March 8, 2016
Studies in Epidemiology8 protocol throughout the design, implementation, analysis, and reporting for this study.
Data Sources and Searches
One person (Dr Mostofsky) performed a literature search of the
CINAHL, Embase, and PubMed databases from January 1966
through March 2015 by using free-text words and Medical Subject
Headings terms without language restrictions. We also reviewed the
reference lists of retrieved articles.
Study Selection
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Using a standardized form, 2 readers (Dr Mostofsky and Mr Chahal)
independently and in duplicate reviewed the list of identified articles
and extracted data from selected articles with disagreements adjudicated by consensus. We selected studies with abstracts suggesting
they were relevant. Studies were eligible for review if: (1) the design
was a cohort, case-control, self-controlled case series or case-crossover study; (2) the investigators reported relative risks (RRs) and
95% confidence intervals (CIs) for the association between alcohol
intake and MI, IS, or HS; (3) the investigators retrospectively evaluated alcohol intake directly from the participant or by proxy for the
1-week period before event onset. We excluded studies that evaluated
the impact of laboratory-administered alcohol on myocardial ischemia, arrhythmia, atrial fibrillation, or intermediate outcomes such as
blood pressure or cardiovascular reactivity.
Data Extraction and Quality Assessment
For each study, we recorded the following details: first author, year of
publication, study location, hazard period, referent period or sample,
number of cases and noncases at each level of alcohol intake, amount
of alcohol consumed before event onset, RRs and corresponding 95%
CIs, and covariates included in statistical models. When analyses of
the same population were reported more than once, we included the
largest study for the appropriate analysis. In case-control studies,
cases and noncases were interviewed about recent alcohol consumption, and potential confounding by between-person differences were
addressed with matching and statistical adjustment. In case-crossover
studies, each case was interviewed about recent alcohol intake and
that same individual’s alcohol intake at other times. By comparing the
same individual at different times, confounding by fixed characteristics is eliminated. When case-crossover studies reported estimates
using either a referent of usual frequency of alcohol intake over several months or a referent of intake at the same time on the previous
day, we included the estimates based on usual frequency. When studies reported estimates from several models, we included the estimates
from the model with the greatest control for potential confounding.
We also recorded information on whether the study was restricted to
incident events, whether both fatal and nonfatal events were included,
and whether the study was restricted to current drinkers.
We qualitatively assessed study quality by recording the timing
between the onset of the cardiovascular event and ascertainment of
alcohol intake, whether alcohol intake was assessed with an interview
or questionnaire and whether proxy respondents provided information on alcohol intake.
Data Synthesis and Analysis
Details of the meta-analysis methods are provided in the online-only
Data Supplement Appendix and are summarized briefly here.
Meta-Analysis of Any Alcohol Intake
For each outcome and hazard period, we included 1 RR and corresponding 95% CI per study reporting the change in cardiovascular
risk immediately following any alcohol intake in comparison with
no alcohol intake. For studies that did not report an overall RR, we
first pooled the RRs across sex and levels of alcohol consumption
by using a random-effects model. We used DerSimonian and Laird9
random-effects models to pool the RRs across studies for each outcome and each hazard period.
Dose–Response Meta-Analysis
To examine the impact of the amount of alcohol consumed prior to
event onset, we conducted a dose–response meta-analysis for each
outcome and the risk in the day and week following intake. For each
study, we assigned the median or mean grams of alcohol intake for
each exposure level to the corresponding RR. To examine potential
nonlinear relationships between alcohol intake and cardiovascular
risk, we performed 2-stage random-effects dose–response meta-analyses.10 We estimated the predicted relative risk by comparing specific
levels of alcohol intake with no alcohol intake based on the linear or
model or spline transformation, as appropriate.
For the analyses of any intake and the dose–response analyses,
we evaluated heterogeneity across studies with the Cochrane Q χ2
test11 and we calculated the I2 statistic to quantify the proportion of
between-study heterogeneity attributable to variability in the association rather than sampling variation.12
Statistical analyses were conducted with 2-tailed α set at ≤0.05
for statistical significance. We used Stata (version 13.0, StataCorp,
College Station, TX) packages to conduct the meta-analyses of any
alcohol intake (metan), dose–response analyses (glst), and evaluation of potential publication bias (metabias) and information bias
(metainf).
Results
The literature search identified 1056 publications. We
excluded 411 duplicates, and 623 articles were excluded after
review of the title or abstract. An additional 15 articles were
identified from manual searches and review of bibliographies
of relevant studies. After reviewing the articles, another 14
articles were excluded, resulting in a meta-analysis of 23 articles (Figure 1). The Table in the online-only Data Supplement
summarizes the characteristics of the eligible studies. The
meta-analysis included 16 case-control and 7 case-crossover
studies published from 1987 to 2015. Combined, there were
29 457 participants including 17 966 cases of MI, 2599 cases
of IS, and 1262 cases of HS. Eleven studies were conducted in
Europe, 1 in Russia, 4 in the United States, 2 in New Zealand,
and 4 in Australia; 1 study included participants from 52
countries worldwide. Two studies included men only, one
included women only, and the remaining 20 studies enrolled
men and women, but only 6 presented sex-specific estimates,
with one reporting an infinite RR for women, so we included
the estimate combining all participants. Fourteen studies
were restricted to incident events. Alcohol consumption was
assessed with a questionnaire in 3 studies and with interviews
in all others. In 10 studies, the estimated median alcohol consumption in the highest category was >4 drinks per day for
men and women combined or for men but not women.
Figure 2 presents a forest plot of RRs and 95% CIs and
heterogeneity statistics for analyses of any alcohol intake,
Figure 3 presents a forest plot of dose-specific data with RRs
and 95% CIs in Figure I in the online-only Data Supplement,
and Figure 4 presents splines, heterogeneity statistics, and P
values for the dose–response analyses.
Myocardial Infarction
One study13 reported a higher risk of sudden cardiac death
within 2 hours after alcohol consumption (RR, 3.00; 95% CI,
1.61–5.68), but we did not include this estimate in our analyses because the cause of death may have been attributable to
cardiomyopathy or arrhythmias. Five case-crossover14–18 and
4 case-control studies19–22 evaluated the association between
Mostofsky et al Alcohol as a Cardiovascular Trigger 981
Figure 1. Selection of studies published
from 1966 to 2015 with information on
any recent alcohol intake or a specific
dose of recent alcohol intake included in
a meta-analysis of alcohol consumption
and risk of cardiovascular events. *One
study included data on myocardial
infarction and hemorrhagic stroke, and 1
study included data on ischemic stroke
and hemorrhagic stroke. RR indicates
relative risk.
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
alcohol intake and the immediate risk of MI or major coronary
event.20 There was a higher MI risk in the hour after alcohol
intake than at other times and a modestly lower risk after 24
hours. Two studies assessed MI risk within 1 week among
men, with one21 reporting a lower MI risk (RR, 0.25; 95%
CI, 0.13–0.50) after ≈18 g of alcohol in the past week and the
other22 reporting higher risk of death from ischemic heart disease or MI after heavy alcohol intoxication for ≥2 days when
the person is withdrawn from normal social life (RR, 3.57;
95% CI, 1.65–7.73).
When accounting for the amount of alcohol consumed in
the 24 hours before MI onset, there was a U-shaped association (Pcurve<0.001) between alcohol intake and MI risk, with
the greatest benefit following ≈28 g of alcohol (≈2 drinks) in 1
day (RR, 0.67) and a higher risk following ≈108 g (≈9 drinks)
in 1 day (RR, 1.59). Within a week following alcohol consumption, there was a lower risk of MI with moderate alcohol
intake but a higher risk following heavy alcohol consumption.
There was no indication of small-study effects for studies of MI risk in the day (Egger P=0.18) and week (Egger
P=0.86) following alcohol consumption. Results were similar
in sensitivity analyses excluding 1 estimate at a time.
Ischemic Stroke
One case-crossover23 and 8 case-control studies24–31 examined
the association between alcohol intake and the immediate risk
of IS. One study27 with RRs by level of alcohol intake could
not be included in the dose–response meta-analysis because
information on the sample size at each level of consumption
was not reported. There was evidence of a higher IS risk within
an hour of any alcohol intake, and a suggestion of protective
benefits thereafter, although the results were inconsistent.
In the dose–response analysis, there was a higher IS risk
with higher alcohol intake in the preceding day, although this
linear association was only based on 2 studies with dose information. There was a U-shaped association (Pcurve=0.007) for
risk in the following week. In comparison with no alcohol
consumption, there was a 19% lower risk of IS in the week
following ≈75 g of alcohol (≈6 drinks/wk) but a 2.25-fold
higher IS risk in the week following 225 g (≈19 drinks) that
continues to climb with higher amounts of alcohol consumption. The dose–response association was apparent for both
men and for women. There was no indication of publication
bias (Egger P=0.39). In sensitivity analyses excluding 1 study
at a time, the RR for IS within 1 day was lower (RR, 0.82;
95% CI, 0.66–1.01) when we removed 1 study’s results29 and
higher (RR, 1.08; 95% CI, 0.74–1.60) when we removed the
estimate from another study,18 but a similar sensitivity analysis
had no impact on the RR for IS risk within a week.
In sensitivity analyses, we included estimates from
case-control studies that did not account for confounders.24,32,33 The estimated risk in 24 hours was similar to the
preliminary analysis. Five studies26,32,34–36 enrolled cases with
either IS or HS, but after restricting the analyses to studies
that accounted for potential confounders and at least some
exposed cases and controls, only 1 study26 with a combined
end point was included. Because the study was composed of
81 cases of IS and only 9 cases of HS, the RR was included
in the analysis of IS risk; results were similar when this estimate was excluded.
982 Circulation March 8, 2016
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Figure 2. Forest plot of relative risks (RRs) and 95% confidence intervals (CIs) for the association between any alcohol consumption
relative to no drinking. Squares indicate study-specific RR estimates, with the size of the square reflecting the proportion of the
DerSimonian and Laird weights under study; horizontal lines indicate the 95% CI; diamonds indicate the pooled RRs with their 95% CI
from a random-effects model. The dotted line indicates the value for no association. *Also included in dose–response meta-analysis. MI
indicates myocardial infarction.
Hemorrhagic Stroke
One case-crossover37 and 6 case-control studies22,27,38–41 examined the immediate risk of HS following alcohol intake, with
most studies reporting a higher risk within a day or a week
after any consumption.
In the dose–response meta-analysis, there was a U-shaped
association (Pcurve=0.02) between alcohol consumption and HS
risk after 24 hours. In comparison with no intake, consumption of 48 g (≈4 drinks) was associated with a 38% lower HS
risk, whereas drinking 81 g (≈7 drinks) was associated with a
1.26-fold higher HS risk in the following day. This association
was apparent for both men and women. There was a linear
association for HS risk within a week of alcohol consumption,
with no evidence of protective benefits.
There was no indication of publication bias for studies of
HS risk in the day (Egger P=0.25) and week (Egger’s P=0.19)
following any alcohol intake. Results were similar in sensitivity analyses excluding 1 estimate at a time.
Discussion
In this systematic review and meta-analysis, moderate alcohol
consumption was associated with an immediately higher risk
of cardiovascular events, but, after 24 hours, there was a lower
risk of MI and HS and, after 1 week, there was a lower risk of
IS, consistent with previous research showing cardiovascular
benefits of habitual intake. Heavy alcohol drinking was associated with higher cardiovascular risk in the following hours
and days.
Immediately following alcohol intake, there are both
harmful and protective physiological responses.7 Within 1 to
3 hours, a single dose of alcohol increases heart rate,3 interarterial electromechanical delay,4 and plasminogen activator
Mostofsky et al Alcohol as a Cardiovascular Trigger 983
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Figure 3. Forest plot of relative risks (RRs) and 95% confidence intervals (CIs) for the association between alcohol consumption and
cardiovascular events in the following day and week by amount of alcohol intake. Squares indicate study-specific RR estimates, with the
size of the square reflecting the proportion of the DerSimonian and Laird weights under study; horizontal lines indicate the 95% CI. The
dotted line indicates the value for no association. MI indicates myocardial infarction.
984 Circulation March 8, 2016
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Figure 4. Relative risk (solid line) and 95% confidence interval (dashed lines) for the association between grams of alcohol and risk
of cardiovascular events within 24 hours. Alcohol consumption was modeled with restricted cubic splines in a random-effects dose–
response model. The lowest value of zero (nondrinkers) was used to estimate all relative risks. The vertical axis is on a log scale. The
dotted line indicates the value for no association.
inhibitor levels,5 but by 12 to 24 hours, an alcohol dose consistent with 2 alcoholic beverages causes transient improvements in flow-mediated vasodilatation, endothelial function,7
and fibrinolytic factors.5
Within weeks of regular intake, there are improvements in
inflammatory markers, lipid profile, and adipokines and insulin sensitivity.7 Habitual moderate alcohol consumption (1–2
drinks per day) is associated with improvements in high-density lipoprotein cholesterol, heart rate variability,42 endothelial function, insulin sensitivity, coagulation and fibrinolytic
cascades,7 and a lower risk of cardiovascular disease and IS
and HS.43 However, heavy drinking (3 to ≥4 drinks per day) is
associated with a higher risk of hypertension,6 diabetes mellitus, cardiovascular disease, IS and HS, and mortality after
MI.43–45 Usual drinking habits may modify the acute physiological response to alcohol. Therefore, the 2015 Dietary
Guidelines Advisory Committee recommended that, if alcohol is consumed, it should be consumed in moderation—up
to 1 drink per day for women and 2 drinks per day for men.46
The results of this meta-analysis show that there may also be
an immediate risk of cardiovascular events even if moderate
habitual consumption yields cardioprotective benefits.
Our dose–response analysis suggests that after 24 hours,
moderate drinkers may experience a lower risk of a cardiovascular event in comparison with other times, whereas
heavy drinking is associated with a higher risk even after 24
hours. This is supported by previous work showing that the
health effects of alcohol intake depend on both the amount
and the pattern of consumption. Heavy episodic drinking,
defined as ≥4 alcoholic beverages within 1 to 2 hours, has
harmful effects, even if individuals who binge only drink 1
or 2 days per week, resulting in the same average alcohol
intake per week that is known to yield cardioprotective
benefits. Among men, drinking a small amount of alcohol
regularly (eg, 1–2 drinks/d, 4 days/wk) lowers cardiovascular risk more than drinking the same total weekly amount
but on fewer days per week.1 Therefore, it is possible that
over time, individuals who frequently drink small amounts
of alcohol may experience a temporarily heightened risk, but
this may be offset in part by the subsequent protective benefits in the hours after consumption, whereas consuming large
amounts of alcohol at once may result in a sharply higher
immediate risk, and consuming large amounts of alcohol in
repeated bouts may result in a higher long-term risk, as well.
The results of studies examining a 1-week risk period are
unclear because most studies did not provide information
on the pattern of drinking in the week before the event; it
is possible that some people only drank early in the previous week, some only drank immediately before the event,
and some drank alcohol on several occasions in the previous
week. However, 1 case-control study31 reported that among
women who drank alcohol in the past week, those who drank
in the past 24 hours had a lower risk of stroke than never
drinkers, and the risk was even lower for women who did not
drink in the past 24 hours. This supports our hypothesis that
there may be protective benefits in the 24 hours after moderate alcohol intake, and perhaps the benefits are even greater
in the following days.
The immediate impact of alcohol consumption may be
influenced by usual alcohol intake. One study18 noted that
the higher MI risk in the hour following alcohol consumption was not apparent for daily drinkers. This may be attributable to alcohol tolerance whereby habitual intake leads to
upregulation of enzymes that metabolize alcohol, resulting
Mostofsky et al Alcohol as a Cardiovascular Trigger 985
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
in a lower physiological response to each drink.47 Although
case-crossover studies are restricted to current drinkers
by design because only cases reporting alcohol in the past
year contribute information, only 2 case-control studies10,11
conducted analyses restricted to current drinkers and 6
studies19,20,28,29,31,39 adjusted for usual intake. In the remaining studies, some of the former drinkers may have stopped
drinking alcohol because of illness, previous alcohol abuse,
or prescription medications that cannot be taken with alcohol, which would overestimate the health benefits of alcohol intake.48 It is possible that some people abstained from
alcohol in response to prodromal symptoms before clinical
onset of the cardiovascular event, resulting in an underestimate of recent intake and a biased estimate. However, the
results were similar in studies18,23 that used symptom onset
rather than hospital admission time to define event onset
and when they conducted sensitivity analyses restricted to
cases with no preclinical symptoms. In 1 study,49 the results
were weaker but still evident after accounting for prodromal
symptoms.
Habitual moderate alcohol consumption is associated with
lower risk of heart disease in both sexes, but the amount of
alcohol associated with cardiovascular benefits is lower among
women than among men. Only some of the studies reported
results separately for men and for women, so we could not
statistically evaluate whether sex modifies the magnitude or
timing of heightened acute risk, but higher cardiovascular
risk following higher levels of alcohol intake was apparent
for both men and women. There were no studies that examined whether the immediate risk following alcohol intake was
modified by medical history, but, in studies of habitual alcohol
consumption, the benefits of moderate intake were similar for
people with existing cardiovascular disease or diabetes mellitus and those in the general population.45
Previous studies have reported racial/ethnic differences
in the magnitude of the association between habitual alcohol
consumption and risk of cardiovascular events17,50 that may
involve ethnic variations in the prevalence of genetic polymorphisms related to alcohol metabolism,51 cultural differences
in past drinking, current drinking patterns, and associations
between drinking patterns and other health risk factors and
health problems.52 Future studies are needed to evaluate
whether there is any racial/ethnic variation in the acute effects
of alcohol intake on cardiovascular risk, and whether genetic
differences may play a role.
Only 5 studies18,23,31,37,40 examined the association by drink
type, so we could not evaluate whether the risk differs for
wine, beer, or liquor consumption. In case-crossover studies
of alcohol types and the acute risk of MI18 and IS,23 there was
a suggestion that the acutely elevated risk in the hour after
alcohol consumption was stronger for liquor than for beer or
wine, and the protective association by 24 hours was apparent for beer and wine but not for liquor. Other studies have
reported that within 24 hours of intake, individuals drinking
wine were protected from intracerebral hemorrhage (ICH) and
there was also a lower risk of ICH for those who recently consumed liquor, but there was little association between either
beer or fortified beverages and ICH,40 whereas another study
reported similar risk of ICH by beverage type for the risk of
ICH.37 However, none of the studies simultaneously evaluated
beverage type and drinking patterns. Furthermore, previous
studies have shown that all alcohol types have similar effects
on high-density lipoprotein cholesterol and other biological
markers of cardiovascular risk. Therefore, differences in the
magnitude of the association between different alcohol types
and cardiovascular outcomes are more likely to result from
differences in lifestyle and the frequency and amount of alcohol intake rather than from different physiological effects of a
specific beverage type.1,7,31
Some studies did not report enough details to be
included in our dose–response meta-analysis, and none of
the studies provided information on heavy episodic drinking, defined as 4 drinks for women and 5 drinks for men
consumed within about 2 hours.53 However, our results suggest that moderate alcohol consumption is associated with
an immediately higher risk of cardiovascular events that
is attenuated by 24 hours, whereas heavy alcohol drinking
remains harmful.
We evaluated the influence of the timing and amount
of alcohol on cardiovascular risk, but we could not address
sources of bias in the original studies. However, although
residual and unmeasured confounding cannot be ruled out,
most of the case-control studies accounted for many confounders and the self-matching in case-crossover studies eliminates confounding by slowly varying characteristics. All the
included studies obtained information on alcohol intake after
the cardiovascular event occurred, and alcohol intake may
have been differentially misreported for cases and controls or
in the case-crossover studies, for recent intake in comparison
with usual intake. If recent alcohol intake impacted the cases’
ability or willingness to participate in the study, selection bias
may have led to incorrect estimates, but many studies used
proxy respondents when the case could not provide information. Finally, we did not identify any unpublished studies and
we cannot exclude the possibility that publication bias may
have affected our results, but we found no evidence of such
bias. There was no evidence of small study effects but tests for
funnel plot asymmetry are not recommended when there are
<10 studies. For some of the analyses, we observed betweenstudy heterogeneity and the results were slightly but not
meaningfully altered when removing a single study, although
the magnitude of the change was also impacted by the amount
of alcohol. Although it may be tempting to infer that the heterogeneity in the magnitude of the association between different cardiovascular events is attributable to different biological
mechanisms linking alcohol and the outcome of interest, it
may also be at least partially attributable to differences in the
baseline risk and drinking patterns of the populations under
study. Despite these limitations, this study is the first attempt
to understand comprehensively the interplay between dose
and timing of alcohol intake and the immediate risks and benefits on both MI and stroke.
In summary, our results suggest that alcohol intake is
associated with an immediately higher risk of cardiovascular events, but after 24 hours, there is a lower risk of MI and
HS, and, within 1 week, there is a lower risk of IS, whereas
heavy drinking continues to confer higher risk even after
24 hours.
986 Circulation March 8, 2016
Sources of Funding
Dr Mostofsky received support from the a National Institutes of
Health (grant L30-HL115623-02) and a KL2/Catalyst Medical
Research Investigator Training award (an appointed KL2 award)
from Harvard Catalyst/The Harvard Clinical and Translational
Science Center (National Center for Research Resources and the
National Center for Advancing Translational Sciences, National
Institutes of Health Award KL2 TR001100). The content is solely the
responsibility of the authors and does not necessarily represent the
official views of the European Research Council, Harvard Catalyst,
Harvard University and its affiliated academic healthcare centers, or
the National Institutes of Health. Mr. Chahal received support from
the Frederick Banting and Charles Best Canada Graduate Scholarship
and the Michael Smith Foreign Study Supplement from the Canadian
Institutes of Health Research. No funding organization had any role
in the design and conduct of the study; collection; management, analysis and interpretation of the data; and preparation of the manuscript.
Disclosures
None.
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
References
1. Mukamal KJ, Conigrave KM, Mittleman MA, Camargo CA Jr, Stampfer
MJ, Willett WC, Rimm EB. Roles of drinking pattern and type of alcohol
consumed in coronary heart disease in men. N Engl J Med. 2003;348:109–
118. doi: 10.1056/NEJMoa022095.
2. Whitfield JB, Heath AC, Madden PA, Pergadia ML, Montgomery GW,
Martin NG. Metabolic and biochemical effects of low-to-moderate alcohol consumption. Alcohol Clin Exp Res. 2013;37:575–586. doi: 10.1111/
acer.12015.
3. Spaak J, Merlocco AC, Soleas GJ, Tomlinson G, Morris BL, Picton P,
Notarius CF, Chan CT, Floras JS. Dose-related effects of red wine and
alcohol on hemodynamics, sympathetic nerve activity, and arterial
diameter. Am J Physiol Heart Circ Physiol. 2008;294:H605–H612. doi:
10.1152/ajpheart.01162.2007.
4. Sengul C, Cevik C, Ozveren O, Sunbul A, Oduncu V, Akgun T, Can
MM, Semiz E, Dindar I. Acute alcohol consumption is associated with
increased interatrial electromechanical delay in healthy men. Cardiol J.
2011;18:682–686.
5. Hendriks HF, Veenstra J, Velthuis-te Wierik EJ, Schaafsma G, Kluft C.
Effect of moderate dose of alcohol with evening meal on fibrinolytic factors. BMJ. 1994;308:1003–1006.
6.Briasoulis A, Agarwal V, Messerli FH. Alcohol consumption and the
risk of hypertension in men and women: a systematic review and metaanalysis. J Clin Hypertens (Greenwich). 2012;14:792–798. doi: 10.1111/
jch.12008.
7. 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.
8. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D,
Moher D, Becker BJ, Sipe TA, Thacker SB. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis
Of Observational Studies in Epidemiology (MOOSE) group. JAMA.
2000;283:2008–2012.
9. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin
Trials. 1986;7:177–188.
10. Orsini N, Bellocco R, Greenland S. Generalized least squares for trend
estimation of summarized dose-response data. Stata J. 2006;6:40–57.
11.Cochran W. The combination of estimates from different experiments.
Biometrics. 1954;10:101–129.
12. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in
meta-analyses. BMJ. 2003;327:557–560. doi: 10.1136/bmj.327.7414.557.
13.Selb Semerl J, Selb K. Coffee and alcohol consumption as triggering
factors for sudden cardiac death: case-crossover study. Croat Med J.
2004;45:775–780.
14. Marshall RJ, Wouters S, Jackson RT. A case-crossover analysis of a casecontrol study of alcohol consumption and coronary events: the effects
of exposure definition and the use of control data. J Epidemiol Biostat.
2000;5:367–373.
15. Gerlich MG, Krämer A, Gmel G, Maggiorini M, Lüscher TF, Rickli H,
Kleger GR, Rehm J. Patterns of alcohol consumption and acute myocardial
infarction: a case-crossover analysis. Eur Addict Res. 2009;15:143–149.
doi: 10.1159/000213641.
16.Gerlich MG, Rehm J. Recall bias in case-crossover designs studying
the potential influence of alcohol consumption. J Stud Alcohol Drugs.
2010;71:619; author reply 620–619; author reply 621.
17. Leong DP, Smyth A, Teo KK, McKee M, Rangarajan S, Pais P, Liu L,
Anand SS, Yusuf S; INTERHEART Investigators. Patterns of alcohol consumption and myocardial infarction risk: observations from 52 countries
in the INTERHEART case-control study. Circulation. 2014;130:390–398.
doi: 10.1161/CIRCULATIONAHA.113.007627.
18.Mostofsky E, van der Bom JG, Mukamal KJ, Maclure M, Tofler GH,
Muller JE, Mittleman MA. Risk of myocardial infarction immediately after alcohol consumption. Epidemiology. 2015;26:143–150. doi:
10.1097/EDE.0000000000000227.
19. Jackson R, Scragg R, Beaglehole R. Does recent alcohol consumption
reduce the risk of acute myocardial infarction and coronary death in regular drinkers? Am J Epidemiol. 1992;136:819–824.
20. McElduff P, Dobson AJ. How much alcohol and how often? Population
based case-control study of alcohol consumption and risk of a major coronary event. BMJ. 1997;314:1159–1164.
21.Schröder H, Masabeu A, Marti MJ, Cols M, Lisbona JM, Romagosa
C, Carión T, Vilert E, Marrugat J; REGICOR investigators. Myocardial
infarction and alcohol consumption: a population-based case-control
study. Nutr Metab Cardiovasc Dis. 2007;17:609–615. doi: 10.1016/j.
numecd.2006.04.010.
22. Leon DA, Shkolnikov VM, McKee M, Kiryanov N, Andreev E. Alcohol
increases circulatory disease mortality in Russia: acute and chronic effects
or misattribution of cause? Int J Epidemiol. 2010;39:1279–1290. doi:
10.1093/ije/dyq102.
23.Mostofsky E, Burger MR, Schlaug G, Mukamal KJ, Rosamond
WD, Mittleman MA. Alcohol and acute ischemic stroke onset:
the stroke onset study. Stroke. 2010;41:1845–1849. doi: 10.1161/
STROKEAHA.110.580092.
24. Gorelick PB, Rodin MB, Langenberg P, Hier DB, Costigan J, Gomez I,
Spontak S. Is acute alcohol ingestion a risk factor for ischemic stroke?
Results of a controlled study in middle-aged and elderly stroke patients at
three urban medical centers. Stroke. 1987;18:359–364.
25.Syrjänen J, Valtonen VV, Iivanainen M, Kaste M, Huttunen JK.
Preceding infection as an important risk factor for ischaemic brain
infarction in young and middle aged patients. BMJ. (Clin Res Ed).
1988;296:1156–1160.
26. Shinton R, Sagar G, Beevers G. The relation of alcohol consumption to
cardiovascular risk factors and stroke. The West Birmingham stroke project. J Neurol Neurosurg Psychiatry. 1993;56:458–462.
27. Jamrozik K, Broadhurst RJ, Anderson CS, Stewart-Wynne EG. The role of
lifestyle factors in the etiology of stroke. A population-based case-control
study in Perth, Western Australia. Stroke. 1994;25:51–59.
28.Numminen H, Hillbom M, Juvela S. Platelets, alcohol consump
tion, and onset of brain infarction. J Neurol Neurosurg Psychiatry.
1996;61:376–380.
29.Haapaniemi H, Hillbom M, Juvela S. Lifestyle-associated risk fac
tors for acute brain infarction among persons of working age. Stroke.
1997;28:26–30.
30. You RX, McNeil JJ, O’Malley HM, Davis SM, Thrift AG, Donnan GA.
Risk factors for stroke due to cerebral infarction in young adults. Stroke.
1997;28:1913–1918.
31. Malarcher AM, Giles WH, Croft JB, Wozniak MA, Wityk RJ, Stolley
PD, Stern BJ, Sloan MA, Sherwin R, Price TR, Macko RF, Johnson
CJ, Earley CJ, Buchholz DW, Kittner SJ. Alcohol intake, type of beverage, and the risk of cerebral infarction in young women. Stroke.
2001;32:77–83.
32. Taylor JR, Combs-Orme T. Alcohol and strokes in young adults. Am J
Psychiatry. 1985;142:116–118. doi: 10.1176/ajp.142.1.116.
33. Bråthen G, Brodtkorb E, Sand T, Helde G, Bovim G. Weekday distribution of alcohol consumption in Norway: influence on the occurrence of
epileptic seizures and stroke? Eur J Neurol. 2000;7:413–421.
34.Taylor JR. Alcohol and strokes. N Engl J Med. 1982;306:1111. doi:
10.1056/NEJM198205063061816.
35. Taylor JR, Combs-Orme T, Anderson D, Taylor DA, Koppenol C. Alcohol,
hypertension, and stroke. Alcohol Clin Exp Res. 1984;8:283–286.
36. Gill JS, Zezulka AV, Shipley MJ, Gill SK, Beevers DG. Stroke and alcohol consumption. N Engl J Med. 1986;315:1041–1046. doi: 10.1056/
NEJM198610233151701.
37. Vlak MH, Rinkel GJ, Greebe P, van der Bom JG, Algra A. Trigger factors and their attributable risk for rupture of intracranial aneurysms:
Mostofsky et al Alcohol as a Cardiovascular Trigger 987
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
a case-crossover study. Stroke. 2011;42:1878–1882. doi: 10.1161/
STROKEAHA.110.606558.
38. Juvela S, Hillbom M, Numminen H, Koskinen P. Cigarette smoking and
alcohol consumption as risk factors for aneurysmal subarachnoid hemorrhage. Stroke. 1993;24:639–646.
39. Juvela S, Hillbom M, Palomäki H. Risk factors for spontaneous intracerebral hemorrhage. Stroke. 1995;26:1558–1564.
40. Thrift AG, Donnan GA, McNeil JJ. Heavy drinking, but not moderate
or intermediate drinking, increases the risk of intracerebral hemorrhage.
Epidemiology. 1999;10:307–312.
41. Saloheimo P, Juvela S, Hillbom M. Use of aspirin, epistaxis, and untreated
hypertension as risk factors for primary intracerebral hemorrhage in middle-aged and elderly people. Stroke. 2001;32:399–404.
42. Janszky I, Ericson M, Blom M, Georgiades A, Magnusson JO, Alinagizadeh
H, Ahnve S. Wine drinking is associated with increased heart rate variability in women with coronary heart disease. Heart. 2005;91:314–318. doi:
10.1136/hrt.2004.035105.
43. 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.
44. Pai JK, Mukamal KJ, Rimm EB. Long-term alcohol consumption in relation to all-cause and cardiovascular mortality among survivors of myocardial infarction: the Health Professionals Follow-up Study. Eur Heart J.
2012;33:1598–1605. doi: 10.1093/eurheartj/ehs047.
45.Breslow RA, Mukamal KJ. Measuring the burden–current and future
research trends: results from the NIAAA Expert Panel on Alcohol and
Chronic Disease Epidemiology. Alcohol Res. 2013;35:250–259.
46. United States Dietary Guidelines Advisory Committee. Scientific Report of
the Dietary Guidelines Advisory Committee on the Dietary Guidelines for
Americans to the Secretary of Agriculture and the Secretary of Health and
Human Services. 2015. http://permanent.access.gpo.gov/gpo51700/2015/
Scientific-Report-of-the-2015-Dietary-Guidelines-Advisory-Committee.
pdf. Accessed July 13, 2015.
47. Tabakoff B, Cornell N, Hoffman PL. Alcohol tolerance. Ann Emerg Med.
1986;15:1005–1012.
48. Shaper AG, Wannamethee G, Walker M. Alcohol and mortality in British
men: explaining the U-shaped curve. Lancet. 1988;2:1267–1273.
49. Wouters S, Marshall R, Yee RL, Jackson R. Is the apparent cardioprotective effect of recent alcohol consumption due to confounding by prodromal symptoms? Am J Epidemiol. 2000;151:1189–1193.
50.Mukamal KJ, Chen CM, Rao SR, Breslow RA. Alcohol consumption
and cardiovascular mortality among U.S. adults, 1987 to 2002. J Am Coll
Cardiol. 2010;55:1328–1335. doi: 10.1016/j.jacc.2009.10.056.
51. Han H, Wang H, Yin Z, Jiang H, Fang M, Han J. Association of genetic
polymorphisms in ADH and ALDH2 with risk of coronary artery disease
and myocardial infarction: a meta-analysis. Gene. 2013;526:134–141. doi:
10.1016/j.gene.2013.05.002.
52. Kerr WC, Greenfield TK, Bond J, Ye Y, Rehm J. Racial and ethnic differences in all-cause mortality risk according to alcohol consumption patterns in the national alcohol surveys. Am J Epidemiol. 2011;174:769–778.
doi: 10.1093/aje/kwr147.
53. Wechsler H, Dowdall GW, Davenport A, Rimm EB. A gender-specific
measure of binge drinking among college students. Am J Public Health.
1995;85:982–985.
Clinical Perspective
There is consistent evidence that habitual moderate consumption is associated with a lower risk of coronary heart disease,
whereas heavy alcohol consumption may be harmful. However, the acute risks following alcohol intake have not been well
characterized. Based on its physiological effects, alcohol may have markedly different effects on immediate and long-term
risk. Therefore, we conducted a systematic review and meta-analysis of observational studies that evaluated the association between alcohol intake and myocardial infarction, ischemic stroke, and hemorrhagic stroke in the following hours and
days. Based on data from 23 full-text articles (29 457 participants), moderate alcohol consumption was associated with an
immediately higher cardiovascular risk that was attenuated after 24 hours, and even protective for myocardial infarction and
hemorrhagic stroke, and protective against ischemic stroke within 1 week. In contrast, heavy alcohol drinking was associated
with higher cardiovascular risk in the following day and week.
Alcohol and Immediate Risk of Cardiovascular Events: A Systematic Review and Dose−
Response Meta-Analysis
Elizabeth Mostofsky, Harpreet S. Chahal, Kenneth J. Mukamal, Eric B. Rimm and Murray A.
Mittleman
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Circulation. 2016;133:979-987; originally published online March 2, 2016;
doi: 10.1161/CIRCULATIONAHA.115.019743
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2016 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/133/10/979
Data Supplement (unedited) at:
http://circ.ahajournals.org/content/suppl/2016/02/29/CIRCULATIONAHA.115.019743.DC1
http://circ.ahajournals.org/content/suppl/2016/12/26/CIRCULATIONAHA.115.019743.DC2
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/
SUPPLEMENTAL MATERIAL
Alcohol and immediate risk of cardiovascular events:
A systematic review and dose-response meta-analysis
Data Synthesis and Analysis
Meta-Analysis of Any Alcohol Intake
For each outcome and hazard period, we included one estimate per study. For studies that did
not report an overall estimate, we first pooled the RRs across sex and/or levels of alcohol
consumption by using a random-effects model. We used DerSimonian and Laird1 randomeffects models to pool the RRs across studies for each outcome and each hazard period, and
we generated a forest plot for each analysis, with the studies sworted by publication year.
Because the DerSimonian and Laird methods can underestimate statistical heterogeneity when
heterogeneity is high or few studies are pooled, we conducted sensitivity analyses using the
Profile Likelihood estimation method.2 Results were almost identical between the two methods,
so DerSimonian and Laird results are presented in the text and figures. We conducted
sensitivity analyses to evaluate potential information bias by excluding one study at a time to
assess the influence of individual studies on the pooled estimate. Using the Egger3 test and
visual inspection of funnel plots,3 we explored the possibility of publication bias due to missing
or different estimates from small studies with less precise estimates compared to larger studies
with greater precision. In a sensitivity analysis, we included estimates from case-control studies
that did not account for confounders, and we conducted an analysis restricted to studies with
only IS rather than a combined endpoint of both IS and HS.
Dose-Response Meta-Analysis
To examine the impact of the amount of alcohol consumed prior to event onset, we generated a
forest plot for each analysis, with studies sorted by amount of alcohol. We conducted a doseresponse meta-analysis for each outcome and the risk in the day and week following intake. For
each study, we assigned the median or mean grams of alcohol intake for each exposure level to
the corresponding RR. When the median or mean intake per category was not reported, we
assigned the midpoint of the upper and lower boundaries in each category. When the median
intake for the lowest category was not provided, we assumed a value of zero. If the upper
boundary was not reported, we assigned a value of 1.2 times the lower boundary for that
category, as in previous work.4 When a study used different amounts of intake for men and
women to calculate a single RR, we calculated a weighted average of the median dose
according to the sample sex distribution. When a study reported alcohol consumption in number
of drinks, we converted it to grams assuming that one drink contains 12 grams of alcohol if
standard drink size was not defined.
To examine potential nonlinear relationships between alcohol intake and cardiovascular risk, we
performed 2-stage random-effects dose–response meta-analyses.5_ENREF_8 First, we
constructed study-specific restricted cubic spline models with 3 knots at fixed percentiles (10%;
50%; 90%) of the exposure distribution6 using generalized least square regression that
accounts for the correlation between estimates within each study.7 Second, we combined studyspecific estimates and the variance/covariance matrix using a random-effects model.1 We
conducted a test for the overall significance of the curve by testing the joint impact of the spline
transformations. We examined whether a nonlinear relationship exists by testing the null
hypothesis that the regression coefficients of the spline transformations are all equal to zero.
We did not have sufficient statistical power to formally assess whether the associations were
different for men and women, so we qualitatively assessed whether there were apparent
differences when sex-specific estimates were available.
For the analyses of any intake and the dose-response analyses, we evaluated heterogeneity
across studies with the Cochrane Q χ2 test8 and we calculated the I2 statistic to quantify the
proportion of between-study heterogeneity attributable to variability in the association rather
than sampling variation; values of 25%, 50% and 75% were considered to represent low,
medium and high heterogeneity respectively.9
Supplementary Figure 1 Legend
Forest plot of relative risks (RRs) and 95% confidence intervals (CIs) for the association
between alcohol consumption and cardiovascular events in the following day and week by
amount of alcohol intake. Squares indicate study-specific RR estimates, with the size of the
square reflecting the proportion of the DerSimonian and Laird weights; horizontal lines indicate
the 95% CI. The dotted line indicates the value for no association. The RRs and 95%
confidence intervals for each amount are presented in the column on the right. These values
were used to conduct the dose-response meta-analyses and resulting splines in the Figure 4
that accounts for the covariance among the estimates from a single study.
Supplementary Figure 1
Supplementary Table 1. Characteristics of Studies of Alcohol Consumption and Cardiovascular Events Included in the Meta-Analysis, 1987-2015
Author,
Year
Country
Sample Size
Jackson,
1992
New
Zealand
McElduff,
1997
Age
Sex
Hazard
Periods Adjustments
(Hours)
Design
Outcome
526 cases,
35 - 64 years 70% men,
1183 controls
30% women
Casecontrol
Nonfatal MI and Coronary
Death
24
Matched for age and sex
Adjusted for age, smoking, usual alcohol
consumption
Australia
600 cases,
801 controls
Casecontrol
Nonfatal and Fatal Major
Coronary Event
24
Adjusted for age, smoking, high blood
pressure, high cholesterol concentration,
previous MI, stroke, angina, usual alcohol
consumption
Marshall,
2000
New
Zealand
547 cases,
35 - 74 years 85% men,
1582 controls
15% women
CaseNonfatal MI and Coronary
crossover Death
24
Self-matched
Schröder,
2007
Spain
244 cases,
25 - 74 years 100% men
1270 controls Mean: 51.6
Casecontrol
168
Matched for region
Adjusted for age, smoking, education,
leisure-time activity, total, LDL and HDLcholesterol, DM, hypercholesterolemia drug,
HTN
Gerlich,
2009
Switzerland 250 cases
30 - 88 years 79% men,
Mean: 59.7
21% women
CaseIncident Nonfatal MI
crossover
12
Self-matched
Gerlich,
2010
Switzerland 397 cases
29 - 88 years 79% men,
Mean: 59.7
21% women
CaseIncident Nonfatal MI
crossover
12
Self-matched
25 - 54 years 100% men
Casecontrol
Death from MI, IHD,
Hemorrhagic Stroke
168
Matched by age
Adjusted for education and smoking
24
Self-matched
1,24
Self-matched
35 - 69 years 68% men,
32% women
Nonfatal MI and Coronary
Death
Leon, 2010 Russia
28 cases,
28 controls
Leong, 2014 52
Countries
11,652 cases Mean: 57.5
75% men,
25% women
CaseIncident Nonfatal MI
crossover
Mostofsky,
2015
3,869 cases
Mean: 61.4
68% men,
32% women
CaseNonfatal MI
crossover
17 cases,
17 controls
Mean: 39.5
59% men,
41% women
Casecontrol
United
States
Taylor, 1985 United
States
Ischemic Stroke and
Hemorrhagic Stroke
24
Matched by age, sex, race, day of week
admitted to the hospital
Crude estimate
Hazard
Periods Adjustments
(Hours)
Author,
Year
Country
Sample Size
Age
Sex
Design
Outcome
Gorelick,
1987
United
States
205 cases,
410 controls
43-89 years
Mean: 65.0
66% men,
34% women
Casecontrol
Incident Nonfatal
Ischemic Stroke
Syrjänen,
1988
Finland
54 cases,
54 controls
17-49 years
Mean: 37.8
61% men,
39% women
Casecontrol
Nonfatal Ischemic Stroke
48
Matched for age and sex
Shinton,
1993
England
125 cases,
198 controls
35 - 74 years Not
Median: 64.1 reported
Casecontrol
Nonfatal Ischemic Stroke,
Intracerebral
Hemorrhage,
Subarachnoid
Hemorrhage
168
Matched for age and sex
Jamrozik,
1994
Australia
59 cases,
279 controls
Not
reported
Not
reported
Casecontrol
Nonfatal Ischemic Stroke,
Primary Intracerebral
Hemorrhage
168
Matched for age and sex
Adjusted for tobacco, HTN, DM, stroke or
TIA, MI, adding salt to food, consume
fish>2X/ month
Numminen, Finland
1996
426 cases,
157 controls
Mean: 46.3
68% men,
32% women
Casecontrol
Incident Nonfatal
Ischemic Stroke
168
Adjusted for age, sex, CHD, MI, DM,
hyperlipidemia, atrial fibrillation, heavy
drinking, HTN, current smoking, platelet
count
You, 1997
201 cases,
201 controls
15 - 60 years 60% men,
Mean: 45.4
40% women
Casecontrol
Incident Nonfatal
Ischemic Stroke
24
Matched by neighborhood, age, sex
Adjusted for cigarette smoking, HTN, high
cholesterol, CHD, DM, oral contraceptive,
physical exercise
Haapaniemi, Finland
1997
506 cases,
345 controls
16 - 60 years 71% men,
Mean: 47.9
29% women
Casecontrol
Incident Nonfatal
Ischemic Stroke
Bråthen,
2000
91 cases,
254 controls
Mean: 48.2
Casecontrol
Nonfatal Ischemic Stroke
Australia
Norway
50% men,
50% women
24,72 Matched by age, sex, race, method of
hospital payment
Adjusted for cigarette smoking, HTN
24,168 Adjusted for sex, age, smoking status,
current smoking, cardiac disease, HTN, DM,
hyperlipemia, history of TIA, migraine, heavy
drinking
72
Not reported
Hazard
Periods Adjustments
(Hours)
Author,
Year
Country
Sample Size
Age
Malarcher,
2001
United
States
224 cases,
392 controls
15 - 44 years 100% women Casecontrol
Mostofsky,
2010
United
States
390 cases
Mean: 68.4
54% men,
46% women
CaseNonfatal Ischemic Stroke
crossover
Vlak, 2011
Netherlands 250 cases
Mean: 54.7
25% men,
75% women
CaseNonfatal Intracranial
crossover Aneurysm
Juvela,
1993
Finland
278 cases,
314 controls
15 - 60 years 52% men,
Mean: 43.8
48% women
Casecontrol
Nonfatal Subarachnoid
Hemorrhage
Juvela,
1995
Finland
156 cases,
332 controls
16 - 60 years 59% men,
Mean: 47.3
41% women
Casecontrol
Incident Nonfatal
24,168 Matched by hospital, sex, age, day of onset
Intracerebral Hemorrhage
of symptoms, and acuteness of onset
Adjusted for HTN, alcohol within day or
week, sex, age,BMI, and smoking status
Thrift, 1999 Australia
331 cases,
331 controls
18 - 80 years 60% men,
Mean: 63.4
40% women
Casecontrol
Incident Nonfatal
Intracerebral Hemorrhage
24
Matched by neighborhood, sex, and age
Adjusted for cholesterol, previous CVD, DM,
exercise, BMI, smoking, education, day of
week of stroke (cases) or interview
(controls)
Saloheimo, Finland
2001
98 cases,
206 controls
36 - 90 years 58% men,
Mean: 65.7
41% women
Casecontrol
Nonfatal Intracerebral
Hemorrhage
168
Matched for age and sex
Adjusted for age, sex, treated and untreated
HTN, IS, epistaxis, epilepsy, recent physical
exertion
DM=diabetes mellitus
HTN=hypertension
BMI=body mass index
TIA=transient ischemic attack
CHD=coronary heart disease
CVD=cardiovascular disease
Sex
Design
Outcome
Incident Nonfatal
Ischemic Stroke
24,168 Matched by age and region of residence
Adjusted for age, race, education, smoking,
BMI, total and HDL cholesterol, history of
HTN, CHD, DM, average alcohol intake in
past year
1,24
Self-matched
24
Self-matched
24,168 Matched by age, sex, day of onset of
symptoms, and acuteness of the disease
onset
Adjusted for HTN, age, smoking status
References
1.
DerSimonian R and Laird N. Meta-analysis in clinical trials. Control Clin Trials.
1986;7:177-88.
2.
Cornell JE, Mulrow CD, Localio R, Stack CB, Meibohm AR, Guallar E and Goodman SN.
Random-effects meta-analysis of inconsistent effects: a time for change. Ann Intern
Med. 2014;160:267-70.
3.
Egger M, Davey Smith G, Schneider M and Minder C. Bias in meta-analysis detected by
a simple, graphical test. BMJ. 1997;315:629-34.
4.
Costanzo S, Di Castelnuovo A, Donati MB, Iacoviello L and de Gaetano G. Alcohol
consumption and mortality in patients with cardiovascular disease: a meta-analysis. J
Am Coll Cardiol. 2010;55:1339-47.
5.
Orsini N, Bellocco R and Greenland S. Generalized least squares for trend estimation of
summarized dose-response data. Stata Journal. 2006;6:40-57.
6.
Harrell FE. Regression modeling strategies : with applications to linear models, logistic
regression, and survival analysis. New York: Springer; 2001.
7.
Greenland S and Longnecker MP. Methods for trend estimation from summarized doseresponse data, with applications to meta-analysis. Am J Epidemiol. 1992;135:1301-9.
8.
Cochran W. The combination of estimates from different experiments. Biometrics.
1954;10:101-129.
9.
Higgins JP, Thompson SG, Deeks JJ and Altman DG. Measuring inconsistency in metaanalyses. BMJ. 2003;327:557-60.
Mostofsky y cols
Alcohol y riesgo inmediato de eventos cardiovasculares
3
Alcohol y riesgo inmediato de eventos cardiovasculares
Una revisión sistemática y meta-análisis de dosis respuesta
Elizabeth Mostofsky, ScD; Harpreet S. Chahal, BMSc; Kenneth J. Mukamal, MD, MPH;
Eric B. Rimm, ScD; Murray A. Mittleman, MD, DrPH
Antecedentes—Si bien una investigación considerable describe los efectos cardiovasculares del consumo de alcohol habitual
moderado y fuerte, los riesgos inmediatos luego de la ingesta de alcohol no han sido bien caracterizados. Sobre la base de
sus efectos fisiológicos, el alcohol puede tener efectos marcadamente diferentes sobre el riesgo inmediato y a largo plazo.
Métodos y resultados—Nosotros buscamos en CINAHL, Embase y PubMed desde el comienzo hasta el 12 de marzo de
2015, suplementado con la selección manual de estudios observacionales que evalúan la asociación entre la ingesta de
alcohol y los eventos cardiovasculares en las horas y días siguientes. Calculamos los riegos correlativos en conjunto y
los intervalos de confianza del 95% para la asociación entre ingesta de alcohol e infarto de miocardio, ACV isquémico
y hemorrágico utilizando modelos de efectos al azar de DerSimonian y Laird para el modelo de alguna ingesta de alcohol o relaciones dosis-respuesta de la ingesta de alcohol y eventos cardiovasculares. Entre las 1056 citas y 37 artículos
completos revisados, se incluyeron 23 estudios (29 457). El consumo moderado de alcohol estuvo asociado con un riesgo
cardiovascular inmediato más alto que fue atenuado después de 24 horas, e incluso protector del infarto de miocardio y
ACV hemorrágico (≈2–4 tragos: riesgo relativo = 30% riesgo más bajo) y protector frente al ACV isquémico dentro de
una semana (≈6 tragos: 19% riesgo más bajo). Por el contrario, la ingesta importante de alcohol estuvo asociada con un
riesgo cardiovascular más alto en el día siguiente (≈6–9 tragos: riesgo relativo =1,3–2,3) y a la semana (≈19–30 tragos:
riesgo relativo = 2,25–6,2).
Conclusiones—Parece ser un hallazgo consistente el riesgo cardiovascular más alto inmediatamente de cualquier consumo de alcohol, pero, a las 24 horas, sólo una ingesta de alcohol importante confiere un riesgo continuado. (Circulation.
2016;133:979-987. DOI: 10.1161/CIRCULATIONAHA.115.019743.)
Palabras clave: beber alcohol ◼ enfermedades cardiovasculares ◼ relación dosis respuesta, drogas ◼ epidemiología
◼ meta-análisis
E
s bien reconocido que la ingesta de alcohol moderada tiene
beneficios cardiovasculares a largo plazo, pero incluso las
exposiciones protectoras pueden conducir a un riesgo incrementado en forma aguda. El alcohol tiene efectos fisiológicos
bifásicos y complejos que resultan en riesgo cardiovascular
más alto y más bajo dependiendo de la cantidad consumida, la
frecuencia de consumo y los resultados en estudio.1,2 Por ejemplo, una ingesta de alcohol moderada y elevada está asociada
con un aumento de la frecuencia cardíaca,3 retraso electromecánico4 y afectación de la fibrinólisis5 dentro de horas de la ingesta, pero existen mejorías a largo plazo en la presión arterial6
y en la coagulación7. Además, el riesgo de eventos cardiovasculares desencadenados por el alcohol puede verse modificado
por los patrones habituales de consumo de bebidas.1 No ha habido un estudio amplio para investigar el riesgo cardiovascular
agudo luego de la ingesta de alcohol. Por lo tanto, llevamos
a cabo una revisión sistemática y un meta-análisis dosis-res-
puesta de la evidencia sobre el riesgo de infarto de miocardio
(IM), ACV isquémico (ACVI) y ACV hemorrágico (ACVH)
en las horas y días luego de la ingesta de alcohol. La principal
hipótesis definida antes del comienzo de la revisión de la literatura fue que, en comparación con el no consumo de alcohol,
el consumo moderado de alcohol se asocia con un riesgo más
alto de eventos cardiovasculares inmediatamente que se hace
protector después de 24 horas, mientras que la ingesta de alcohol importante está asociada con un riesgo cardiovascular más
alto tanto inmediatamente como en los días siguientes.
Perspectiva clínica en p 11
Métodos
Nosotros realizamos una revisión sistemática, meta-análisis, y metaanálisis dosis-respuesta de acuerdo con el protocolo de Meta-Analysis
of Observational Studies in Epidemiology8 todo a lo largo del diseño,
implementación, análisis e informe de este estudio.
Recibido el 2 de octubre de 2015; aceptado el 19 de enero de 2016.
Del Cardiovascular Epidemiology Research Unit, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (E.M., H.S.C., M.A.M.);
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA (E.M., E.B.R., M.A.M.); Department of Epidemiology and Biostatistics,
Schulich School of Medicine & Dentistry, Western University, London, ON, Canada (H.S.C.); Division of General Medicine and Primary Care, Beth Israel
Deaconess Medical Center, Boston, MA (K.J.M.); Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA (E.B.R.); y Channing
Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA (E.B.R.).
El autor invitado para este artículo fue Mercedes R. Carnethon, PhD.
El suplemento de datos solamente en forma online está disponible con este artículo en http://circ.ahajournals.org/lookup/suppl/doi:10.1161/
CIRCULATIONAHA.115.019743/-/DC1.
Correspondencia a Elizabeth Mostofsky, ScD, Harvard T.H. Chan School of Public Health, Kresge Bldg Rm 505B, 677 Huntington Ave, Boston MA
02115. Correo electrónico [email protected]
© 2016 American Heart Association, Inc.
Circulation está disponible en http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.115.019743
3
4
Circulation
Mayo 2016
Fuente de datos y búsquedas
Una persona (Dr Mostofsky) realizó una búsqueda de la literatura en las
bases de datos de CINAHL, Embase y PubMed desde enero de 1966
hasta marzo del 2015 utilizando palabras de texto libre y términos de
Medical Subject Headings sin restricciones de lenguaje. También revisamos el listado de referencias de los artículos recuperados.
Selección del estudio
Utilizando una forma estandarizada, dos lectores (Dr Mostofsky y Mr
Chahal) revisaron en duplicado y en forma independiente la lista de
artículos identificados y de datos extractados a partir de artículos seleccionados con discrepancias adjudicadas por consenso. Seleccionamos
estudios con resúmenes que sugirieran que eran relevantes. Los estudios eran elegibles para revisión si: (1) el diseño era un estudio cruzado
o una serie de casos autocontrolada, control de casos o cohorte; (2)
los investigadores comunicaron riesgos relativos (RR) e intervalos de
confianza del 95% (IC) para la asociación entre ingesta de alcohol e IM,
ACVI o ACVH; (3) los investigadores evaluaron en forma retrospectiva la ingesta de alcohol directamente a partir del participante o de una
persona cercana durante un período de una semana antes del comienzo
del evento. Excluimos los estudios que evaluaron el impacto del alcohol administrado en laboratorio sobre la isquemia miocárdica, arritmia,
fibrilación auricular o resultados intermedios, tales como reactividad
cardiovascular o de la presión arterial.
Extracción de datos y calidad de evaluación
Para cada estudio, registramos los siguientes detalles: primer autor,
año de publicación, ubicación del estudio, período de riesgo, período o
muestra referente, cantidad de casos y de no casos en cada nivel de ingesta de alcohol, cantidad de alcohol consumido antes del comienzo del
evento, RR y el correspondiente IC del 95%, y las covariables incluidas
en los modelos estadísticos. Cuando el análisis de la misma población
se comunicó más de una vez, incluimos el estudio más grande para el
análisis adecuado. En los estudios de control de casos, se entrevistaron
casos y no casos acerca del consumo reciente de alcohol, y los factores
de confusión potenciales por las diferencias entre personas fueron enfocados con ajustes apareados y estadísticos. En los estudios cruzados,
cada caso se entrevistaba acerca de la ingesta de alcohol reciente y la ingesta de alcohol del mismo individuo en otros momentos. Comparando
el mismo individuo en diferentes momentos, los factores de confusión
se eliminan por características fijas. Cuando los estudios cruzados comunicaban estimados que utilizaban un referente de frecuencia habitual de
ingesta de alcohol durante varios meses o una referencia de ingesta en
el mismo tiempo en los días previos, incluimos los estimados basados
en la frecuencia habitual. Cuando los estudios comunicaban estimados
provenientes de modelos diferentes, nosotros incluimos los estimados
del modelo con el mayor control de factores de confusión potenciales.
También registramos información sobre si el estudio estaba restringido a
eventos incidentales, se hayan incluido o no ambos eventos fatales y no
fatales, y si el estudio estaba restringido a bebedores actuales.
Evaluamos cuantitativamente la calidad del estudio a través del
registro del tiempo entre el comienzo del evento cardiovascular y la
determinación de la ingesta de alcohol, si la ingesta de alcohol se evaluó con una entrevista o cuestionario o si una persona cercana brindó
la información sobre la ingesta de alcohol.
Síntesis y análisis de datos
Los detalles de los métodos de meta-análisis se brindan solamente
online en el apéndice de suplemento de datos que está resumido brevemente aquí.
Meta-análisis de cualquier ingesta de alcohol
Para cada resultado o período de riesgo, incluimos un RR y el IC
del 95% correspondiente por estudio que comunicaba el cambio en
el riesgo cardiovascular que sigue inmediatamente a alguna ingesta de alcohol en comparación con la no ingesta de alcohol. Para los
estudios que no comunicaron un RR global, primero reunimos los
RR a través del sexo y niveles de consumo de alcohol utilizando un
modelo de efectos al azar. Utilizamos los modelos de efectos al azar
DerSimonian y Laird9 para reunir los RR a través de los estudios para
cada resultado y cada período de riesgo.
Meta-análisis dosis - respuesta
Para examinar el impacto de la cantidad de alcohol consumida antes del
comienzo del evento, llevamos a cabo un meta-análisis dosis-respuesta
para cada resultado y el riesgo en el día y en la semana siguiente a la
ingesta. Para cada estudio, asignamos los gramos promedio o mediana
de ingesta de alcohol para cada nivel de exposición a RR correspondiente. Para examinar relaciones no lineares potenciales entre la ingesta
de alcohol y el riesgo cardiovascular, realizamos meta-análisis dosisrespuesta de efectos al azar de 2 estadios.10 Estimamos el riesgo relativo
predicho comparando los niveles específicos de ingesta de alcohol con
la no ingesta de alcohol basada en un modelo linear o transformación
spline (curva diferenciable definida en porciones), según sea adecuado.
Para el análisis de alguna ingesta y los análisis de dosis-respuesta
evaluamos la heterogeneidad a través de estudios con la prueba de
Cochrane Q χ2 11 y calculamos el I2 estadístico para cuantificar la proporción de heterogeneidad entre el estudio atribuible a la variabilidad
en la asociación en lugar de la variación de la muestra.12
Los análisis estadísticos se llevaron a cabo con un conjunto α de dos
colas establecido a ≤ 0,05 para la significación estadística. Utilizamos
paquetes Stata (version 13.0, StataCorp, College Station, TX) para
conducir los meta-análisis de alguna ingesta de alcohol (metan), los
análisis dosis-respuesta (glst) y la evaluación del sesgo de publicación
potencial (metabias) y el sesgo de la información (metainf).
Resultados
La literatura buscada identificó 1056 publicaciones. Excluimos
411 duplicados y 623 artículos fueron excluidos después de la
revisión del título o el resumen. 15 artículos adicionales fueron identificados a partir de búsquedas manuales de revisión
de la bibliografía de estudios relevantes. Después de revisar
los artículos, otros 14 artículos fueron excluidos, que resulta
en un meta-análisis de 23 artículos (Figura 1). La Tabla en el
suplemento de datos solamente online resume las características de los estudios elegibles. Los meta-análisis incluyeron 16
controles de casos y siete estudios cruzados publicados desde
1987 hasta 2015. Combinados, había 29 457 participantes que
incluyeron 17 966 casos de IM, 2599 casos de ACVI y 1262
casos de ACVH. Hubo 11 estudios que fueron llevados a cabo
en Europa, 1 en Rusia, 4 en los Estados Unidos, 2 en Nueva
Zelanda y 4 en Australia; un estudio incluyó participantes de
52 países a nivel mundial. Dos estudios incluyeron solamente hombres, uno incluyó solamente mujeres y los restantes
20 estudios incluyeron hombres y mujeres, pero solamente
6 representaron estimados específicos por sexo, con uno que
comunica un RR infinito para las mujeres, por lo que incluimos el estimado que combina todos los participantes. Hubo
14 estudios que estuvieron restringidos a eventos incidentales.
El consumo de alcohol fue evaluado con un cuestionario en 3
estudios y con entrevistas en todos los demás. En 10 estudios,
el consumo de alcohol promedio estimado en la categoría más
alta fue > 4 tragos por día para los hombres y mujeres combinados o para los hombres, pero no para las mujeres.
La Figura 2 presenta un gráfico en bosque de RR y del IC
del 95% y las estadísticas de heterogeneidad para los análisis
de alguna ingesta de alcohol, la Figura 3 presenta un gráfico
en bosque de datos específicos de dosis con RR e IC del 95%
en la figura l en el suplemento de datos sólo online y la Figura
4 presenta splines, estadísticas de heterogeneidad y valores de
P para los análisis dosis-respuesta.
Infarto de miocardio
Un estudio13 comunicó un riesgo más alto de muerte súbita
cardíaca dentro de las dos horas después del consumo de alcohol (RR, 3,00; IC del 95%, 1,61–5,68), pero no incluimos
este estimado en nuestro análisis debido a que la causa de
Mostofsky y cols
Alcohol y riesgo inmediato de eventos cardiovasculares
5
1056 artículos identificados en la
búsqueda de literatura electrónica
339 Pubmed
405 Embase
312 Cinahl
411 duplicados removidos
645 resúmenes revisados
623 resúmenes excluidos
562 tema diferente
45 editorial, revista libro, estudio de caso
11 RR no estimables
5 análisis anteriores del estudio incluido
15 resúmenes identificados de
búsqueda manual
37 artículos revisados por extracción
de datos
14 artículos excluidos
1meta-análisis
5 análisis anteriores de estudio incluido
5 RR crudo o no estimable
3 otro resultado
Figura 1. Selección de estudios
publicados desde 1966 hasta 2015 con
información sobre alguna ingesta de
alcohol reciente o una dosis específica
de ingesta de alcohol reciente incluida en
un meta-análisis de consumo de alcohol
y riesgo de eventos cardiovasculares.
*Un estudio incluyó datos sobre infarto
de miocardio y ACV hemorrágico, y
un estudio incluyó datos sobre ACV
isquémico y ACV hemorrágico. RR indica
riesgo relativo
23* artículos incluidos
en meta-análisis
9 artículos sobre infarto
de miocardio
5 alguna solamente
1 dosis solamente
3 ambas, alguna y dosis
9 artículos sobre ACV
isquémico
2 alguna solamente
0 dosis solamente
7 ambas, alguna y dosis
muerte puede haber sido atribuible a miocardiopatía o arritmias. Hubo cinco estudios cruzados14–18 y 4 estudios de control de casos19–22 que evaluaron la asociación entre ingesta de
alcohol y el riesgo inmediato de IM o evento coronario mayor.20 Hubo un riesgo de IM más alto después de la ingesta de
alcohol que en otros momentos y riesgo modestamente más
bajo después de 24 horas. Los 2 estudios evaluaron el riesgo
de IM en hombres, con uno21 que comunica un riesgo de IM
más bajo (RR, 0,25; IC del 95%, 0,13–0,50) después de ≈18 g
de alcohol en la semana anterior y el otro22 que comunica un
riesgo más alto de muerte por enfermedad cardíaca isquémica
o IM después de intoxicación importante con alcohol durante
≥2 días cuando la persona se retira de su vida social normal
(RR, 3.57; IC del 95%, 1,65–7,73).
Cuando se representa por el monto de alcohol consumido en
las 24 horas antes del comienzo de IM, existe una asociación
en forma de U (Pcurva < 0,001) entre la ingesta de alcohol y
el riesgo de IM, con el beneficio más alto luego de ≈28 g de
alcohol (≈2 tragos) en un día (RR, 0,67) y un riesgo más alto
luego de ≈108 g (≈9 tragos) en un día (RR, 1,59). Dentro de
una semana luego del consumo de alcohol, hubo un riesgo más
bajo de IM con la ingesta moderada, pero un riesgo más alto
luego del consumo fuerte de alcohol.
No hubo indicación de efectos de estudio pequeño para los
estudios de riesgo de IM en el día (Egger P = 0,18) y la semana
(Egger P = 0,86) luego del consumo de alcohol. Los resultados
fueron similares en el análisis de sensibilidad que excluye un
estimado en el momento.
ACV isquémico
Examinaron la asociación entre la ingesta de alcohol y el
riesgo inmediato de ACVI en un estudio cruzado23 y ocho
7 artículos sobre ACV
hemorrágico
0 alguna solamente
0 dosis solamente
7 ambas, alguna y dosis
estudios de control de casos24-31. Un estudio27 con RR por
nivel de ingesta de alcohol podría no estar incluido en el
meta-análisis dosis-respuesta debido a que la información
sobre el tamaño de la muestra en cada nivel de consumo no
estaba informada. Existe evidencia del riesgo de ACVI más
alto dentro de una hora de alguna ingesta de alcohol, y la
sugerencia de beneficios protectores de ahí en más, aunque
los resultados fueron inconsistentes.
En el análisis dosis-respuesta, hubo un riesgo más alto de
ACVI con una ingesta más elevada de alcohol en el día precedente, aunque esta asociación lineal sólo se basó en dos estudios con información de la dosis. Hubo una asociación en
forma de U (Pcurva = 0,007) para el riesgo en la semana siguiente. En comparación con el no consumo de alcohol, hubo un
riesgo del 19% más bajo de ACVI en la semana que sigue a
una ingesta de alcohol ≈75 g (≈6 tragos/semana), pero 2,25
veces más alto el riesgo de ACVI en la semana luego de 225
g (≈19 tragos) que continúa escalando con cantidades más
altas de consumo de alcohol. La asociación dosis-respuesta
fue aparente tanto para hombres como para mujeres. No hubo
indicación de sesgo de publicación (Egger P = 0,39). En un
análisis de sensibilidad que excluye un estudio en un momento, el RR para ACVI dentro de un día fue más bajo (RR, 0,82;
IC del 95%, 0,66–1,01) cuando se removió el resultado de un
estudio29 y más alto (RR, 1,08; IC del 95%, 0,74–1,60) cuando
removimos el estimado de otro estudio,18 pero un análisis de
sensibilidad similar no tuvo impacto sobre RR para el riesgo
de ACVI dentro de una semana.
En un análisis de sensibilidad, incluimos estimados de estudios de control de casos que no dieron cuenta de factores de
confusión.24,32,33 El riesgo estimado en 24 horas fue similar al
de los análisis preliminares. En 5 estudios,32,34–36 se incluyeron
6
Circulation
Mayo 2016
IM o evento coronario
1 hora Mostofsky, 2015
1,72 (1,37; 2,16)
12 horas Gerlich, 2010*
1,60 (0,73; 3,52)
24 horas Jackson, 1992*
McElduff, 1997*
Marshall, 2000
Leong, 2014
Mostofsky,2015
Subtotal (I2 = 75,7%, p = 0,002)
0,69 (0,60; 0,79)
0,79 (0,61; 1,02)
0,67 (0,49; 0,91)
1,00 (0,87; 1,15)
0,86 (0,78; 0,94)
0,81 (0,70; 0,94)
1 semana Schröder, 2007*
Leon, 2010
0,25 (0,13; 0,50)
3,57 (1,65; 7,73)
ACV isquémico
1 hora Mostofsky, 2010
2,30 (1,36; 3,89)
24 horas Gorelick, 1987
Haapaniemi, 1997*
You, 1997*
Malarcher, 2001
Mostofsky, 2010
Subtotal (I2= 48,6%; p = 0,10)
1,02 (0,72; 1,44)
2,33 (0,97; 5,61)
0,90 (0,27; 3,03)
0,77 (0,36; 1,63)
0,70 (0,52; 0,94)
0,94 (0,66; 1,32)
48 horas Syrjänen, 1988
6,00 (1,30; 55,20)
1 semana Shinton, 1993*
Jamrozik, 1994
Numminen, 1996*
Malarcher, 2001*
Subtotal (I2= 36,8%; p = 0,19)
0,62 (0,37; 1,04)
0,80 (0,51; 1,24)
1,83 (0,80; 4,22)
0,81 (0,47; 1,40)
0,84 (0,59; 1,19)
ACV hemorrágico
24 horas Juvela, 1993*
Juvela, 1995*
Thrift, 1999*
Vlak, 2011*
Subtotal (I2= 89,8%; p < 0,001)
2,36 (0,39; 14,27)
2,47 (0,31; 19,90)
0,94 (0,53; 1,64)
0,20 (0,14; 0,28)
0,81 (0,23; 2,87)
1 semana Juvela, 1993*
Jamrozik, 1994
Juvela, 1995*
Saloheimo, 2001*
Leon, 2010
Subtotal (I2= 32,5%, p = 0,21)
2,42 (0,77;7,57)
0,55 (0,08; 3,99)
3,47 (1,64; 7,37)
3,40 (0,84; 13,73)
6,89 (2,80; 16,97)
3,33 (1,82; 6,09)
El peso es de análisis de efectos al azar
0,5
1
2
4
8
16
Riesgo relativo (Escala log)
Figura 2. Diagrama de bosque de riesgos relativos (RR) y el intervalo de confianza del 95% para la asociación entre algún consumo de
alcohol relativo a no beber. Los cuadrados indican estimaciones de RR específicas del estudio, con el tamaño del cuadrado reflejando la
proporción de los pesos de DerSimonian y Laird en estudio; las líneas horizontales indican el IC del 95%; los diamantes indican los RR
unificados con su IC del 95% de un modelo de efectos al azar. La línea punteada indica el valor para no asociación. *También incluida en
meta-análisis de dosis-respuesta. IM indica infarto de miocardio.
casos con ACVI o ACVH, pero después de restringir el análisis a los estudios que dan cuenta de los factores de confusión
potenciales y por lo menos algunos casos expuestos y controles, solamente se incluyó un estudio26 con objetivo combinado. Debido a que el estudio estaba compuesto de 81 casos de
ACVI y solamente nueve casos de ACVH, el RR fue incluido
en el análisis de riesgo de ACVI; los resultados fueron similares cuando este estimado fue excluido.
ACV hemorrágico
Se examinó un estudio cruzado37 y 6 estudios de control de
casos22,27,38–41 sobre el riesgo inmediato de ACVH luego de la
ingesta de alcohol, con la mayoría de los estudios que informaron un riesgo más alto dentro de un día o una semana después
de cualquier consumo.
En el meta-análisis de dosis-respuesta, hubo una asociación
en forma U (Pcurva = 0,02) entre el consumo de alcohol y el
riesgo de ACVH después de 24 horas. En comparación con
la no ingesta, el consumo de 48 g (≈4 tragos) estuvo asociado
con un riesgo de ACVH del 38% más bajo, mientras que beber
81 g (≈7 tragos) estuvo asociado con un riesgo de ACVH 1,26
veces más alto en el día siguiente. Esta asociación fue aparente
tanto para los hombres como para las mujeres. Hubo una asociación linear para el riesgo de ACVH dentro de una semana
de consumo de alcohol sin evidencia de beneficios protectores.
No hubo indicación de sesgo de publicación para los estudios de riesgo de ACVH en el día (Egger P = 0,25) y en la semana (Egger’s P = 0,19) que sigue a alguna ingesta de alcohol.
Los resultados fueron similares en los análisis de sensibilidad
que excluyeron un estimado en el momento.
Mostofsky y cols
IM o evento coronario
12 horas
Gerlich, 2009
Gerlich, 2009
24 horas
Jackson, 1992
Jackson, 1992
Jackson, 1992
Jackson, 1992
MacElduff,1997
MacElduff,1997
Jackson, 1992
Jackson, 1992
Jackson, 1992
Jackson, 1992
McElduff,1997
McElduff,1997
Jackson, 1992
Jackson, 1992
Jackson, 1992
Jackson, 1992
MacElduff,1997
MacElduff,1997
MacElduff,1997
1 semana
Schröder, 2007
Schröder, 2007
Schröder, 2007
ACV isquémico
24 horas
Haapaniemi, 1997
Haapaniemi, 1997
Haapaniemi, 1997
You, 1997
Haapaniemi, 1997
Alcohol y riesgo inmediato de eventos cardiovasculares
mujeres: ≤ 24 g, hombres: ≤ 36 g
mujeres: ≥ 48 g, hombres: ≤ 60 g
1-2 tragos, hombres, muerte coronaria
1-2 tragos, hombres, IM no fatal
1-2 tragos, mujeres, muerte coronaria
1-2 tragos, mujeres, IM no fatal
1-2 tragos, hombres
1-2 tragos, mujeres
3-4 tragos, hombres, muerte coronaria
3-4 tragos, hombres, IM no fatal
3-4 tragos, mujeres, muerte coronaria
3-4 tragos, mujeres, IM no fatal
3-4 tragos, hombres
3-4 tragos, mujeres
> 4 tragos, hombres, muerte coronaria
> 4 tragos, hombres, IM no fatal
> 4 tragos, mujeres, muerte coronaria
> 4 tragos, mujeres, IM no fatal
≥ 5 tragos, mujeres
5-8 tragos, hombres
≥ 9 tragos, hombres
≤ 140 g, hombres
> 20, <= 30 g/d, hombres
> 30 g/d, hombres
1-40 g, hombres
1-40 g, mujeres
> 40 g, mujeres
≥ 60 g
41-120 g, hombres
Haapaniemi, 1997 > 120 g, hombres
48 horas
Syrjänen, 1988
1 semana
Malarcher, 2001
Shinton, 1993
Jamrozik, 1994
Numminen, 1996
Malarcher, 2001
Shinton, 1993
Malarcher, 2001
Jamrozik, 1994
Numminen, 1996
Shinton, 1993
Jarmozik, 1994
Numminen, 1996
Jamrozik, 1994
ACV hemorrágico
24 horas
Thrift, 1999
Vlak, 2011
Juvela, 1993
Juvela, 1993
Juvela, 1993
Thrift, 1999
Juvela, 1993
Thrift, 1999
Juvela, 1993
Juvela, 1993
Juvela, 1993
Juvela, 1993
1 semana
Jamrozik, 1994
Juvela, 1993
Juvela, 1993
Juvela, 1993
Jamrozik. 1994
Juvela, 1993
Juvela, 1993
Juvela, 1995
Jamrozik, 1994
Juvela, 1993
Juvela, 1993
Juvela, 1995
Saloheimo, 2001
Jamrozik, 1994
> 80 g durante unas pocas horas
< 12 g/d, mujeres
1-14/tragos
7-140 g
1-150 g
12-24 g/d, mujeres
15-29 tragos
> 24 g, mujeres
147-280 g
151-300 g
> 29 tragos
287-420 g
> 300 g
≥ 427 g
Hombres: 1-40 g, mujeres: 1-20 g
≥ un vaso
1-40 g, hombres
1-40 g, mujeres
1-40 g
hombres: > 40-60 g, mujeres:> 20-40 g
> 40 g, mujeres
hombres:> 60 g, mujeres:> 40 g
41-120 g, hombres
41-120 g
> 120 g, hombres
> 120 g
7-140 g
7-150 g, hombres
1-150 g mujeres
1-150 g
147-280 g
150-300 g, hombres
150-300 g, mujeres
150-300 g
287-420 g
> 300 g, hombres
> 300 g, mujeres
> 300 g
> 300 g
≥ 427 g
Riesgo relativo (Escala log)
0,5
1
2
4
8
16
Figure 3. Diagrama de bosque de riesgos relativos (RR) e intervalos de confianza del 95% para la asociación entre consumo de alcohol
y eventos cardiovasculares en los días y semanas siguientes por cantidad de ingesta alcohólica. Los cuadrados indican estimaciones
del RR específicas del estudio, con el tamaño del cuadrado reflejando la proporción de los pesos de DerSimonian y Laird en estudio; las
líneas horizontales indican el IC del 95%. La línea de puntos indica el valor para no asociación. IM indica infarto de miocardio.
7
Mayo 2016
Infarto de miocardio, 1 día
Pcurva < 0,001 Plinealidad < 0,001
I2 = 3,3%
Pheterogeneidad = 0,42
Riesgo relativo (Escala log)
3
ACV isquémico, 1 día
Pcurva < 0,03 Plinealidad < 0,52
I2 = 64,4% Pheterogeneidad = 0,08
32
2
1
0,5
16
8
4
2
1
0,5
0
10
20
30
40
50
60
70
80
90
100
110
ACV hemorrágico, 1 día
Pcurva < 0,02 Plinealidad < 0,005
I2 = 90,5% Pheterogeneidad = 0,0001
50
Riesgo relativo (Escala log)
Circulation
Riesgo relativo (Escala log)
8
32
16
8
4
2
1
0,5
0
10 20 30 40 50 60 70 80 90 100 110 120 130 140 150
0
10 20 30 40 50 60 70 80 90 100 110 120 130 140 150
Ingesta de alcohol, g/día
Ingesta de alcohol, g/día
ACV isquémico, 1 semana
Pcurva < 0,007 Plinealidad < 0,02
I2 = 8,6%
Pheterogeneidad = 0,36
8
ACV hemorrágico, 1 semana
Pcurva < 0,001 Plinealidad < 0,42
I2 = 8,3%
Pheterogeneidad = 0,37
16
Riesgo relativo (Escala log)
Riesgo relativo (Escala log)
Ingesta de alcohol, g/día
4
2
1
0,5
8
4
2
1
0,5
0
50
100
150
200
250
Ingesta de alcohol, g/día
300
350
400
0
50
100
150
200
250
300
350
400
Ingesta de alcohol, g/día
Figura 4. Riesgo relativo (línea sólida) e intervalo de confianza del 95% (línea discontinua) para la asociación entre gramos de alcohol
y riesgo de eventos cardiovasculares dentro de las 24 horas. El consumo de alcohol fue modelado con splines cúbicos restrictos en un
modelo de dosis – respuesta con efectos al azar. El valor más bajo de cero (no bebedores) se usó para estimar todos los riesgos relativos.
El eje vertical es sobre escala log. La línea de puntos indica el valor de no asociación.
Discusión
En esta revisión sistemática y de meta-análisis, el consumo
moderado de alcohol estuvo asociado con un riesgo inmediatamente más alto de eventos cardiovasculares, pero, después de
24 horas, hubo un riesgo más bajo de IM y ACVH y, después
de una semana, hubo un riesgo más bajo de ACVI, compatible
con investigación previa que muestra los beneficios cardiovasculares de la ingesta habitual. Beber alcohol en forma importante estuvo asociado con un riesgo cardiovascular más alto en
las horas y días siguientes.
Inmediatamente luego de la ingesta de alcohol, existen
tanto respuestas fisiológicas peligrosas como protectoras.7
Entre 1 y 3 horas, una dosis única de alcohol incrementa
la frecuencia cardíaca,3 el retraso electromecánico interarterial4 y los niveles de inhibidor de activador del plasminógeno,5 pero entre las 12 a 24 horas, una dosis de alcohol
consistente con dos bebidas alcohólicas causan mejorías
transitorias en la vasodilatación mediada por flujo, función
endotelial7 y factores fibrinolíticos.5
En las semanas de ingesta regular, hay mejorías en los marcadores inflamatorios, perfil lipídico, y adipoquinas y sensibilidad a la insulina.7 El consumo moderado habitual de alcohol
(1–2 tragos por día) está asociado con mejorías en el colesterol de la lipoproteína de alta densidad, la variabilidad de
la frecuencia cardíaca,42 función endotelial, sensibilidad a la
insulina, cascadas de coagulación y fibrinolítica,7 y un riesgo
más bajo de enfermedad cardiovascular y de ACVI y ACVH.43
Sin embargo, el consumo fuerte de bebida (3 a ≥ 4 tragos por
día) está asociado con un riesgo más alto de hipertensión,6 diabetes mellitus, enfermedad cardiovascular, ACVI y ACVH, y
mortalidad después de IM.43–45 Los hábitos usuales de beber
puede modificar la respuesta fisiológica aguda al alcohol. Por
lo tanto, las pautas Dietary Guidelines Advisory Committee de
2015 recomendaron que, si se consume alcohol, debería ha-
cerse con moderación, hasta un trago por día para las mujeres
y dos tragos por día para los hombres.46 Los resultados de este
meta-análisis muestran que también puede haber un riesgo
inmediato de eventos cardiovasculares incluso si el consumo
habitual moderado alcanza beneficios cardioprotectores.
Nuestro análisis dosis-respuesta sugiere que después de
24 horas, los bebedores moderados pueden experimentar un
riesgo menor de un evento cardiovascular en comparación
con otros momentos, mientras que beber en forma importante
está asociado con un riesgo más elevado incluso después de
24 horas. Esto está respaldado por trabajos previos que muestran que los efectos de la ingesta de alcohol sobre la salud
dependen tanto de la cantidad como del patrón de consumo.
Beber en forma episódica importante, definida como ≥ 4 bebidas alcohólicas dentro de 1 a 2 horas, tiene efectos peligrosos,
incluso si los individuos que se emborrachan beben solamente
uno o dos días por semana, quedan en el mismo promedio de
ingesta alcohólica por semana que se conoce como que genera
beneficios cardioprotectores. Entre los hombres, beber una pequeña cantidad de alcohol regularmente (por ej., 1–2 tragos/d,
4 días/sem) disminuye el riesgo cardiovascular más que beber
la misma cantidad total en forma semanal, pero en menor cantidad de días por semana.1 Por lo tanto, es posible que, con
el tiempo, los individuos que toman frecuentemente pequeñas
cantidades de alcohol puedan experimentar un riesgo aumentado temporariamente, pero esto puede ser compensado en
parte por los beneficios protectores subsiguientes en las horas
posteriores al consumo, mientras que el consumo de grandes
cantidades de alcohol de una vez puede producir un riesgo inmediato y agudamente más alto, y consumir grandes cantidades de alcohol en ataques repetidos puede generar también un
riesgo a largo plazo más alto. Los resultados de los estudios
que examinan el riesgo en un período de una semana no son
claros debido a que la mayoría de los estudios no brindan in-
Mostofsky y cols
formación sobre el patrón de consumo de bebida en la semana
previa al evento; es posible que algunas personas sólo hayan
bebido tempranamente en la semana previa, algunos sólo habrán bebido inmediatamente antes del evento y algunos habrán
bebido alcohol en varias ocasiones en la semana previa. Sin
embargo, un estudio de control de casos31 comunicó que entre
las mujeres que bebieron alcohol en la última semana, aquellas que bebieron en las últimas 24 horas tienen un riesgo más
bajo de ACV que los que nunca toman, y el riesgo fue incluso
más bajo para las mujeres que no habían bebido en las últimas
24 horas. Esto respalda nuestra hipótesis de que puede haber
beneficios protectores en las 24 horas después en la ingesta de
alcohol moderada, y quizás los beneficios son incluso mayores
en los días subsiguientes.
El impacto inmediato del consumo de alcohol puede estar
influido por la ingesta habitual de alcohol. Un estudio18 observó que el riesgo más alto de IM en la hora siguiente al consumo de alcohol no es aparente para los bebedores diarios. Esto
puede ser atribuible a la tolerancia al alcohol conduciendo de
ese modo la ingesta habitual al aumento de las enzimas que
metabolizan el alcohol, lo que genera una respuesta fisiológica
más baja a cada trago.47 Si bien los estudios cruzados están restringidos a los bebedores actuales por el diseño debido a que
sólo los casos que informan alcohol en el último año contribuyen con información, solamente dos estudios del control de casos10,11 llevaron a cabo análisis restringidos a bebedores actuales y seis estudios19,20,28,29,31,39 ajustados por la ingesta habitual.
En los estudios restantes, algunos de los antiguos bebedores
pueden haber dejado de beber alcohol debido a enfermedades,
abuso previo de alcohol o prescripción de medicaciones que
no pueden ser tomadas con alcohol, lo que podría sobrestimar
los beneficios de la ingesta de alcohol sobre la salud.48 Es posible que algunas personas que se abstienen de alcohol en respuesta a síntomas prodrómicos antes del comienzo clínico del
evento cardiovascular, generen una subestimación de la ingesta reciente y un sesgo estimado. Sin embargo, los resultados
fueron similares en los estudios18,23 que utilizaron el comienzo
de los síntomas en lugar del momento de la internación en el
hospital para definir el comienzo del evento y cuando llevaron
a cabo los análisis de sensibilidad restringidos a los casos sin
síntomas preclínicos. En un estudio,49 los resultados fueron
más débiles, pero aún evidentes después de dar cuenta de los
síntomas prodrómicos.
El consumo de alcohol moderado habitual se asocia con
un riesgo más bajo de enfermedad cardíaca en ambos sexos,
pero la cantidad de alcohol asociada con beneficios cardiovasculares es más baja entre las mujeres que en los hombres.
Solamente algunos de los estudios informados están separados
por hombres y mujeres, de manera tal que nosotros no podríamos evaluar estadísticamente si el sexo modifica la magnitud
o el momento del riesgo agudo aumentado, pero el riesgo cardiovascular más alto luego de niveles más altos de ingesta alcohólica fueron aparentes tanto en hombres como en mujeres.
No hay estudios que hayan examinado si el riesgo inmediato
luego de la ingesta alcohólica se modificó por la historia clínica, pero, en estudios de consumo de alcohol habitual, los
beneficios de la ingesta moderada fueron similares para las
personas con enfermedad cardiovascular existente o diabetes
mellitus y aquellos en la población general.45
Los estudios previos han informado diferencias raciales/
étnicas en la magnitud de la asociación entre el consumo habitual de alcohol y el riesgo de eventos cardiovasculares17,50
que puede involucrar variaciones étnicas en la prevalencia
Alcohol y riesgo inmediato de eventos cardiovasculares
9
de polimorfismos genéticos relacionados con el metabolismo
del alcohol,51 diferencias culturales en los patrones previos
de consumo, patrones actuales de consumo de alcohol, y asociaciones entre patrones de manera de beber y otros factores
de riesgo para la salud y problemas de salud.52 Se necesitan
estudios futuros para evaluar si existe alguna variación racial/
étnica en los efectos agudos de la ingesta de alcohol sobre el
riesgo cardiovascular, y si las diferencias genéticas pueden
tener un papel.
Solamente 5 estudios18,23,31,37,40 examinaron la asociación por
tipo de bebida, por lo que nosotros no podríamos evaluar si
los riesgos difieren con el consumo de vino, cerveza o licores.
En los estudios cruzados de tipos de alcohol y riesgo agudo
de IM18 y de ACVI23 hubo una sugerencia sobre que el riesgo
elevado agudamente en la hora posterior al consumo de alcohol era más fuerte para los licores que para la cerveza o el
vino, y la asociación protectora por 24 horas fue aparente para
la cerveza y el vino, pero no para los licores. Otros estudios
han comunicado que dentro de las 24 horas de la ingesta, los
individuos que beben vino estaban protegidos de hemorragia
intracerebral (HIC) y también un menor riesgo de HIC para
aquellos que recientemente consumieron licores, pero existe
una pequeña asociación entre cerveza o bebidas fortificadas e
HIC,40 mientras que otro estudio comunicó un riesgo similar
de HIC por tipo de bebida para el riesgo de HIC.37 Sin embargo, ninguno de los estudios evaluaron en forma simultánea el
tipo de bebida y los patrones de consumo de alcohol. Además,
los estudios previos han mostrado que todos los tipos de alcohol tienen efectos similares sobre el colesterol de la lipoproteína de alta densidad y otros marcadores biológicos de riesgo
cardiovascular. Por lo tanto, las diferencias en la magnitud de
la asociación entre diferentes tipos de alcohol y resultados cardiovasculares es más probable que resulten en las diferencias
en el estilo de vida en la frecuencia y cantidad de ingesta alcohólica en lugar de a partir de efectos fisiológicos diferentes de
un tipo de bebida específico.1,7,31
Algunos estudios no comunicaron suficientes detalles para
incluir en nuestro meta-análisis de dosis-respuesta, y ninguno
de los estudios brindaron información sobre los bebedores episódicos importantes, que se define como cuatro tragos para las
mujeres y cinco tragos para los hombres consumidos dentro de
alrededor de dos horas.53 Sin embargo, nuestros resultados sugieren que el consumo de alcohol moderado está asociado con
un riesgo de eventos cardiovasculares inmediatamente más
alto que se atenúa hacia las 24 horas, mientras que la ingesta
de alcohol importante continúa siendo peligrosa.
Evaluamos la influencia del momento y la cantidad de alcohol sobre el riesgo cardiovascular, pero no pudimos dirigirnos
a las fuentes de sesgos en los estudios originales. Sin embargo, aunque no se puedan descartar factores de confusión no
medidos y residuales, la mayoría de los estudios de control
de casos dieron cuenta de muchos factores de confusión y el
emparejamiento automático en casos de estudios cruzados elimina confusión variando levemente las características. Todos
los estudios incluidos obtuvieron información sobre la ingesta
de alcohol después de que se produjo el evento cardiovascular, y la ingesta de alcohol puede haber sido mal comunicada
diferencialmente para los casos y controles o en el caso de
estudios cruzados, para la ingesta reciente en comparación con
la ingesta habitual. Si la ingesta de alcohol reciente impactó sobre la capacidad o el deseo de los sujetos de participar
en el estudio, un sesgo de selección puede haber conducido
a estimados incorrectos, pero numerosos estudios utilizaron
10
Circulation
Mayo 2016
las respuestas de personas cercanas cuando el sujeto no podía brindar información. Por último, nosotros no identificamos
ningún estudio no publicado y no pudimos excluir la posibilidad de que el sesgo de publicación pueda haber afectado nuestros resultados, pero no encontramos evidencia de sesgos de
este tipo. No hubo evidencia de efectos de estudio pequeño,
pero las pruebas para la asimetría de los gráficos en embudo
no se recomiendan cuando existen menos de 10 estudios. Para
algunos de los análisis, nosotros observamos heterogeneidad
entre estudios y los resultados fueron levemente, pero no significativamente alterados cuando removimos un único estudio,
aunque la magnitud del cambio también estuviera impactada
por la cantidad de alcohol. Si bien puede ser atractivo inferir
que la heterogeneidad en la magnitud de la asociación entre
diferentes eventos cardiovasculares es atribuible a diferentes
mecanismos biológicos que vinculan el alcohol y los resultados de interés, también puede ser por lo menos parcialmente
atribuible a las diferencias en el riesgo basal y a los patrones
de consumo de alcohol de las poblaciones en estudio. A pesar
de estas limitaciones, este estudio es el primer intento para
comprender exhaustivamente el interjuego entre las dosis y el
momento de ingesta de alcohol y los riesgos y beneficios inmediatos sobre IM y ACV.
En resumen, nuestros resultados sugieren que la ingesta de
alcohol se asocia con un riesgo de eventos cardiovasculares
inmediatamente más alto, pero después de 24 horas, existe un
menor riesgo de IM y ACVH, y, en una semana existe un menor riesgo de ACVI, mientras que beber fuertemente continúa
confiriendo el riesgo más alto incluso después de 24 horas.
Origen de los fondos
El Dr Mostofsky recibió apoyo de una subvención del National
Institutes of Health (grant L30-HL115623-02) y un premio de KL2/
Catalyst Medical Research Investigator Training (un premio determinado por KL2) de Harvard Catalyst/The Harvard Clinical
and Translational Science Center (National Center for Research
Resources and the National Center for Advancing Translational
Sciences, National Institutes of Health Award KL2 TR001100). El
contenido solamente es responsabilidad de los autores y no necesariamente representa la mirada oficial de European Research Council,
Harvard Catalyst, Harvard University y sus centros de salud académicos afiliados o los National Institutes of Health. Mr. Chahal recibió apoyo de Frederick Banting and Charles Best Canada Graduate
Scholarship y del Michael Smith Foreign Study Supplement de los
Canadian Institutes of Health Research. Ninguna de las organizaciones que brindaron fondos tuvo ningún papel en el diseño y conducción del estudio; recolección; manejo, análisis e interpretación de los
datos; ni la preparación del manuscrito.
Ninguna
Declaraciones de intereses
Bibliografía
1. Mukamal KJ, Conigrave KM, Mittleman MA, Camargo CA Jr, Stampfer
MJ, Willett WC, Rimm EB. Roles of drinking pattern and type of alcohol
consumed in coronary heart disease in men. N Engl J Med. 2003;348:109–
118. doi: 10.1056/NEJMoa022095.
2. Whitfield JB, Heath AC, Madden PA, Pergadia ML, Montgomery GW,
Martin NG. Metabolic and biochemical effects of low-to-moderate alcohol consumption. Alcohol Clin Exp Res. 2013;37:575–586. doi: 10.1111/
acer.12015.
3. Spaak J, Merlocco AC, Soleas GJ, Tomlinson G, Morris BL, Picton P, Notarius CF, Chan CT, Floras JS. Dose-related effects of red wine and alcohol
on hemodynamics, sympathetic nerve activity, and arterial diameter. Am
J Physiol Heart Circ Physiol. 2008;294:H605–H612. doi:10.1152/ajpheart.01162.2007.
4. Sengul C, Cevik C, Ozveren O, Sunbul A, Oduncu V, Akgun T, Can MM,
Semiz E, Dindar I. Acute alcohol consumption is associated with increased
interatrial electromechanical delay in healthy men. Cardiol J. 2011;18:682–
686.
5. Hendriks HF, Veenstra J, Velthuis-te Wierik EJ, Schaafsma G, Kluft C. Effect of moderate dose of alcohol with evening meal on fibrinolytic factors.
BMJ. 1994;308:1003–1006.
6. Briasoulis A, Agarwal V, Messerli FH. Alcohol consumption and the risk of
hypertension in men and women: a systematic review and metaanalysis. J
Clin Hypertens (Greenwich). 2012;14:792–798. doi: 10.1111/ jch.12008.
7. 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.
8. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D,
Moher D, Becker BJ, Sipe TA, Thacker SB. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis
Of Observational Studies in Epidemiology (MOOSE) group. JAMA.
2000;283:2008–2012.
9. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188.
10.Orsini N, Bellocco R, Greenland S. Generalized least squares for trend estimation of summarized dose-response data. Stata J. 2006;6:40–57.
11.Cochran W. The combination of estimates from different experiments. Biometrics. 1954;10:101–129.
12.Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–560. doi: 10.1136/
bmj.327.7414.557.
13.Selb Semerl J, Selb K. Coffee and alcohol consumption as triggering factors
for sudden cardiac death: case-crossover study. Croat Med J. 2004;45:775–
780.
14.Marshall RJ, Wouters S, Jackson RT. A case-crossover analysis of a casecontrol study of alcohol consumption and coronary events: the effects
of exposure definition and the use of control data. J Epidemiol Biostat.
2000;5:367–373.
15.Gerlich MG, Krämer A, Gmel G, Maggiorini M, Lüscher TF, Rickli H,
Kleger GR, Rehm J. Patterns of alcohol consumption and acute myocardial
infarction: a case-crossover analysis. Eur Addict Res. 2009;15:143–149.
doi: 10.1159/000213641.
16.Gerlich MG, Rehm J. Recall bias in case-crossover designs studying
the potential influence of alcohol consumption. J Stud Alcohol Drugs.
2010;71:619; author reply 620–619; author reply 621.
17.Leong DP, Smyth A, Teo KK, McKee M, Rangarajan S, Pais P, Liu L,
Anand SS, Yusuf S; INTERHEART Investigators. Patterns of alcohol consumption and myocardial infarction risk: observations from 52 countries
in the INTERHEART case-control study. Circulation. 2014;130:390–398.
doi: 10.1161/CIRCULATIONAHA.113.007627.
18.Mostofsky E, van der Bom JG, Mukamal KJ, Maclure M, Tofler GH,
Muller JE, Mittleman MA. Risk of myocardial infarction immediately after alcohol consumption. Epidemiology. 2015;26:143–150. doi: 10.1097/
EDE.0000000000000227.
19.Jackson R, Scragg R, Beaglehole R. Does recent alcohol consumption reduce the risk of acute myocardial infarction and coronary death in regular
drinkers? Am J Epidemiol. 1992;136:819–824.
20.McElduff P, Dobson AJ. How much alcohol and how often? Population
based case-control study of alcohol consumption and risk of a major coronary event. BMJ. 1997;314:1159–1164.
21.Schröder H, Masabeu A, Marti MJ, Cols M, Lisbona JM, Romagosa C,
Carión T, Vilert E, Marrugat J; REGICOR investigators. Myocardial infarction and alcohol consumption: a population-based case-control study.
Nutr Metab Cardiovasc Dis. 2007;17:609–615. doi: 10.1016/j. numecd.2006.04.010.
22.Leon DA, Shkolnikov VM, McKee M, Kiryanov N, Andreev E. Alcohol
increases circulatory disease mortality in Russia: acute and chronic effects or misattribution of cause? Int J Epidemiol. 2010;39:1279–1290. doi:
10.1093/ije/dyq102.
23.Mostofsky E, Burger MR, Schlaug G, Mukamal KJ, Rosamond WD, Mittleman MA. Alcohol and acute ischemic stroke onset: the stroke onset study.
Stroke. 2010;41:1845–1849. doi: 10.1161/ STROKEAHA.110.580092.
24.Gorelick PB, Rodin MB, Langenberg P, Hier DB, Costigan J, Gomez I,
Spontak S. Is acute alcohol ingestion a risk factor for ischemic stroke? Results of a controlled study in middle-aged and elderly stroke patients at
three urban medical centers. Stroke. 1987;18:359–364.
25.Syrjänen J, Valtonen VV, Iivanainen M, Kaste M, Huttunen JK. Preceding
infection as an important risk factor for ischaemic brain infarction in young
and middle aged patients. BMJ. (Clin Res Ed). 1988;296:1156–1160.
26.Shinton R, Sagar G, Beevers G. The relation of alcohol consumption to cardiovascular risk factors and stroke. The West Birmingham stroke project. J
Neurol Neurosurg Psychiatry. 1993;56:458–462.
Mostofsky y cols
Alcohol y riesgo inmediato de eventos cardiovasculares
27.Jamrozik K, Broadhurst RJ, Anderson CS, Stewart-Wynne EG. The role of
lifestyle factors in the etiology of stroke. A population-based case-control
study in Perth, Western Australia. Stroke. 1994;25:51–59.
28.Numminen H, Hillbom M, Juvela S. Platelets, alcohol consumption, and onset of brain infarction. J Neurol Neurosurg Psychiatry. 1996;61:376–380.
29.Haapaniemi H, Hillbom M, Juvela S. Lifestyle-associated risk factors for
acute brain infarction among persons of working age. Stroke. 1997;28:26–30.
30.You RX, McNeil JJ, O’Malley HM, Davis SM, Thrift AG, Donnan GA.
Risk factors for stroke due to cerebral infarction in young adults. Stroke.
1997;28:1913–1918.
31.Malarcher AM, Giles WH, Croft JB, Wozniak MA, Wityk RJ, Stolley PD,
Stern BJ, Sloan MA, Sherwin R, Price TR, Macko RF, Johnson CJ, Earley
CJ, Buchholz DW, Kittner SJ. Alcohol intake, type of beverage, and the risk
of cerebral infarction in young women. Stroke. 2001;32:77–83.
32.Taylor JR, Combs-Orme T. Alcohol and strokes in young adults. Am J Psychiatry. 1985;142:116–118. doi: 10.1176/ajp.142.1.116.
33.Bråthen G, Brodtkorb E, Sand T, Helde G, Bovim G. Weekday distribution
of alcohol consumption in Norway: influence on the occurrence of epileptic
seizures and stroke? Eur J Neurol. 2000;7:413–421.
34.Taylor JR. Alcohol and strokes. N Engl J Med. 1982;306:1111. doi:
10.1056/NEJM198205063061816.
35.Taylor JR, Combs-Orme T, Anderson D, Taylor DA, Koppenol C. Alcohol,
hypertension, and stroke. Alcohol Clin Exp Res. 1984;8:283–286.
36.Gill JS, Zezulka AV, Shipley MJ, Gill SK, Beevers DG. Stroke and alcohol consumption. N Engl J Med. 1986;315:1041–1046. doi: 10.1056/
NEJM198610233151701.
37.Vlak MH, Rinkel GJ, Greebe P, van der Bom JG, Algra A. Trigger factors and their attributable risk for rupture of intracranial aneurysms:
a case-crossover study. Stroke. 2011;42:1878–1882. doi: 10.1161/
STROKEAHA.110.606558.
38.Juvela S, Hillbom M, Numminen H, Koskinen P. Cigarette smoking and
alcohol consumption as risk factors for aneurysmal subarachnoid hemorrhage. Stroke. 1993;24:639–646.
39.Juvela S, Hillbom M, Palomäki H. Risk factors for spontaneous intracerebral hemorrhage. Stroke. 1995;26:1558–1564.
40.Thrift AG, Donnan GA, McNeil JJ. Heavy drinking, but not moderate or
intermediate drinking, increases the risk of intracerebral hemorrhage. Epidemiology. 1999;10:307–312.
41.Saloheimo P, Juvela S, Hillbom M. Use of aspirin, epistaxis, and untreated
hypertension as risk factors for primary intracerebral hemorrhage in middle- aged and elderly people. Stroke. 2001;32:399–404.
11
42.Janszky I, Ericson M, Blom M, Georgiades A, Magnusson JO, Alinagizadeh H, Ahnve S. Wine drinking is associated with increased heart rate
variability in women with coronary heart disease. Heart. 2005;91:314–318.
doi: 10.1136/hrt.2004.035105.
43.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.
44.Pai JK, Mukamal KJ, Rimm EB. Long-term alcohol consumption in relation to all-cause and cardiovascular mortality among survivors of myocardial infarction: the Health Professionals Follow-up Study. Eur Heart J.
2012;33:1598–1605. doi: 10.1093/eurheartj/ehs047.
45.Breslow RA, Mukamal KJ. Measuring the burden–current and future research trends: results from the NIAAA Expert Panel on Alcohol and Chronic Disease Epidemiology. Alcohol Res. 2013;35:250–259.
46.United States Dietary Guidelines Advisory Committee. Scientific Report of
the Dietary Guidelines Advisory Committee on the Dietary Guidelines for
Americans to the Secretary of Agriculture and the Secretary of Health and
Human Services. 2015. http://permanent.access.gpo.gov/gpo51700/2015/
Scientific-Report-of-the-2015-Dietary-Guidelines-Advisory-Committee.
pdf. Accessed July 13, 2015.
47.Tabakoff B, Cornell N, Hoffman PL. Alcohol tolerance. Ann Emerg Med.
1986;15:1005–1012.
48.Shaper AG, Wannamethee G, Walker M. Alcohol and mortality in British
men: explaining the U-shaped curve. Lancet. 1988;2:1267–1273.
49.Wouters S, Marshall R, Yee RL, Jackson R. Is the apparent cardioprotective effect of recent alcohol consumption due to confounding by prodromal
symptoms? Am J Epidemiol. 2000;151:1189–1193.
50.Mukamal KJ, Chen CM, Rao SR, Breslow RA. Alcohol consumption and
cardiovascular mortality among U.S. adults, 1987 to 2002. J Am Coll Cardiol. 2010;55:1328–1335. doi: 10.1016/j.jacc.2009.10.056.
51.Han H, Wang H, Yin Z, Jiang H, Fang M, Han J. Association of genetic
polymorphisms in ADH and ALDH2 with risk of coronary artery disease
and myocardial infarction: a meta-analysis. Gene. 2013;526:134–141. doi:
10.1016/j.gene.2013.05.002.
52.Kerr WC, Greenfield TK, Bond J, Ye Y, Rehm J. Racial and ethnic differences in all-cause mortality risk according to alcohol consumption patterns
in the national alcohol surveys. Am J Epidemiol. 2011;174:769–778. doi:
10.1093/aje/kwr147.
53.Wechsler H, Dowdall GW, Davenport A, Rimm EB. A gender-specific
measure of binge drinking among college students. Am J Public Health.
1995;85:982–985.
PERSPECTIVA CLÍNICA
Existe evidencia consistente de que el consumo moderado habitual se asocia con un menor riesgo de enfermedad coronaria, mientras que el consumo de alcohol importante puede ser peligroso. Sin embargo, los riesgos agudos que siguen
a la ingesta de alcohol no han sido bien caracterizados. Sobre la base de sus efectos fisiológicos, el alcohol puede tener
efectos marcadamente diferentes sobre el riesgo inmediato y a largo plazo. Por lo tanto, llevamos a cabo una revisión
sistemática y meta-análisis de estudios observacionales que evaluaron la asociación entre la ingesta de alcohol y el infarto de miocardio, el ACV isquémico y el ACV hemorrágico en las horas y días siguientes. Sobre la base de los datos
provenientes de 23 artículos de texto completo (29 457 participantes) el consumo de alcohol moderado estuvo asociado
con un riesgo cardiovascular más alto en forma inmediata que fue atenuado después de las 24 horas, e incluso protector
del infarto de miocardio y el ACV hemorrágico, y protector frente al ACV isquémico dentro de la semana. En contraste,
beber alcohol de manera importante estuvo asociado con un mayor riesgo cardiovascular en el día y la semana siguiente.