University of Miami Miller School of Medicine Presented by Dr Daniele Wikoff ToxStrategies 1 Systematic review of the potential adverse effects of caffeine consumption in healthy adults pregnant women adolescents and ID: 595809
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Dr. Jeffrey GoldbergerUniversity of Miami Miller School of MedicinePresented byDr. Daniele WikoffToxStrategies
1
Systematic review of the potential adverse effects of caffeine consumption in healthy adults, pregnant women, adolescents, and
children:
Cardiovascular OutcomeSlide2PECO Questions for the Cardiovascular Outcome
2
For [population], is caffeine intake above [dose], compared to intakes [dose] or less, associated with adverse effects
on cardiovascular health outcomes
?
Example: For healthy adults,
is caffeine intake
above 400 mg/day, compared to intakes 400 mg/day or less, associated with adverse effects on cardiovascular health outcomes?
P
opulation
Healthy
Adults
Healthy
Pregnant
Women
Healthy Adolescents
Healthy
Children
E
xposure
> 400 mg/day
> 300 mg/day
> 2.5 mg/kg-day
> 2.5 mg/kg-day
C
omparator
≤ 400 mg/day
≤ 300 mg/day
≤ 2.5 mg/kg-day
≤ 2.5 mg/kg-day
O
utcome
Adverse cardiovascular effectsSlide3Characterization of Data for Cardiovascular
OutcomeData TypeCharacterizationNumber of studies
203 included; 73 excluded
Study types
Mostly randomized controlled trials; some observational studies; 5 meta-analyses
Populations
Mostly healthy adults; few children/adolescentsExposurePure caffeine (RCTs) orDietary, e.g., coffee, tea soda, energy drinks etc. (observational studies)Outcome (Endpoints)Clinical:
Mortality (e.g. stroke, coronary heart disease) Morbidity (e.g. acute myocardial infarctions, atrial fibrillation, stroke)Physiological: aortic stiffness, blood pressure, cerebral blood flow, heart rate, heart rate variability, LDL, cholesterol, plasma and urinary constituents, other hemodynamic measurements, ventricular function3Slide4Mortality
The majority of evidence support that 400 mg caffeine/day in healthy adult populations is an acceptable intake which is not associated with significant concern for cardiovascular mortalityAt higher intakes up to ~855 mg/day, there are no consistently reported effects Several studies, reported findings that are suggestive of protective effects Studies
reporting effects, both above and below the comparator, were conditional (e.g., observed in subset of data evaluated) M
oderate
level of confidence in the body of
evidence
4Slide5Morbidity
Evidence support that 400 mg caffeine/day in healthy adult populations is an acceptable intake which is not associated with significant concern regarding cardiovascular morbidity Several studies (including meta-analyses) suggested that the comparator is too low All comparison points above 400 mg/day (up to 1050 mg/day) were no effect levelsSome studies, including two meta-analyses reported
effect levels below the comparator Associations were observed only in specific
genotypes (highlighting potential
role of kinetic
influence)
Moderate level of confidence in the evidence baseincreased by the low level of indirectness, low risk of bias in the individual studies 5Slide6
Blood PressureIntakes both below and above the comparator, have the potential to result in an increase in blood pressure (often only a few mmHg) in all populations evaluatedBiological
significance of this small magnitude of change is difficult to interpret (and is conditional) The
range of normal blood pressure variation during the day exceeds the increase that is associated with caffeine
The
blood pressure increase with exercise is typically substantially greater than that observed with
caffeineThe comparator of 400 mg/day in healthy adults is too high if one is only considering the potential for caffeine to cause a physiological change in blood pressure The comparator of 400 mg/day is likely acceptableConsidering the small magnitude of changes in this physiological parameter Lack of information demonstrating an association between chronic caffeine-mediated blood pressure increases relative to known cardiovascular risk factorsModerate level of confidence in this evidence base
6Slide7
Evaluation of Individual Study Quality (Risk of Bias)Overall “probably low” risk of biasLimited by exposure characterization in observational studies (Q8)7
+2
: Definitely low
+1
: Probably low
-1: Probably high-2: Definitely highSlide8Factors that increased or decreased confidence in the body of evidence by endpoint
8EndpointNo. of Studies
Initial Confidence Rating
Based on study type and study features (OHAT, 2015)
Overall
RoB Domain-based evaluation of risk of bias per the OHAT RoB tool (OHAT, 2015) IndirectnessWas the study designed to evaluate the PECO? Magnitude
Strength of effect (when effect observed below the comparator) ConfoundingWere plausible confounders that would change the observed effect accounted for? Consistency Were findings consistent in demonstrating effects or lack of effects at or below the comparator Final Confidence RatingWhat is the overall rating when factors that increase or decrease confidence were consideredAdults
Mortality
13
Moderate
↑/-
↑
--
↑
↑/-
Moderate
Morbidity
18
Moderate
↑/-
↑
--
↑
↓
Moderate
Blood
pressure
115
Moderate to high
↑/-
↑
↓/-
↑
--ModerateHeart rate53Moderate to high↑/-↑—Cholesterol24Moderate to high↑/-↑/-↓—↑Moderate to highHeart rate viability13Moderate to high↑/-↑--—↑/-Moderate to highAdolescents and childrenBlood pressure10Moderate to high↑/-↑↓—↑HighHeart rate6High↑↑——↑/-High
↑
increased confidence - no
change
to confidence
↓
decreased
confidence Slide9Developing Conclusions for the Outcome: Integration of Weight of Evidence Considerations
9Slide10WoE Conclusion: Cardiovascular
Adults: When the weight of evidence was considered, with particular emphasis on level of adversity, 400 mg caffeine/day was found to be an acceptable intake which is not associated with significant concern regarding adverse cardiovascular effects. Some findings suggested that the comparator was too low (clinical endpoints)Some findings reported effects below the comparator (mostly physiological endpoints)Limited by the inability to ascertain the conditions and magnitude of change that would be considered adverse
Moderate to high level of confidence in the evidence base.
Children and adolescents: the
evidence base was insufficient
to develop conclusion
Available data (blood pressure and heart rate) are inconsistent10Slide11Future Research Needs
More research in children and adolescent populationsBetter understanding of dose-response relationships following chronic exposure for some endpoints (e.g. endothelial function and heart rate variability)In some cases (e.g. certain physiological endpoints), a better characterization of what, if any, magnitude of change may be associated with adverse effects11