Systematic review of the potential adverse effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children: Cardiovascular Outcome D R. J E F F R E Y G O L D B E R G E R U N I V E R S I T Y O F M I A M I M I L L E R S C H O O L O F M E D I C I N E P R E S E N T E D B Y DR. D A N I E L E W I K O F F T O X S T R AT E G I E S 1
PECO Questions for the Cardiovascular Outcome For [population], is caffeine intake above [dose], compared to intakes [dose] or less, associated with adverse effects on cardiovascular health outcomes? Population Healthy Adults Healthy Pregnant Women Healthy Adolescents Healthy Children Exposure > 400 mg/day > 300 mg/day > 2.5 mg/kg-day > 2.5 mg/kg-day Comparator 400 mg/day 300 mg/day 2.5 mg/kg-day 2.5 mg/kg-day Outcome Adverse cardiovascular effects 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? 2
Characterization of Data for Cardiovascular Outcome Data Type Number of studies 203 included; 73 excluded Characterization Study types Populations Exposure Outcome (Endpoints) Mostly randomized controlled trials; some observational studies; 5 meta-analyses Mostly healthy adults; few children/adolescents Pure caffeine (RCTs) or Dietary, e.g., coffee, tea soda, energy drinks etc. (observational studies) 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 function 3
Mortality 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 mortality At 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) Moderate level of confidence in the body of evidence 4
Morbidity 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 levels Some 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 base increased by the low level of indirectness, low risk of bias in the individual studies 5
Blood Pressure Intakes 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 evaluated Biological 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 caffeine The 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 acceptable Considering 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 factors Moderate level of confidence in this evidence base 6
Evaluation of Individual Study Quality (Risk of Bias) Overall probably low risk of bias Limited by exposure characterization in observational studies (Q8) +2: Definitely low +1: Probably low -1: Probably high -2: Definitely high 7
Factors that increased or decreased confidence in the body of evidence by endpoint Adults Endpoint No. of Studies Initial Confidence Rating Based on study type and study features (OHAT, 2015) Overall RoB Domainbased evaluation of risk of bias per the OHAT RoB tool (OHAT, 2015) Indirectness Was the study designed to evaluate the PECO? Magnitude Strength of effect (when effect observed below the comparator) Confounding Were 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 Rating What is the overall rating when factors that increase or decrease confidence were considered Mortality 13 Moderate /- -- /- Moderate Morbidity 18 Moderate /- -- Moderate Blood pressure 115 Moderate to high /- /- -- Moderate Heart rate 53 Moderate to high /- Cholesterol 24 Moderate to high /- /- Moderate to high Heart rate viability 13 Moderate to high /- -- /- Moderate to high Adolescents and children Blood pressure 10 Moderate to high /- High increased confidence - no change to confidence decreased confidence Heart rate 6 High /- High 8
Developing Conclusions for the Outcome: Integration of Weight of Evidence Considerations 9
WoE 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 inconsistent 10
Future Research Needs More research in children and adolescent populations Better 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 effects 11