PROSPERO International prospective register of systematic reviews
Systematic review of the adverse cardiovascular effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children
Daniele Wikoff, Candace Doepker, Brian Welsh, Jon Urban, Rayetta Henderson, Greg Brorby, Janice Britt, Seneca Harvey, Jeffrey Goldberger, Esther Myers, Charles O'Brien, Jennifer Peck, Harris Lieberman, Connie Weaver, Milton Tenebein
Daniele Wikoff, Candace Doepker, Brian Welsh, Jon Urban, Rayetta Henderson, Greg Brorby, Janice Britt, Seneca Harvey, Jeffrey Goldberger, Esther Myers, Charles O'Brien, Jennifer Peck, Harris Lieberman, Connie Weaver, Milton Tenebein. Systematic review of the adverse cardiovascular effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children.
Available from http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015026673
For [population], is caffeine intake above [exposure dose], compared to intakes [exposure dose] or less, associated with adverse effects on cardiovascular outcomes?
Problem formulation was based on providing an update of Nawrot et al. (2003), “Effects of caffeine on human health,” [PMID 12519715]. No comprehensive studies of similar scope have been published in the peer-reviewed literature, and thus the overall objective is to conduct an update to Nawrot et al. that applies the rigor of a systematic review. This review is one of five systematic reviews being conducted simultaneously (other endpoints include acute toxicity and adverse effects on behavior, bone and calcium balance, and reproductive and developmental outcomes. Exposure and comparators were thus based on levels determined by Nawrot et al., (2003).
Associated with the primary PECO question, there is a secondary objective to identify and characterize information regarding the pharmacokinetics of caffeine. Specifically, with respect to studies that advance the current understanding of differences/similarities between our populations of interest, characterization of pharmacokinetics in non-adult populations of interest, and characterization of pharmacokinetics (e.g., fast/slow phenotypes) in the context of adverse effects on cardiovascular outcomes.
The searches will be conducted using: PubMed, EMBASE, and the Cochrane Database of Systematic Review.
The restrictions will be articles published in English between 2001 and June 8, 2015. Embase searches were exclusive of MEDLINE and restricted to selected journals (430 journals were selected based on relevance). The Cochrane library was searched between Jan 2001 and June 2015 for review articles.
Search strategies were informed and reviewed by a librarian.
Types of study to be included
All study types (excluding case studies without a control arm ) characterizing a quantitative exposure to caffeine and an adverse cardiovascular endpoint will be included. Both exposure and response must be evaluated at the individual level.
Reviews will not be included in the systematic assessment (unless original data, such as a meta analysis, were conducted), but selected reviews will be consulted for context.
Include: studies reporting parameters or effects associated with adverse effects within a benefit/therapy study.
Exclude: Studies assessing only beneficial or therapeutic endpoints or outcomes following exposure to caffeine.
Include: Studies evaluating a healthy population; this will include athletes, military, and pregnant women, unless otherwise noted as unhealthy. Healthy in this context was defined as subjects who were not specifically described as hospitalized, diagnosed with disease, and/or receiving medical treatment for a disease at the time of the study.
Include: Studies that evaluate the effects of caffeine exposure in humans. This included studies in which healthy individuals were included as a control group (or similar) as part of a study on unhealthy populations (only information from the healthy individuals would be carried forward).
Exclude: Studies evaluating unhealthy populations with no healthy control arm; this includes asthmatics and smoking populations.
Exclude: Studies that describe effects of caffeine exposure in animal species or in vitro studies.
Include: Studies that provide a quantitative exposure to a caffeine source associated with an adverse effect. Acceptable forms of caffeine are coffee, tea, chocolate, cola-type beverages, energy drinks (e.g. Monster, Red Bull, Rockstar), supplements, medicines, energy shots, caffeinated chewing gum, caffeinated sport gel, and caffeinated sport bars.
Include: Studies evaluating the effects of caffeine alone, in one of the aforementioned forms, or in combination with one or more compounds occurring in the approved sources at levels designed to match constituents of valid sources (e.g., caffeine and green tea extract).
Exclude: Studies that do not provide a quantitative exposure to an acceptable caffeine source associated with an adverse effect. This includes studies that evaluate only decaffeinated coffee/tea and caffeine placebo exposures (i.e. exposures where participants were expecting caffeine but did not receive the drug), Yerba mate, guarana, damiana and/or contaminants of caffeine or caffeine metabolites.
Exclude: Studies that evaluate the effects of caffeine in combination with another pharmacologically active compound in an OTC medicine such as Excedrin (acetaminophen + caffeine) or in a prescribed drug, alcohol, or nicotine.
Adverse cardiovascular effects include, but are not limited to, effects on blood pressure and heart rate, myocardial infarction, and stroke (inclusive investigation).
Pharmacokinetic data that could be used to interpret the primary outcome (e.g., contextual information).
Risk of bias (quality) assessment
Risk of bias will be evaluated using the U.S. National Toxicology Program: Office of Health Assessment and Translation Risk of Bias Rating Tool for Human and Animal studies (2015).
Study reliability will also be characterized using the systematic approach for evaluating and scoring human data proposed by Money et al (2013) [PMID 23579077]
Strategy for data synthesis
The body of evidence will be evaluated and integrated using the U.S. National Toxicology Program: Office of Health Assessment and Translation Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review an Evidence Integration (2015). The process will involve generation of evidence tables and a qualitative synthesis of the available data. Evidence analysts will use a weight of evidence approach incorporating concepts such as consistency, dose response, imprecision, indirectness, magnitude of effect, confounding, and risk of bias to determine conclusions regarding levels of caffeine associated with adverse cardiovascular effects. Analytical tools, such as forest plots and descriptive statistical parameters, will be used to aid in the weight of evidence assessment. Pending the availability of data, considerations will also be made regarding the severity of the outcome as well as the event(s) relative to the progression of the outcome.
Analysis of subgroups or subsets
Conclusions will be drawn, where data are available, for each of the populations under investigation.
Contact details for further information
9390 Research Blvd
Austin, TX, 78759
Organisational affiliation of the review
ToxStrategies and the North American Branch of the International Life Sciences Institute (ILSI) Caffeine Working Group
Dr Daniele Wikoff, ToxStrategies Dr Candace Doepker, ToxStrategies Dr Brian Welsh, ToxStrategies Dr Jon Urban, ToxStrategies Dr Rayetta Henderson, ToxStrategies Mr Greg Brorby, ToxStrategies Dr Janice Britt, ToxStrategies Ms Seneca Harvey, ToxStrategies Dr Jeffrey Goldberger, Feinberg School of Medicine, Northwestern University Dr Esther Myers, EF Myers Consulting Dr Charles O'Brien, Department of Psychiatry, University of Pennsylvania Dr Jennifer Peck, College of Public Health, University of Oklahoma Health Science Center Dr Harris Lieberman, Research Psychologist, U.S. Army Research Institute of Environmental Medicine Dr Connie Weaver, Head of the Department of Nutrition Science, Purdue University Dr Milton Tenebein, Department of Pharmacology and Therapeutics, Department of Pediatrics and Child Health University of Manitoba
Details of any existing review of the same topic by the same authors
Conducted in coordination with: Systematic review of the adverse bone and calcium balance effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children. PROSPERO 2015:CRD42015026609 Available from http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015026609. Daniele Wikoff, Candace Doepker, Brian Welsh, Jon Urban, Rayetta Henderson, Janice Britt, Seneca Harvey, Jeffrey Goldberger, Esther Myers, Charles O'Brien, Jennifer Peck, Harris Lieberman, Connie Weaver, Milton Tenebein.
Anticipated or actual start date
31 October 2014
Anticipated completion date
31 August 2016
The systematic review of the adverse cardiovascular effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children is sponsored by the North American Branch of the International Life Sciences Institute (ILSI) Caffeine Working Group and unrestricted grants from the American Beverage Association (ABA) and the National Coffee Association (NCA). ILSI North America is a public, nonprofit foundation that provides a forum for government, academia and industry, to advance understanding of scientific issues related to the nutritional quality and safety of the food supply by sponsoring research programs, educational seminars and workshops, and publications. ILSI North America receives support primarily from its industry membership. ABA is the national trade association that represents the U.S. non-alcoholic beverage industry. NCA is the national trade association that represents the U.S. coffee industry. ToxStrategies and some of the members of the Scientific Advisory Board received funds or an honorarium from ILSI North America for conducting the work on the systematic review of caffeine.
Conflicts of interest
Each study team member and scientific advisory board member completed a comprehensive COI questionnaire. This process included documentation of both financial and non-financial COI. The questions addressed investments, employment, consultancies/advisories, contracts/grants, patents/royalties/trademarks, expert witness testimonial, speaking/writing, past financial interests, other involvements and relationships, personal beliefs, previous published opinions, career advancement, advocacy/policy positions, and other conflicts of interest. Declarations were reviewed and determined, overall, not to exert undue influence on the primary interest of the systematic review. It is recognized that the project team includes experts on caffeine (CD, CO, JG, JP, HL, and MT); the inclusion of these team members is consistent with recommendations of the Institute of Medicine (IOM) guidance, “Finding What Works in Health Care – Standards for Systematic Reviews, regarding inclusion of knowledgeable experts in the field of interest (as well as other expert areas). The scope of the relationships between the authors with declarations and conduct of the systematic review will be cautiously managed via implementation practices; none of the team members conducting literature review, individual study assessment, and body of evidence assessment declared any conflicts of interest. None of the authors will directly benefit from the conclusions of the systematic review.
CW, DW, BW, JU, GB, RH, and SH declare that they have no known conflict of interest.
As a recognized expert in caffeine, CD is employed by a consulting firm that conducts work on caffeine and coffee for various confidential clients. CD has given talks on this topic at seminars, conferences, and meetings for which travel and accommodation has been paid for by the organizers; she has also been asked to provide opinions in various public forums on caffeine and health as part of her role with previous employers.
CO has published in the area of caffeine withdrawal and has previously provided expert consultation to ILSI (<$7,500).
Cardiotoxicology expert (JG) has published a review on the effects of caffeine on cardiac arrhythmias and has provided expert consultation and expert witness testimony (single event) for an energy drink company (total combined compensation <$20,000 USD).
HL has published 10 peer-review articles on the topic of caffeine and authored/co-authored 4 book chapters. HL (uncompensated) serves as a scientific liaison for the ILSI-NA Caffeine Working Group.
EM reported being a member of the Committee on Dietary Supplement Use by Military Personnel and Food and Nutrition Board (IOM) as well as the Chief Scientific Officer for the Academy of Nutrition and Dietetics (EAL oversight). EM also reported a bias toward a stance of moderations in intake.
JP reported previous consultancies to ILSI to serve as a scientific advisor to the caffeine working group and published a peer-reviewed review of caffeine and reproductive outcomes (total compensation <$15,000).
MT reported making a public statement that consumption of routine amounts of energy drinks would be not be expected to produce significant adverse effects.
United States of America
Subject index terms status
Subject indexing assigned by CRD
Subject index terms
Adolescent; Adult; Caffeine; Cardiovascular System; Child; Coffee; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Pregnancy
Stage of review
Date of registration in PROSPERO
29 September 2015
Date of publication of this revision
29 September 2015
Stage of review at time of this submission
Piloting of the study selection process
Formal screening of search results against eligibility criteria
Risk of bias (quality) assessment
PROSPERO This information has been provided by the named contact for this review. CRD has accepted this information in good faith and registered the review in PROSPERO. CRD bears no responsibility or liability for the content of this registration record, any associated files or external websites.