the effects of dietary nitrate supplementation on

RESEARCH ARTICLE Open Access

The effects of dietary nitratesupplementation on endurance exerciseperformance and cardiorespiratorymeasures in healthy adults: a systematicreview and meta-analysisChloe Gao1, Saurabh Gupta2, Taranah Adli3, Winston Hou4, Reid Coolsaet5, Abigail Hayes6, Kevin Kim7,8,Arjun Pandey4, Jacob Gordon4, Gurneet Chahil9,10, Emilie P. Belley-Cote9,11 and Richard P. Whitlock2,8,9,12*

Abstract

Background: Nitrate supplementation is thought to improve performance in endurance sports.

Objective: To meta-analyze studies evaluating the effect of nitrate supplementation on endurance sportsperformance among adults.

Data sources: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Webof Science and CINAHL without language restrictions.

Methods: We included studies that: 1) compared nitrate supplementation with placebo; 2) enrolled adultsengaging in an endurance-based activity; and 3) reported a performance measure or surrogate physiologicoutcome. We evaluated risk of bias using the Cochrane Collaboration tool and pooled data with a random-effectsmodel. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach toevaluate confidence in estimates.

Results: We included 73 studies (n = 1061). Nitrate supplementation improved power output (MD 4.6 watts, P <0.0001), time to exhaustion (MD 25.3 s, P < 0.00001), and distance travelled (MD 163.7 m, P = 0.03). We found nosignificant difference on perceived exertion, time trial performance and work done. Nitrate supplementationdecreased VO2 (MD − 0.04 L/min, P < 0.00001) but had no significant effect on VO2max or blood lactate levels.

Conclusion: The available evidence suggests that dietary nitrate supplementation benefits performance-relatedoutcomes for endurance sports.

Keywords: Nitrate supplementation, Endurance exercise, Systematic review and meta-analysis

© The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.

* Correspondence: [email protected] of Surgery, McMaster University, Hamilton, Ontario, Canada8Department of Health Research Methods, Evidence and Impact, McMasterUniversity, Hamilton, Ontario, CanadaFull list of author information is available at the end of the article

Gao et al. Journal of the International Society of Sports Nutrition (2021) 18:55 https://doi.org/10.1186/s12970-021-00450-4

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Strengths and limitations of this study

� Systematic review and meta-analysis of randomizedstudies with a comprehensive search strategy andpre-specified protocol

� Rigorous methods and systematic evaluation ofrandomized data

� Insufficient details on randomization procedures instudy reports, leading to unclear risk of bias

� Heterogeneity in study methodologies and outcomereporting

BackgroundEndurance capacity is an important component ofphysical fitness that relates to the ability of the circula-tory and respiratory systems to support sustained phys-ical activity [1]. The performance of athletes trainingand competing in sports such as distance running, tri-athlons, swimming, biking and rowing depends on theirendurance capacity [2, 3]. Different macronutrients andmicronutrients have been used as ergogenic aids to po-tentially improve performance [4]. Specifically, nitratesare thought to potentially improve athletic perform-ance. Beetroot juice, pomegranate extract and greenleafy vegetables such as collard greens, lettuce, andspinach constitute substantial sources of dietary nitrate[5]. While the exact mechanism underlying the ergo-genic benefits of nitrate supplementation has not yetbeen established, it has been proposed that dietary ni-trate, once ingested, is reduced to nitric oxide (NO).Classically, NO was thought to be generated by

oxidation of L-arginine, resulting in endogenous pro-duction of nitrate (NO3-) and nitrite (NO2-). A vaso-dilator, it is believed to influence muscle function bymodulating skeletal muscle function through its role inblood flow regulation, contractility, glucose and calciumhomeostasis, and mitochondrial biogenesis [5]. In-creased levels of NO in tissues and peripheral circula-tion may lead to improved oxygen transport and uptakein muscles during exercise [3, 6]. Figure 1 gives detailson the potential mechanisms that nitrate supplementa-tion can, eventually, result in improved physicalperformance.While animal studies (in dogs, cats and horses) have

demonstrated that reduction in endogenous NO produc-tion increases oxygen consumption (VO2), controversyremains in human performance. In fact, recent researchsuggesting nitrate supplementation may have perform-ance benefits has resulted in its increased popularityamong individuals attempting to improve their athleticperformance [7]. However, the results of primary investi-gations examining nitrate supplementation have been in-consistent, with some studies suggesting a benefit ([8–11]) and others no effect ([12–15]). In reviewing thesestudies, along with input from elite athlete (co-author,RC), we decided to focus on power output, time to ex-haustion, and VO2, among others as metrics of athleticperformance.This systematic review and meta-analysis aimed to

summarize the placebo-controlled trials evaluating diet-ary nitrate supplementation’s effect on endurance exer-cise performance.

Fig. 1 Possible mechanisms of effect of nitrate on athletic performance

Gao et al. Journal of the International Society of Sports Nutrition (2021) 18:55 of 11

MethodsIdentification of studiesWe searched the Cochrane Central Register of Con-trolled Trials (CENTRAL), MEDLINE, EMBASE, Webof Science and CINAHL from inception to February2021 without language restrictions (Search strategy –Supplementary Table 1).

Study inclusion and selectionWe included comparative studies that examined the ef-fect of dietary nitrate supplementation on endurance ac-tivities. We performed title and abstract screeningindependently and in duplicate using the Covidence on-line software (Veritas Health Innovation, Melbourne,Australia). If either reviewer deemed a study relevant, weretrieved it for full-text review. We resolved disagree-ments between reviewers regarding eligibility throughdiscussion or third-party arbitration. Eligible studies hadto meet the following criteria:The population of interest was healthy adults (over the

age of 18) participating in endurance-based activities, in-cluding: distance running, rowing, cycling, swimming,kayaking, and triathlon. The study had to examine atleast one source of dietary nitrate, to compare it to noexposure, and to report on any one of the outcomes ofinterest: power output, time to exhaustion, rating of per-ceived exertion, time trial performance, distance trav-elled, work done, VO2, VO2max, or blood lactate.The outcome of time to exhaustion is one of signifi-

cant complexity. Studies varied in use of constant exer-cise versus incremental/gradual exercise test; thisinformation was not readily available in all studies. Assuch, whenever possible, we recorded time to exhaustionfor controls and nitrate supplementation for available in-crements and meta-analysed them together. Thisallowed a comparison (with limitations) of no nitrate tonitrate on time to exhaustion at all potential power out-puts. Unfortunately, not enough studies explicity statedincremental versus constant to conduct a sensitivityanalysis.

Data collection and managementWe performed data extraction independently and in du-plicate using pre-piloted extraction forms. If there was adiscrepancy, a third party reviewed the data.

Risk of bias assessment for RCTsWe judged risk of bias as “low, “high” or “unclear” usingthe Cochrane Collaboration Risk of Bias Tool [16]. Twoindependent reviewers evaluated each trial for six as-pects: random sequence generation, allocation conceal-ment, blinding of participants and personnel, blinding ofoutcome assessment, selective reporting and othersources of bias. If all aspects were considered to have

“low” risk of bias, we considered the study at “low” risk.If even one aspect or more was considered to have “un-clear” risk of bias, we considered the paper at “unclear”risk. Studies with at least one aspect considered to have“high” risk of bias were considered at “high” risk.

Summary measures of treatment effect and unit ofanalysisWe analysed data using RevMan 5.3. Expecting hetero-geneity among studies, we used a random effects modelto pool results and summarize evidence. We evaluatedthe clinical, methodological and statistical heterogeneityof the included studies to assess whether pooling datawas appropriate. We pooled studies using the DerSimo-nian and Laird method and planned to analyse RCTsand observational studies separately. We presented pointestimates as mean difference (MD), with 95% confidenceinterval (CI).

Summary measures of treatment effect and unit ofanalysisWe performed analyses using Review Manager 5.3 (RevMan5.3). We expected heterogeneity among studies and applieda random effects model to pool relevant results and reviewthe evidence. We presented all outcomes as mean differences(MD) with 95% confidence intervals (CI).

Assessment of heterogeneityWe used the chi-squared test for homogeneity and theI2 statistic to analyse for heterogeneity. We performedsubgroups analyses (described later) to explain any het-erogeneity observed.

Publication biasWe inspected the funnel plots for potential publicationbias.

SubgroupsWe prespecified the following possible subgroups to ex-plain possible heterogeneity within data:

1. Dose: less than ~ 4mmol per day versus more than~ 4mmol per day;

2. Duration of supplementation: single day versusmultiple days;

3. Athletic level: sedentary, recreational athletes, andnational−/international-level or elite athletes;

4. Source of dietary nitrate: beetroot juice, nitratetablet/capsule/beetroot crystals, non-beet foods(pomegranate extract, watercress, red radish) andother (dissolved betaine, high nitrate diet, nitrate-rich gels, sodium nitrate dissolved in water);

5. Age profile: under 20 years of age, 20–29 years ofage, and older than 30 years of age;


6. Study design: Randomized or non-randomized com-parative study design.

In addition, we evaluated the following subgroupspost-hoc:

1. Co-supplementation with one of the followingsubstances: L-arginine, sodium phosphate, caffeine,ultraviolet light A, sodium bicarbonate, N-acetyl-cysteine (NAC);

2. Risk of bias: high and unclear versus low risk ofbias.

Assessment of confidence in pooled effect estimatesWe used the Grading of Recommendations Assessment,Development and Evaluation (GRADE) approach toevaluate confidence in effect estimate s[17]. In theGRADE framework, RCTs are considered high-qualityevidence, but they can be rated down for risk of bias, im-precision, inconsistency, indirectness or publication bias.

ResultsFigure 2 summarizes the screening and study selec-tion process. We identified 17,048 citations for titleand abstract screening and we reviewed the full-textof 449 studies. Seventy-three RCTs (n = 1061) met in-clusion criteria, which we pooled [references providedin Supplemental Table 2]. Supplemental Table 2 sum-marizes the characteristics of the included studies.These trials were all placebo-controlled, single-centre,and examined nitrate-containing substances in a totalof 1061 participants undergoing various endurance-based exercise tests. The participants ranged fromsedentary to elite athletes in their level of athletic in-volvement, with the majority of participants character-ized as recreationally active, healthy adults. The trialsreported power output (28 studies), time to exhaus-tion (20 studies), rating of perceived exertion (20studies), time trial performance (28 studies), distancetravelled (2 studies), work done (4 studies), VO2 (42studies), VO2max (10 studies), and blood lactate (23studies).

Fig. 2 PRISMA flow diagram for study selection


Three trials were at low risk of bias, while theremaining trials were at high risk of bias due to uncleardescriptions of random sequence generation and/or allo-cation concealment. Table 1 presents the quality of evi-dence assessment for each outcome.

Power output (Fig. 3)Nitrates led to an increase in power output comparedplacebo (MD 4.59 watts, 95% CI [2.6, 6.58], 95%CI, P <0.0001, I2 = 0%, low-quality evidence). We downgradedthe quality of evidence for serious risk of bias and sus-pected publication bias (Table 1).

Time to exhaustion (Fig. 4)Nitrates increased the time to exhaustion compared toplacebo (MD 25.27 s, 95% CI [12.69, 37.84], P < 0.00001,I2 = 38%, low-quality evidence). We downgraded thequality of evidence for serious risk of bias and suspectedpublication bias (Table 1).

Distance travelled (Fig. 5)Participants in the nitrate group had a travelled 163.7 mfurther compared to participants in the placebo group(MD 163.73 m, 95% CI [18.4, 309.1], P = 0.03, I2 = 0%,

very low-quality evidence). We downgraded the qualityof evidence for serious risk of bias and very serious im-precision (Table 1).

VO2 (Fig. 6)Participants in the nitrate group had a significant de-crease in VO2 compared to participants in the placebogroup (MD − 0.04 L/min, 95% CI [− 0.05, − 0.02], P <0.0001, I2 = 0%, low-quality evidence). We downgradedthe quality of evidence for serious risk of bias and ser-ious indirectness (Table 1).

VO2max (Fig. 7)Nitrates did not increase VO2max compared with placebo(MD 0.04 L/min, 95% CI [− 0.02, 0.10], P = 0.23, I2 = 0%,very low-quality evidence). We downgraded the qualityof evidence for serious risk of bias, serious indirectness,and serious imprecision (Table 1).

Rating of perceived exertion (Supplemental Fig. 1)Nitrates did not affect the rating of perceived exertion(Borg scale) (MD -0.11, 95% CI [− 0.34, 0.12], P = 0.36,I2 = 62%, very low-quality evidence). We downgraded the

Table 1 Quality of Evidence - GRADE Assessment

CI Confidence interval, MD Mean difference


quality of evidence for serious risk of bias, serious incon-sistency, and serious imprecision (Table 1).

Time trial performance (Supplemental Fig. 2)Time trials appeared unchanged with and without ni-trates (MD − 1.98 s, 95% CI [− 4.37, 0.41], P = 0.1, I2 =8%, low-quality evidence). We downgraded the quality ofevidence for serious risk of bias and serious imprecision(Table 1).

Work done (Supplemental Fig. 3)Nitrates did not significantly increase work done com-pared with placebo (MD 0.02 kJ, 95% CI [0.0, 0.03], p =0.09, I2 = 0%, low-quality evidence). We downgraded the

quality of evidence for serious risk of bias and serious in-consistency (Table 1).

Blood lactate (Supplemental Fig. 4)Nitrates did not significantly decrease blood lactate com-pared with placebo (MD − 0.08 mM, 95%CI [− 0.21,0.05], P = 0.22, I2 = 12%, very low-quality evidence). Wedowngraded the quality of evidence for serious risk ofbias, serious indirectness, serious imprecision, and sus-pected publication bias (Table 1).

Subgroup analysesWe attempted to perform subgroup analyses accordingto the length of dosing, athletic level, source of dietarynitrate, mean age profile, co-supplementation, and risk

Fig. 3 Forest plot for power output in watts for nitrate supplementation versus placebo. Square markers represent mean difference for individualstudies, with square size proportional to the weight given to each study in the meta-analysis. Horizontal lines indicate 95% confidence intervals(CI). The solid diamond represents the estimated 95% confidence interval for effect size of all meta-analyzed data


of bias. The available data were insufficient to performsubgroup analyses based on the daily dose of nitrate. Weidentified only one statistically interaction – an inter-action (p = 0.005) between athletic level and treatmenton VO2, with no significant effect of nitrate supplemen-tation in elite (MD 0.01, 95% CI [− 0.02, 0.04]) or seden-tary athletes (MD 0.06, 95% CI [− 0.16, 0.29]), but asignificant effect in recreational athletes (MD -0.05, 95%CI [− 0.07, − 0.03]) (Supplemental Figure 5).

DiscussionWe meta-analyzed the results of 73 trials including par-ticipants undergoing various endurance-based exercisetests either with or without nitrate supplementation. Ni-trate supplementation improved power output, time toexhaustion, and distance travelled, but did not impactperceived exertion, time trial performance, work done

generation of lactate, or VO2max. Nitrates led to a reduc-tion in VO2 at different exercise intensities. Therefore,the existing randomized data suggests that nitrate sup-plementation improves endurance exercise performanceby reducing the oxygen cost of the exercise.Dietary nitrate supplementation may enhance muscle

function and exercise performance through the nitrate-nitrite-NO pathway. Dietary inorganic nitrate intake in-creases circulating nitrate levels, which is then reducedto bioactive nitrite by facultative anaerobic bacteria inthe saliva, and subsequently converted into NO in theacidic environment of the stomach. The NO generatedvia this pathway supplements endogenous NO, producedby oxidation of circulating L-arginine. Further, after ni-trate ingestion, plasma nitrate and nitrite concentrationspeak after a few hours, and both gradually fall to base-line values in approximately 24 h. Subsequently, many

Fig. 4 Forest plot for time to exhaustion in seconds for nitrate supplementation versus placebo. Square markers represent mean difference forindividual studies, with square size proportional to the weight given to each study in the meta-analysis. Horizontal lines indicate 95% confidenceintervals (CI). The solid diamond represents the estimated 95% confidence interval for effect size of all meta-analyzed data

Fig. 5 Forest plot for distance travelled in metres for nitrate supplementation versus placebo. Square markers represent mean difference forindividual studies, with square size proportional to the weight given to each study in the meta-analysis. Horizontal lines indicate 95% confidenceintervals (CI). The solid diamond represents the estimated 95% confidence interval for effect size of all meta-analyzed data


Fig. 6 Forest plot for VO2 in litres/minute for nitrate supplementation versus placebo. Square markers represent mean difference for individualstudies, with square size proportional to the weight given to each study in the meta-analysis. Horizontal lines indicate 95% confidence intervals(CI). The solid diamond represents the estimated 95% confidence interval for effect size of all meta-analyzed data


enzymes and proteins, such as deoxyhemoglobin catalyzenitrite to NO in blood and other tissues. This process isfacilitated in conditions of low oxygen availability (ische-mia and hypoxia), enabling NO production where it ismost required; these conditions may exist in skeletalmuscle during endurance exercis e[18]. By mediatingsmooth muscle relaxation, NO promotes vasodilation,increasing oxygen delivery to skeletal muscles [19].The subsequent improvements in type II muscle fiberfunction and efficiency have been implicated in diet-ary nitrate’s positive effects on cardiorespiratory en-durance [20].This postulated mechanism for nitrates to improve

muscle contraction efficiency is supported by our finding(albeit with low certainty) that dietary nitrate reducedVO2, or the oxygen cost of physical activity. These find-ings are also congruent with studies suggesting that diet-ary nitrate supplementation (pure sodium nitrate orbeetroot juice) in young, healthy volunteers reduces thesubmaximal oxygen cost of a given intensity of musclecontractions [21]. Evidence also supports that nitrate sup-plementation may improve mitochondrial efficiency [21],calcium handling and contractile function [22], translatinginto higher fraction of oxygenated hemoglobin in muscle,as well as lower rate of whole-body oxygen uptake (VO2)in endurance exercise. Our findings indicate that nitratesupplementation’s effect is independent of the maximaloxygen uptake (VO2max), which is regarded as one of thebest indicators of an athlete’s physical capacity to work ata higher intensity for a longer period of time, among otherfactors [23]. As mentioned previously, assessing time toexhaustion is a nuanced outcome. While some studiesmay test the difference in time over a set distance traveled,others may test distance traveled over increments of time(as seen in graded or incremental exercise testing); bothwould produce significant differences in absolute values.For instance, an improvement of 25 s might be beneficial

over 10 km, but may be even more important at 5 km.Even so, our approach to meta-analysing this outcome atall reported power outputs, along with lack of heterogen-eity (I2 = 0%), does demonstrate that the increase in timeto exhaustion with nitrates is of note.The significant interaction between athletic level and

nitrate treatment may be a spurious finding or may re-late to the benefit of nitrates being less dependent onmuscle fibre efficiency in elite athletes which mayalready be optimized. In particular, we cannot draw con-clusive inferences from this potential interaction as sub-group analyses are prone to type II errors, especially in ameta-analysis where subgroup analyses are not adjustedfor multiplicity.

Strengths and limitationsOur systematic review and meta-analysis has severalstrengths: a comprehensive search strategy, the inclusionof randomized data, and a rigorous evaluation of the qual-ity of evidence. However, it also has limitations. First,many studies lacked sufficient methodological details,which led us to adjudicate them at unclear or high risk ofbias for evaluated outcomes. Second, the methods of in-cluded studies varied in terms of type of exercise test(wide variability in performance variables – in some casestime to exhaustion was a constant load, while in others, itwas graded), participants’ athletic background, forms andquantities of nitrate supplementation (wide variability ofdoses, dose routines and sources used), and co-interventions such as caffeine and ultraviolet-A light.Third, this included trials had small, select study popula-tions and well-monitored adherence, which may limit ex-ternal validity. Lastly, while we discuss dietary nitrates,with vegetables comprising 80% of naturally availablesources, the included trials used a variety of commerciallyavailable nitrate supplementary products. These productscontain a blend of nitrate-rich foods, extracts and other

Fig. 7 Forest plot for VO2max in litres/minute in kilojoules for nitrate supplementation versus placebo. Square markers represent mean differencefor individual studies, with square size proportional to the weight given to each study in the meta-analysis. Horizontal lines indicate 95%confidence intervals (CI). The solid diamond represents the estimated 95% confidence interval for effect size of all meta-analyzed data


ingredients, which may modulate nitrate bioavailability[24]. As such, our results should be interpreted in con-text of commercial nitrate supplementation, rather thaningestion of natural foods.

Athletes experience and perspective (Reid Coolsaet,Olympic Marathon 2012, 2016)In 2011 I used beetroot juice in training and in five com-petitions. My protocol was to drink at least 500 ml ofbeetroot juice approximately 2–3 h before a competitionor run. The competitions all went well as I met orexceeded expectations. Of course, it’s impossible tocredit beetroot supplementation alone as there are manyvariables that lead to successful competitions. I did ex-perience GI distress, which was not problematic in the10 km distance, slightly problematic competing in thehalf marathon distance, and problematic over the mara-thon distance. It was the GI distress that led me to stopsupplementing with beetroot juice.World Athletics lists 5 supplements that improve per-

formance; caffeine, nitrate, creatine, B-alanine and bicar-bonate [4]. For endurance sports, the two believed to bemost effective are caffeine and nitrate. This meta-analysis suggests that the improvement in endurance ac-tivities from nitrates is significant, supporting the en-dorsement by the World Athletics Organization.With the knowledge that multiple-day ingestion is ef-

fective and high nitrate doses are available commerciallyin smaller volumes, as an elite athlete I am interested intesting nitrate supplementation again. Future researchshould establish the best dosing strategy including howlong before competition one can stop supplementingwithout losing the benefit.

ConclusionsBased on very low- to moderate-quality, RCT data, thissystematic review and meta-analysis suggests that dietarynitrate supplementation improves performance duringendurance sports. This is especially evident when evalu-ating important outcomes, such as power output, timeto exhaustion and distance traveled. However, given itsmixed effects on explanatory variables, like blood lactateand VO2, further research is needed to determine thespecific means by which nitrate supplementation im-pacts physical endurance and establish the optimal dos-ing strategy accounting for adverse GI effects that mayaccompany some formulations.

Supplementary InformationThe online version contains supplementary material available at https://doi.org/10.1186/s12970-021-00450-4.

Additional file 1: Supplemental Figure 1. Forest plot for rating ofperceived exertion for nitrate supplementation versus placebo. Square

markers represent mean difference for individual studies, with square sizeproportional to the weight given to each study in the meta-analysis. Hori-zontal lines indicate 95% confidence intervals (CI). The solid diamond rep-resents the estimated 95% confidence interval for effect size of all meta-analyzed data. Supplemental Figure 2. Forest plot for time trial per-formance of nitrate supplementation versus placebo. Square markers rep-resent mean difference for individual studies, with square sizeproportional to the weight given to each study in the meta-analysis. Hori-zontal lines indicate 95% confidence intervals (CI). The solid diamond rep-resents the estimated 95% confidence interval for effect size of all meta-analyzed data. Supplemental Figure 3. Forest plot for work done of ni-trate supplementation versus placebo. Square markers represent meandifference for individual studies, with square size proportional to theweight given to each study in the meta-analysis. Horizontal lines indicate95% confidence intervals (CI). The solid diamond represents the esti-mated 95% confidence interval for effect size of all meta-analyzed data.Supplemental Figure 4. Forest plot of blood lactate levels with nitratesupplementation versus placebo. Square markers represent mean differ-ence for individual studies, with square size proportional to the weightgiven to each study in the meta-analysis. Horizontal lines indicate 95%confidence intervals (CI). The solid diamond represents the estimated95% confidence interval for effect size of all meta-analyzed data. Supple-mental Figure 5. Forest plot with subgroup analysis of VO2 with nitratesupplementation versus placebo, based on athletic level. Square markersrepresent mean difference for individual studies, with square size propor-tional to the weight given to each study in the meta-analysis. Horizontallines indicate 95% confidence intervals (CI). The solid diamond representsthe estimated 95% confidence interval for effect size of all meta-analyzeddata.

Additional file 2: Supplementary Table 1. Search strategies andsearch terms used with various databases.

Additional file 3: Supplemental Table 2. Study Characteristics ofIncluded Randomized Controlled Trials

Authors’ contributionsChloe Gao, Richard Whitlock, Emilie Belley-Cote developed the study ques-tion and study protocol; they also drafted the manuscript. Saurabh Gupta,Taranah Adli, Winston Hou, Reid Coolsaet, Abigail Hayes, Kevin Kim ArjunPandey, Jacob Gordon and Gurneet Chahil provided the critical input on theprotocol, collected data. Chloe Gao and Saurabh Gupta performed the ana-lysis. All authors provided critical input on the final manuscript. The authorsread and approved the final manuscript.

FundingNo funding was required to conduct this study. Dr. Whitlock is supported bya career award from the Heart and Stroke Foundation and a CanadaResearch Chair.

Availability of data and materialsThe authors will consider written requests for data.

Declarations

Ethics approval and consent to participateEthics approval was not required for this systematic review.

Consent for publicationAll authors of the manuscript have read and agreed to its content and areaccountable for all aspects of the accuracy and integrity of the manuscript inaccordance with ICMJE criteria.

Competing interestsDr. Whitlock reports grants from Bayer, Roche, and Boeringer-Ingelheim out-side the submitted work. He also reports speaker honorarium fromBoeringer-Ingelheim and consultancy for AtriCure and PhaseBio outside thesubmitted work.Dr. Belley-Cote reports grants from Bayer and Roche outside this submittedwork.The other authors have no conflict of interest.


https://doi.org/10.1186/s12970-021-00450-4

https://doi.org/10.1186/s12970-021-00450-4

Author details1Faculty of Medicine, University of British Columbia, Vancouver, BritishColumbia, Canada. 2Department of Surgery, McMaster University, Hamilton,Ontario, Canada. 3Faculty of Biomedical Sciences, University of WesternOntario, London, Ontario, Canada. 4Faculty of Health Sciences, McMasterUniversity, Hamilton, Ontario, Canada. 5University of Guelph, Guelph, Ontario,Canada. 6Queen’s University, Kingston, Ontario, Canada. 7Michael G.DeGroote School of Medicine, McMaster University, Hamilton, Ontario,Canada. 8Department of Health Research Methods, Evidence and Impact,McMaster University, Hamilton, Ontario, Canada. 9Population Health ResearchInstitute, Hamilton, Ontario, Canada. 10Saint James School of Medicine, ParkRidge, USA. 11Department of Medicine, McMaster University, Hamilton,Ontario, Canada. 12David Braley Cardiac, Vascular and Stroke ResearchInstitute, 237 Barton St. E., Hamilton, Ontario L8L 2X2, Canada.

Received: 15 January 2021 Accepted: 4 June 2021

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