Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT03394339 |
| Other study ID # |
CIHR-FRU VEG & CVD 2017 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
April 1, 2017 |
| Est. completion date |
December 1, 2018 |
Study information
| Verified date |
October 2018 |
| Source |
University of Toronto |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Fruit and vegetables are a cornerstone of healthy dietary patterns and dietary guidelines
worldwide. The supporting evidence, however, is largely derived from observational studies of
protective associations with cardiovascular disease (CVD) in health-conscious populations or
from randomized trials of the effect of specific fruit or vegetable derived nutrients on CVD
risk factors. A growing body of literature has influenced a shift away from a focus on single
nutrients to a focus on whole foods and dietary patterns. To what extent fruit and vegetables
should contribute to dietary patterns for cardiovascular health and whether specific types of
fruit or vegetables should be recommended is unclear. Although previous systematic reviews
and meta-analyses have elucidated the association between the intake of total and some
specific fruit and vegetables with cardiovascular outcomes, a comprehensive synthesis
comparing the certainty of the evidence for the different types of fruit and vegetables in
relation to a range of cardiovascular outcomes has yet to be completed. We propose to conduct
a systematic review and meta-analysis of the available prospective cohort studies using the
Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess
the association between different types of fruit and vegetables and different cardiovascular
outcomes that include CVD, coronary heart disease [CHD], and stroke incidence and mortality.
Description:
Background:
A high intake of fruit and vegetables is a common trait among healthy dietary patterns and a
cornerstone of nutrition interventions for cardiovascular disease (CVD) prevention. There is
an international consensus that at least 5 servings per day of fruit and vegetables is
beneficial to overall population health (WHO, 2003). This guidance, however, is largely
founded on observational studies showing protective associations of high intakes of fruit and
vegetables with CVD in health-conscious individuals (Reddy and Katan, 2004). Recommendations
to consume specific types of fruit and vegetables, such as citrus fruit and green leafy
vegetables, have been established mainly on the association of isolated nutrients with CVD
risk reduction in observational studies or the effect of isolated nutrients on CVD risk
factors in small randomized trials (Katamay et al., 2007). Given its prominence in dietary
guidelines, there is a need to determine the extent of CVD risk reduction that may be
attributed to the consumption of fruit and vegetables. As guidelines are shifting away from a
focus on single nutrients to a focus on whole foods and dietary patterns and achieving
adequate intakes continue to be a challenge worldwide and (Hall et al., 2009), there is also
an advantage in establishing which types of fruit and vegetables are associated with the
greatest protection in CVD incidence and mortality per serving. Although several systematic
reviews and meta-analyses of prospective cohort studies have demonstrated protective
associations between the intake of total fruit and vegetables and CVD risk (Aune et al.,
2017; Zhan et al., 2017; Gan et al., 2015; Wang et al, 2014; Hu et al., 2007; He et al.,
2007; Dauchet et al., 2006), few have focused on specific fruit and vegetables or explored a
range of cardiovascular outcomes which may have different etiologies. Several large
prospective cohort studies have recently been published which may strengthen the certainty of
the evidence by increasing the number of observations for the relationship between different
fruit and vegetables exposures and different cardiovascular outcomes. We propose to build and
expand on the exiting systematic reviews and meta-analyses by conducting a comprehensive
synthesis of prospective cohort studies comparing the certainty of the evidence for the
different types of fruit and vegetables in relation to a range of cardiovascular outcomes.
Objective:
To conduct a systematic review and meta-analysis of the available prospective cohort studies
using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach
to assess the association between different types of fruit and vegetables and different
cardiovascular outcomes including CVD, CHD, and stroke incidence and mortality.
Design:
The conduct of the proposed systematic review and meta-analysis will follow the Cochrane
handbook for systematic reviews of interventions and the GRADE handbook for grading the
certainty of the evidence and the strength of recommendations using the GRADE approach. The
reporting will follow the Meta-Analysis Of Observational Studies in Epidemiology (MOOSE) and
the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements.
Data Sources:
MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) will be
searched using relevant search terms. Search of databases will be supplemented by manual
searches of bibliographies.
Study Selection:
Prospective cohort studies exploring the relation of fruit and/or vegetable intake to
incident cardiovascular disease for a minimum follow-up time of 1 year will be included.
Data extraction:
Two independent reviewers will extract relevant information including study design, sample
size, subject characteristics, exposure form (i.e. total fruit and vegetables, citrus fruit,
green leafy vegetables, etc.), duration/person-years of follow-up, adjustments of models and
risk ratios for clinical outcomes derived from clinical event data across quantiles of
exposure. Any disagreements will be reconciled by consensus with arbitration by the Principal
Investigator.
Risk of bias:
Risk of bias (ROB) will be assessed by two independent reviewers using the Newcastle-Ottawa
Scale (NOS). Up to 9 points can be awarded based on cohort selection (max 4 points), the
comparability of cohort design and analysis (max 4 points), and adequacy of the outcome
measures (max 3 points). Studies that receive ≥6 points will be considered as higher quality.
Again, any disagreements will be reconciled by consensus with arbitration by the Principal
Investigator.
Outcomes:
We will assess 6 outcomes: CVD incidence and mortality, CHD incidence and mortality, and
stroke incidence and mortality.
Data Synthesis:
We will pool the natural log-transformed relative risks for the 6 cardiovascular outcomes
using the inverse variance method with random effects models with data expressed as risk
ratios (RR) with 95% confidence intervals (CIs). Analyses will be conducted by extreme
quantiles analyses, comparing the highest with the lowest (reference) level of exposure. Data
will also be scaled to allow for per serving/day analyses. Between-study heterogeneity will
be assessed by the Cochran Q test and quantified by the I2 statistic with significance at
P<0.1. An I2≥50% and P<0.1 will be considered as evidence of substantial heterogeneity.
Sensitivity analyses and a priori subgroup analyses will be undertaken to explore sources of
heterogeneity. Sensitivity analyses will include the systematic removal of included cohorts
with the recalculation of summary estimates. A priori subgroup analyses will be conducted
when ≥10 cohort comparisons are available by age, sex, location of cohort, follow-up
duration, dietary assessment tool, risk of bias (NOS score). A separate subgroup analysis
will also be conducted by each domain of risk of bias by NOS. Meta-regression analyses will
assess the significance of categorical and continuous subgroups analyses. Dose-response
analyses will be undertaken using random-effects generalized least squares trend estimation
models (GLST) to assess linear relationships and spline curve modeling (the MKSPLINE
procedure) to assess non-linear relationships. If ≥10 cohort comparisons are available, then
publication bias will be assessed by visual inspection of funnel plots and formal testing
with the Egger and Begg tests at a significance level of p≤ 0.10. If publication bias is
suspected, then the investigators will attempt to adjust for funnel plot asymmetry by
imputing the missing study data using the Duval and Tweedie trim and fill method.
Grading the Evidence:
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) method will be
used to assess the overall certainty of the evidence for each of the cardiovascular outcomes.
This system grades the evidence as "high quality", "moderate quality", "low quality", or
"very low quality". Observational studies including prospective cohort studies start at a
"low quality" and then can be downgraded or upgraded based on established criteria. Criteria
to downgrade will include study limitations (weight of studies show risk of bias by NOS),
inconsistency (substantial unexplained inter-study heterogeneity, I2>50%, P<0.10),
indirectness (presence of factors relating to the population, exposures, and outcomes that
limit generalizability), imprecision (95% CI are wide or cross a minimally important
difference of 5% [RR 0.95- 1.05]), and publication bias (significant evidence of publication
bias or small-study effects). Criteria to upgrade will include a large magnitude effect (RR>2
or RR<0.5 in the absence of plausible confounders), a dose-response gradient, and attenuation
by plausible confounding effects.
Knowledge translation plan:
The results will be disseminated through interactive presentations at local, national, and
international scientific meetings and publication in high impact factor journals. Target
audiences will include the public health and scientific communities with interest in
nutrition, physical activity, lifestyle modification, obesity, diabetes, and cardiovascular
disease. Feedback will be incorporated and used to improve the public health message and key
areas for future research will be defined.
Significance:
The study will aid in establishing a stronger evidence-base to determine the extent to which
a high fruit and vegetable intake may be associated with reduction in incident CVD. It may
also bring to light categories of fruits and/or vegetables that could provide additional
benefit in CVD prevention.
References:
World Health Organization. (2003). Fruit and Vegetable Promotion Initiative - report of the
meeting. Geneva.
Reddy KS and Katan MB. (2004). Diet, nutrition and the prevention of hypertension and
cardiovascular disease. Public Health Nutrition. 7(1A): 167-186
Katamay SW, Esslinger KA, Vigneault M, et al. (2007) Nutrition Reviews. 65(4): 155-166.
Hall JN, Moore S, Harper SB, et al. (2009). Global variability in fruit and vegetable
consumption. American Journal of Preventative Medicine. 36:402-409
Aune D, Giovannucci E, Boffetta P, et al. (2017). Fruit and vegetable intake and the risk of
cardiovascular disease, total cancer and all-cause mortality - a systematic review and
dose-response meta-analysis of prospective studies. International Journal of Epidemiology.
1-28
Zhan J, Liu Y, Cai L, et al. (2017). Fruit and vegetable consumption and risk of
cardiovascular disease: A meta-anaylsis of prospective cohort studies. Critical Reviews in
Food Science and Nutrition. 57(8):1650-1663
Gan Y, Tong X, Liqing L, et al. (2015). Consumption of fruit and vegetable and risk of
coronary heart disease: A meta-analysis of prospective cohort studies. International Journal
of Cardiology. 183: 129-137
Wang X, Ouyang Y, Liu J, et al. (2014). Fruit and vegetable consumption and mortality from
all causes, cardiovascular disease, and cancer: systematic review and dose-response
meta-analysis of prospective cohort studies. British Medical Journal. 349
Hu D, Hunag J, Wang Y, et al. (2014). Fruits and vegetables consumption and risk of stroke: A
meta-analysis of prospective cohort studies. Stroke. 45: 1613-1619
He FG, Nowson CA, Lucas M et al. (2007). Increased consumption of fruit and vegetables is
related to reduced risk of coronary heart disease: meta-analysis of cohort studies. Journal
of Human Hypertension. 21:717-728
He FJ, Nowson CA and MacGregor GA. (2006). Fruit and vegetable consumption and stroke: a
meta-analysis of cohort studies. Lancet: 367:320-326.
Dauchet L, Amouyel P, Hereberg S, et al. (2006). Fruit and vegetable consumption and risk of
coronary heart disease: A meta-analyses of cohort studies. The Journal of Nutrition. 136:
2588-2593.
