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The effect of folic acid supplementation on carotid intima-media thickness
in patients with cardiovascular risk: A randomized, placebo-controlled trial
George Ntaios , Christos Savopoulos, Dimitrios Karamitsos, Ippoliti Economou,Evangelos Destanis, Ioannis Chryssogonidis, Ifigenia Pidonia, Pantelis Zebekakis,
Christos Polatides, Michael Sion, Dimitrios Grekas, Apostolos Hatzitolios
First Propedeutic Department of Internal Medicine, AHEPA Hospital, Aristotle University, Thessaloniki, Greece
Received 6 September 2008; received in revised form 17 December 2008; accepted 10 January 2009
Available online 8 February 2009
Abstract
Introduction:Observational studies have suggested a causal relationship between hyperhomocysteinemia and cardiovascular complications
such as stroke and ischemic heart disease. The Homocysteine Lowering Trialists' Collaboration has shown that daily administration of folic
acid can significantly decrease homocysteine levels up to 25%.
Aim of this study was to investigate the effect of daily supplementation of folic acid (5 mg) on IMT after 18 months of treatment in
patients with at least one cardiovascular risk factor.
Methods: We enrolled 103 patients with at least one cardiovascular risk factor who were randomized to receive either a daily dose of 5 mg
folic acid (group I, n =53) or placebo (group II, n =50) for 18 months.
Results: After 18 months of folic acid supplementation, homocysteine levels were significantly reduced in the active treatment group
compared to a non-significant increase in the placebo group. Folic acid levels were markedly increased in the former group and non-
significantly reduced in the latter. Significant regression of carotid IMT was observed (0.961 0.092 to 0.933 0.077 mm, pb0.001)compared to significant IMT progression in the placebo group (0.9640.099 to 0.9840.094 mm).
Conclusion:Folic acid supplementation results in significant IMT reduction after 18 months in patients with at least one cardiovascular risk.
2009 Elsevier Ireland Ltd. All rights reserved.
Keywords: Atherosclerosis; Folic acid; Homocysteine; Intima-media thickness
1. Introduction
Observational studies have suggested a causal relationship
between hyperhomocysteinemia and cardiovascular compli-cations such as stroke and ischemic heart disease [1]. The
Homocysteine Lowering Trialists' Collaboration has shown
that daily administration of folic acid can significantly
decrease homocysteine levels up to 25% [2]. The effectof B12supplementation is much weaker resulting in a further
reduction of up to 5%, whereas B6 had no significant
influence [2]. Currently, several large, prospective, rando-
mized, placebo-controlled, clinical trials are underway to
investigate the effect of homocysteine-lowering therapy on
cardiovascular risk [3]. The results of the trials that havealready been published are controversial, raising the hypoth-
esis that perhaps, homocysteine is just an epiphenomenon of
atherosclerosis and not a causative risk factor.
Carotid intima-media thickness (IMT) is a reliable marker
of early atherosclerosis and has been associated with
increased incidence of cardiovascular events [4]. Intima-
media thickness has been used extensively as a primary end
point in interventional trials which sought to investigate the
effect of antihypertensives[5]and hypolipidemic[6]drugs
on atherosclerosis.
International Journal of Cardiology 143 (2010) 1619
www.elsevier.com/locate/ijcard
Corresponding author. S. Kiriakidi 1, AHEPA Hospital, Thessaloniki,
54636, Greece. Tel.: +30 6972770288; fax: +30 2310993480.
E-mail address: [email protected](G. Ntaios).
0167-5273/$ - see front matter 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijcard.2009.01.023
mailto:[email protected]://dx.doi.org/10.1016/j.ijcard.2009.01.023http://dx.doi.org/10.1016/j.ijcard.2009.01.023mailto:[email protected]7/25/2019 Ntai Os 2010
2/4
The aim of this prospective, randomized, double blind,
placebo-controlled trial was to investigate the effect of daily
supplementation of folic acid (5 mg) on IMT after 18 months
of treatment in patients with at least one cardiovascular risk
factor.
2. Methods
2.1. Study population
We enrolled one hundred and three patients who were followed
up in our Internal Medicine Department between October 2005 and
February 2008. Inclusion criteria were the presence of at least one
cardiovascular risk factor, such as diabetes mellitus, arterial
hypertension, coronary artery disease, dyslipidaemia, smoking
and previous ischemic stroke. Exclusion criteria were the use of
drugs which interfere with homocysteine levels (such as cyclos-
porine, methotrexate, fibrates and antiepileptics), impaired renal
function (glomerular filtration rateb60 ml/min), renal transplanta-
tion, malignancy, pregnancy, vitamin supplementation and prior
carotid endarterectomy. The patients were randomized to receive
either a daily dose of 5 mg folic acid (group I, n =53) or placebo
(group II, n =50) for 18 months. The local ethics committee
approved the study protocol and informed consent was obtainedfrom all patients.
2.2. Carotid ultrasound
The measurement of IMT was performed by B-mode ultrasound
with a Siemens Sonoline Elegra system with a 7.5 MHz transducer.
For each patient, the mean IMT value was calculated from 6
measurements in each carotid artery in the longitudinal plane. These
measurements involved both the near and far carotid wall at the
carotid bifurcation, at the common carotid artery (1 cm proximal to
the bifurcation) and at the internal carotid artery (1 cm distal to the
bifurcation). The measurement of IMT at sites where carotid plaque
was present, was not taken into account and in these cases, the mean
value was calculated from the remaining measurements. All IMT
measurements were assessed blindly by a single experienced
ultrasonographer.
2.3. Statistical analysis
The observed values in all continuous variables were found to be
normally distributed (assessed by Chi-square test) and hence, 2-tail
Student'st-test was applied for the statistical analysis of these data.
In particular, Fig. 1 presents the adjustment of the normal
Fig. 1. Adjustment of the normal distribution (red curve) on the histogram of baseline IMT values. The application of chi-square test ( X2) in this case shows thatthe probability density of these values can be reliably (pb0.05) approximated by the normal distribution curve.
Table 1
Clinical characteristics and biochemical parameters of the patients on
randomization.
Group I (n =53) Group II (n =50) p
Female gender (n %) 30 (56.6%) 27 (54%) 0.94a
Age (years SD) 73.2 4.6 73.9 4.3 0.99b
Body mass index (kg/m2 SD) 26.26 3.42 27.57 3.03 0.37 b
Coronary artery disease (n %) 17 (32%) 16 (32%) 0.99 a
Prior stroke (n%) 39 (73.6%) 33 (66%) 0.53 a
Arterial hypertension (n %) 36 (67.9%) 33 (66%) 0.99 a
Diabetes mellitus (n %) 19 (35.8%) 19 (38%) 0.98 a
Smoking (n %) 20 (37.7%) 20 (40%) 0.97 a
Statins 34 (64.1%) 36 (72%) 0.51a
Antiplatelets 48 (90.5%) 42 (84%) 0.62 a
Beta blockers 31 (58.5%) 34 (68%) 0.47 a
Calcium channel blockers 17 (32. 1%) 12 (24%) 0.56 a
ACE inhibitors/ARB 31 (58.5%) 24 (48%) 0.45 a
Homocysteine (mol/l SD) 13.9 4.9 14.1 4.9 0.84 b
Folic acid (nmol/l SD) 19.9 8.7 18.2 6.1 0.26 b
B12 (pmol/l SD) 321 319 352 329 0.63 b
Triglycerides (mg/dlSD) 160.291.7 172.457.1 0.43 b
Total cholesterol (mg/dlSD) 202.639.6 213.146.8 0.20b
LDL- cholesterol (mg/dlSD) 179.247.7 194.147.9 0.12b
HDL-cholesterol (mg/dlSD) 51.414.9 49.89.2 0.52 b
Creatinine (mg/dl SD) 0.94 0.26 0.95 0.28 0.85 b
SD: Standard Deviation, ACE: Angiotensin Converting Enzyme, ARB:
Angiotensin-II Receptor Blockers, aChi-square test, bStudent'st-test.
17G. Ntaios et al. / International Journal of Cardiology 143 (2010) 1619
7/25/2019 Ntai Os 2010
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distribution curve on the histogram of baseline IMT values; the
application of chi-square test in this case shows that the probability
density of these values can be reliably (pb0.05) approximated by
the normal distribution curve. Chi square test was applied for
categorical variables. All values were reported as meanstandard
deviation. The level of significance was set at 95% (pb0.05). The
statistical analysis of data was performed with SPSS 14.0 andMicrosoft Excel.
3. Results
The baseline clinical characteristics and biochemical parameters
of the patients are presented inTable 1. There were no statistically
significant differences between the two groups. After 18 months of
folic acid supplementation, homocysteine levels were significantly
reduced in the active treatment group compared to a non-significant
increase in the placebo group (Table 2). Folic acid levels were
markedly increased in the former group and non-significantly
reduced in the latter. Significant regression of carotid IMT was
observed at the end of the study (0.961 0.092 to 0.9330.077 mm,
pb0.001) compared to significant IMT progression in the placebogroup (0.9640.099 to 0.9840.094 mm) (Table 2).
4. Discussion
Our study confirmed the beneficial effect of folic acid
supplementation on homocysteine levels and demonstrated a
significant regression of IMT after 18 months of treatment in
patients with at least one cardiovascular risk factor. We chose
to supplement patients only with folic acid (and not with B12and B6 as well) because it has been shown that the main
reduction of homocysteine is due to folic acid, whereas B12provides only little further decrease[2]. The limitations inour study were the modest sample size and the medium
duration of follow-up.
The impact of B-vitamins on IMT has been previously
investigated in certain patient groups with conflicting,
however, results. Till et al. showed that supplementation
with B-vitamins (folic acid, B12 and B6) resulted in significant
reduction of IMT (1.50 0.44 to 1.42 0.48 mm) in patients at
risk for cerebral ischemia (IMT1 mm) after 1 year of
treatment, whereas IMT increased in placebo-controlled
patients (1.47 0.57 to 1.54 0.71 mm) [7]. Similar results
were reported by Marcucci et al. in renal transplant patientsafter 6 months of B-vitamin supplementation[8]. However,
both studies were modest in sample size (50 and 56 patients
respectively) and had a short follow-up (12 and 6 months
respectively). Recently, Vianna et al. demonstrated a sig-
nificant IMT reduction in hyperhomocysteinemic, end-stage
renal disease patients after 2 years of intermittent (10 mg, three
times a week) folic acid supplementation[9].
However, the ASFAST trial failed to confirm the results
reported by Vianna et al, since they found no significant
change of IMT in 315 patients with chronic renal failure
compared to controls, after supplementation with high-dose
folic acid for a median duration of 3.6 years[10]. In a similarmanner, Fernandez-Miranda et al. reported that there was no
significant change of IMT in patients with coronary artery
disease treated with folic acid (5 mg) for 3 years compared to
controls [11]. It is interesting to notice that actually, there
was a reduction in IMT (0.71 0.23 to 0.69 0.20 mm) in the
active treatment group, which was not statistically significant
[11]; however, it would not be irrational to consider it as
clinically significant, since the expected change (due to
aging) of IMT over this 3-years' follow-up would be
progression[12]. Moreover, this IMT reduction in the active
treatment group would be possibly statistically significant if
the control group did not exhibit a similar IMT reduction
which was attributed to the fact that patients were also treatedwith drugs that have been shown to decrease IMT, such as
statins, angiotensin-converting enzyme inhibitors, angioten-
sin-II receptor blockers and calcium-channels antagonists
[12].
Along with the aforementioned studies, our results add
further controversy on the impact of folic acidsupplementation
on IMT. Obviously, the large, randomized studies of the
clinical effects of B-vitamin supplementation will provide a
definite answer whether hyperhomocysteinemia is indeed a
causative cardiovascular risk factor or just an epiphenomenon
in the atherosclerotic process[3]. However, the results of the
trials that already have been completed are also conflicting. Arecent meta-analysis by Wang et al. on eight randomized trials
of folic acid with stroke as a primary end point, showed a
significant reduction in the risk of stroke by 18% [13].
Similarly, the HOPE-2 reported that fewer patients assigned to
B-vitamins suffered a stroke compared to controls, although
the study yielded negative results regarding all other major
cardiovascular events[14]. Furthermore, a population-based
cohort study by Yang et al. demonstrated that the slowly
declining trend in stroke mortality rates which was observed
sinceat least1990 in the United States and Canada, accelerated
significantly after 1998, when folic acid fortification of cereals
became mandatory [15]. On the contrary, there was no
Table 2
IMT, folic acid and homocysteine plasma concentrations on randomization
and after treatment.
Group I (n =53) Group II (n =50) p
Folic acid
Baseline (nmol/l SD) 19.9 8.7 18.2 6.1 ns
Follow up (nmol/l SD) 44.6 1.6 17.1 5.4 sp (baseline vs. follow up) s ns
Homocysteine
Baseline (mol/l SD) 13.9 4.9 14.1 4.9 ns
Follow up (mol/l SD) 11.2 3.6 14.5 4.9 s
p (baseline vs. follow up) s ns
Mean IMT
Baseline (mm SD) 0.961 0.092 0.964 0.099 ns
Follow up (mm SD) 0.933 0.077 0.984 0.094 s
p (baseline vs. follow up) s s
Overall difference (mm SEM) -0.0280.004 0.01980.0024 s
SD: standard deviation, SEM: Standard Error of the Mean, s: p b0.001, ns:
pN0.05.
18 G. Ntaios et al. / International Journal of Cardiology 143 (2010) 1619
7/25/2019 Ntai Os 2010
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improvement in the decline of stroke mortality in England and
Wales, where folic acid fortification is not mandatory [15].
Hence, it is plausible that the dietary supplementation of folic
acid via fortification could offer a long-term cardiovascular
protection[16,17].
On the other hand, the recently published WAFACS and
WENBIT trials reported no significant reduction in cardio-vascular complications after B-vitamins supplementation
[18,19]. However, these trials recruited mainly normoho-
mocysteinemic patients and it cannot be excluded that a
beneficial effect might have been observed if the studies
included solely hyperhomocysteinemic patients. The Homo-
cysteine Lowering Trialists' Collaboration concluded that
the folic acid-mediated homocysteine reduction is greater at
higher pretreatment homocysteine concentrations [2].
Hence, if these trials recruited only hyperhomocysteinemic
patients, it would not be unreasonable to expect greater
homocysteine reduction and thence, greater and possibly
significant reduction in primary and/or secondary clinicalend points[20].
Summarizing, our study reported a significant IMT
reduction after 18 months of folic acid supplementation in
patients with at least one cardiovascular risk. Further studies
with larger sample size and longer follow up are necessary to
provide definite answers about the effect of folic acid on
IMT.
Acknowledgements
We would like to express our gratitude to Dr. J.F.
Moschonas for his valuable assistance in the preparation ofthe manuscript.
The authors of this manuscript have certified that they
comply with the Principles of Ethical Publishing in the
International Journal of Cardiology[21].
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http://dx.doi.org/10.1016/j.ejim.2008.03.015http://dx.doi.org/10.1016/j.ejim.2008.03.015http://dx.doi.org/10.1016/j.ejim.2008.03.015http://dx.doi.org/10.1016/j.ejim.2008.03.015