Abstract
Objectives
We conducted a meta-analysis of relevant randomized trials to assess whether folic
acid supplementation reduces the progression of atherosclerosis as measured by carotid
intima-media thickness (CIMT).
Methods
This analysis included 2052 subjects from ten folic acid randomized trials with the
change in CIMT reported as one of the end points. Summary estimates of weighted mean
differences (WMDs) and 95% CIs were obtained by using random-effect models. Meta-regression
and subgroup analyses were performed to identify the source of heterogeneity.
Results
Our analysis showed that folic acid supplementation significantly reduces the progression
of CIMT (WMD: −0.04 mm; 95%CI: −0.07, −0.02; P < 0.001), particularly in subjects with chronic kidney disease (CKD) (WMD: −0.16 mm; 95%CI: −0.26, −0.07; P = 0.0006) or high cardiovascular disease (CVD) risk (WMD: −0.05 mm; 95%CI: −0.11, 0.00; P = 0.06) but not in subjects who were generally healthy with only elevated homocysteine
concentrations (WMD:0.00 mm; 95%CI: −0.01, 0.01; P = 0.35). Furthermore, meta-regression analysis of the data showed that the baseline
CIMT levels (P = 0.011) and the percent reduction of homocysteine (P < 0.001) were positively related to the effect size. Consistently, a greater beneficial
effect was seen in those trials with baseline CIMT levels ≥0.8 mm (WMD: −0.14 mm; 95%CI: −0.19, −0.08; P < 0.0001), and a reduction in the homocysteine concentration ≥30% (WMD: −0.22 mm; 95%CI: −0.38, −0.06; P = 0.009). In the corresponding comparison groups, the effect sizes were attenuated and
insignificant.
Conclusions
Our findings indicate that folic acid supplementation is effective in reducing the
progression of CIMT, particularly in subjects with CKD or high CVD risk and among
trials with higher baseline CIMT levels or a larger homocysteine reduction.
Keywords
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References
- Do trends in population levels of blood pressure and other cardiovascular risk factors explain trends in stroke event rates? Comparisons of 15 populations in 9 countries within the WHO MONICA Stroke Project. World Health Organization Monitoring of Trends and Determinants in Cardiovascular Disease.Stroke. 2002; 33: 2367-2375
- Vascular pathology of homocystinemia: implications for the pathogenesis of arteriosclerosis.Am J Pathol. 1969; 56: 111-128
- Homocysteine theory of atherosclerosis.Atherosclerosis. 1975; 22: 215-227
- Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis.BMJ. 2002; 325: 1202-1206
- Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis.JAMA. 2002; 288: 2015-2022
- Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis.Circulation. 2007; 115: 459-467
- Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials.Am J Clin Nutr. 2005; 82: 806-812
- The effect of long-term homocysteine-lowering on carotid intima-media thickness and flow-mediated vasodilation in stroke patients: a randomized controlled trial and meta-analysis.BMC Cardiovasc Disord. 2008; 8: 24
- Effect of 3 y of folic acid supplementation on the progression of carotid intima-media thickness and carotid arterial stiffness in older adults.Am J Clin Nutr. 2011; 93: 941-949
- High-dose B vitamin supplementation and progression of subclinical atherosclerosis: a randomized controlled trial.Stroke. 2009; 40: 730-736
- Role of folic acid in atherosclerosis after kidney transplant: a double-blind, randomized, placebo-controlled clinical trial.Exp Clin Transplant. 2009; 7: 33-39
- The effect of folic acid supplementation on carotid intima-media thickness in patients with cardiovascular risk: a randomized, placebo-controlled trial.Int J Cardiol. 2010; 143: 16-19
- Preferred reporting items for systematic reviews and meta-analyses: the PRIsMa statement.Ann Intern Med. 2009; 151: 264-269
- Does quality of reports of randomized trials affect estimates of intervention efficacy reported in meta-analyses?.Lancet. 1998; 352: 609-613
- Variance imputation for overviews of clinical trials with continuous response.J Clin Epidemiol. 1992; 45: 769-773
- Measuring inconsistency in meta-analyses.BMJ. 2003; 327: 557-560
- Homocysteine-lowering therapy and carotid intima-media thickness in renal transplant recipients.Transplant Proc. 2005; 37: 2491-2492
- Longitudinal ultrasound evaluation of carotid atherosclerosis in one, two and three dimensions.Ultrasound Med Biol. 2009; 35: 367-375
- Effect of Sclerovit on endothelial dysfunction, hemorheological parameters, platelet aggregation, plasma concentration of homocysteine and progression of atherosclerosis in patients with vascular diseases.Clin Hemorheol Microcirc. 2009; 42: 19-28
- Effect of short-term folate and vitamin B supplementation on blood homocysteine level and carotid artery wall thickness in chronic hemodialysis patients.J Med Assoc Thai. 2006; 89: 1187-1193
- Effect of a treatment strategy consisting of pravastatin, vitamin E, and homocysteine lowering on carotid intima-media thickness, endothelial function, and renal function in patients with mild to moderate chronic kidney disease: results from the Anti-Oxidant Therapy in Chronic Renal Insufficiency (ATIC) Study.Arch Intern Med. 2007; 167: 1262-1270
- Vitamin supplementation reduces the progression of atherosclerosis in hyperhomocysteinemic renal-transplant recipients.Transplantation. 2003; 75: 1551-1555
- Decrease of carotid intima-media thickness in patients at risk to cerebral ischemia after supplementation with folic acid, vitamins B6 and B12.Atherosclerosis. 2005; 181: 131-135
- Folate supplementation fails to affect vascular function and carotid artery intima media thickness in cyclosporin A-treated renal transplant recipients.Clin Nephrol. 2006; 66: 373-379
- Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure.J Am Coll Cardiol. 2006; 47: 1108-1116
- Uremic hyperhomocysteinemia: a randomized trial of folate treatment for the prevention of cardiovascular events.Hemodialysis Int. 2007; 11: 210-216
- Effect of folic acid treatment on carotid intima-media thickness of patients with coronary disease.Int J Cardiol. 2007; 118: 345-349
- Efficacy of folic acid supplementation in stroke prevention: a meta-analysis.Lancet. 2007; 369: 1876-1882
- Folic acid therapy and cardiovascular disease in ESRD or advanced chronic kidney disease: a meta-analysis.Clin J Am Soc Nephrol. 2011; 6: 482-488
- Associations of plasma homocysteine and the methylenetetrahydrofolate reductase C677T polymorphism with carotid intima media thickness among South Asian, Chinese and European Canadians.Atherosclerosis. 2004; 176: 361-370
- B-group vitamins, MTHFR C677T polymorphism and carotid intima-media thickness in clinically healthy subjects.Eur J Clin Nutr. 2007; 61: 996-1003
- Homocysteine-lowering therapy: a role in stroke prevention?.Lancet Neurol. 2007; 6: 830-838
- Association between carotid artery intima-media thickness and early-stage CKD in a Chinese population.Am J Kidney Dis. 2007; 49: 786-792
- Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project.JAMA. 1997; 277: 1775-1781
- Hyperhomocysteinaemia is associated with coronary events in type 2 diabetes.J Intern Med. 2003; 253: 293-300
- Homocysteine and lipoprotein(a) interact to increase CAD risk in young men and women.Arterioscler Thromb Vasc Biol. 2000; 20: 493-499
- Pronounced association of elevated serum homocysteine with stroke in subgroups of individuals: a nationwide study.J Neurol Sci. 2010; 298: 153-157
- Homocysteine-lowering and cardiovascular disease outcomes in kidney transplant recipients: primary results from the folic Acid for vascular outcome reduction in transplantation trial.Circulation. 2011; 123: 1763-1770
- Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials.BMJ. 1998; 316: 894-898
- Effect of high dose folic acid therapy on hyperhomocysteinemia in hemodialysis patients: results of the Vienna multicenter study.J Am Soc Nephrol. 2000; 11: 1106-1116
- Meta-analysis of folic acid supplementation trials on risk of cardiovascular disease and risk interaction with baseline homocysteine levels.Am J Cardiol. 2010; 106: 517-527
- Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials.Lancet. 2011; 378: 584-594
- Carotid intima-media thickening indicates a higher vascular risk across a wide age range: prospective data from the Carotid Atherosclerosis Progression Study (CAPS).Stroke. 2006; 37: 87-92
Article info
Publication history
Published online: January 03, 2012
Accepted:
December 5,
2011
Received in revised form:
December 2,
2011
Received:
November 2,
2011
Identification
Copyright
© 2011 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
