Ningling Sun

Efficacy of folic acid supplementation in stroke prevention: a meta-analysis

BACKGROUND The efficacy of treatments that lower homocysteine concentrations in reducing the risk of cardiovascular disease remains controversial. Our aim was to do a meta-analysis of relevant randomised trials to assess the efficacy of folic acid supplementation in the prevention of stroke. METHODS We collected data from eight randomised trials of folic acid that had stroke reported as one of the endpoints. Relative risk (RR) was used as a measure of the effect of folic acid supplementation on the risk of stroke with a random effect model. The analysis was further stratified by factors that could affect the treatment effects. FINDINGS Folic acid supplementation significantly reduced the risk of stroke by 18% (RR 0.82, 95% CI 0.68-1.00; p=0.045). In the stratified analyses, a greater beneficial effect was seen in those trials with a treatment duration of more than 36 months (0.71, 0.57-0.87; p=0.001), a decrease in the concentration of homocysteine of more than 20% (0.77, 0.63-0.94; p=0.012), no fortification or partly fortified grain (0.75, 0.62-0.91; p=0.003), and no history of stroke (0.75, 0.62-0.90; p=0.002). In the corresponding comparison groups, the estimated RRs were attenuated and insignificant. INTERPRETATION Our findings indicate that folic acid supplementation can effectively reduce the risk of stroke in primary prevention.

Efficacy of Folic Acid Therapy in Primary Prevention of Stroke Among Adults With Hypertension in China: The CSPPT Randomized Clinical Trial

IMPORTANCE Uncertainty remains about the efficacy of folic acid therapy for the primary prevention of stroke because of limited and inconsistent data. OBJECTIVE To test the primary hypothesis that therapy with enalapril and folic acid is more effective in reducing first stroke than enalapril alone among Chinese adults with hypertension. DESIGN, SETTING, AND PARTICIPANTS The China Stroke Primary Prevention Trial, a randomized, double-blind clinical trial conducted from May 19, 2008, to August 24, 2013, in 32 communities in Jiangsu and Anhui provinces in China. A total of 20,702 adults with hypertension without history of stroke or myocardial infarction (MI) participated in the study. INTERVENTIONS Eligible participants, stratified by MTHFR C677T genotypes (CC, CT, and TT), were randomly assigned to receive double-blind daily treatment with a single-pill combination containing enalapril, 10 mg, and folic acid, 0.8 mg (n = 10,348) or a tablet containing enalapril, 10 mg, alone (n = 10,354). MAIN OUTCOMES AND MEASURES The primary outcome was first stroke. Secondary outcomes included first ischemic stroke; first hemorrhagic stroke; MI; a composite of cardiovascular events consisting of cardiovascular death, MI, and stroke; and all-cause death. RESULTS During a median treatment duration of 4.5 years, compared with the enalapril alone group, the enalapril-folic acid group had a significant risk reduction in first stroke (2.7% of participants in the enalapril-folic acid group vs 3.4% in the enalapril alone group; hazard ratio [HR], 0.79; 95% CI, 0.68-0.93), first ischemic stroke (2.2% with enalapril-folic acid vs 2.8% with enalapril alone; HR, 0.76; 95% CI, 0.64-0.91), and composite cardiovascular events consisting of cardiovascular death, MI, and stroke (3.1% with enalapril-folic acid vs 3.9% with enalapril alone; HR, 0.80; 95% CI, 0.69-0.92). The risks of hemorrhagic stroke (HR, 0.93; 95% CI, 0.65-1.34), MI (HR, 1.04; 95% CI, 0.60-1.82), and all-cause deaths (HR, 0.94; 95% CI, 0.81-1.10) did not differ significantly between the 2 treatment groups. There were no significant differences between the 2 treatment groups in the frequencies of adverse events. CONCLUSIONS AND RELEVANCE Among adults with hypertension in China without a history of stroke or MI, the combined use of enalapril and folic acid, compared with enalapril alone, significantly reduced the risk of first stroke. These findings are consistent with benefits from folate use among adults with hypertension and low baseline folate levels. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00794885.

Efficacy of folic acid supplementation in stroke prevention: new insight from a meta-analysis

Aims:  There are growing data and a continuing controversy over the efficacy of folic acid supplementation in stroke prevention. We conducted a meta‐analysis based on relevant, up‐to‐date published randomised trials to further examine this issue.

Folic acid supplementation and cancer risk: A meta-analysis of randomized controlled trials

There are growing data and a continuing controversy over the effect of folic acid supplementation on cancer risk. We conducted a meta‐analysis based on up‐to‐date published relevant randomized trials to further examine this issue. Relative risk (RR) was used to measure the effect of folic acid supplementation on risk of cancer using a random‐effects model. Overall, folic acid supplementation had no significant effect on total cancer incidence (13 trials, n = 49,406, RR = 1.05; 95% CI: 0.99–1.11, p = 0.13), colorectal cancer (seven trials, n = 33,824, 1.01; 0.82–1.23, p = 0.95), other gastrointestinal cancer (two trials, n = 20,228, 1.00; 0.75–1.33, p = 0.99), prostate cancer (five trials, n = 27,065, 1.17; 0.84–1.62, p = 0.35), other genitourinary cancer (two trials, n = 20,228, 0.97; 0.75–1.27, p = 0.84), lung cancer (five trials, n = 31,864, 1.00; 0.84–1.21, p = 0.97), breast cancer (four trials, n = 19,800, 0.82; 0.63–1.07, p = 0.15), hematological malignancy (three trials, n = 25,670, 0.87; 0.64–1.17, p = 0.35) and total cancer mortality (six trials, n = 31,930, 1.02; 0.90–1.15, p = 0.81). However, a significantly reduced risk was observed for melanoma (three trials, n = 19,128, 0.47; 0.23–0.94, p = 0.03). Furthermore, higher total cancer incidence risk was observed among those trials with a higher percent use of lipid‐lowering drugs (>60%, 1.10; 1.00–1.20, p = 0.04), or with lower percent baseline hypertension (≤70%, 1.08; 1.00–1.16, p = 0.057).Consistently, meta‐regression analyses suggested that the similar trend between percent use of lipid‐lowering drugs (p = 0.084) or percent baseline hypertension (p = 0.056) and log‐RR for total cancer incidence associated with folic acid supplementation. Our findings indicate that folic acid supplementation has no significant effect on total cancer incidence, colorectal cancer, prostate cancer, lung cancer, breast cancer or hematological malignancy, but reduces the risk of melanoma.

Prevalence of hyperhomocysteinaemia and its major determinants in rural Chinese hypertensive patients aged 45–75 years

We aimed to investigate the prevalence of hyperhomocysteinaemia (total plasma homocysteine (tHcy) ≥ 10 μmol/l) and its major determinants in rural Chinese hypertensive patients. A cross-sectional investigation was carried out in Lianyungang of Jiangsu province, China. This analysis included 13 946 hypertensive adults. The prevalence of hyperhomocysteinaemia was 51.6 % (42.7 % in women and 65.6 % in men). The OR of hyperhomocysteinaemia were 1.52 (95 % CI 1.39, 1.67) and 2.32 (95 % CI 2.07, 2.61) for participants aged 55-65 and 65-75 v. 45-55 years; 1.27 (95 % CI 1.18, 1.37) for participants with a BMI ≥ 25 v. < 25 kg/m²; 1.14 (95 % CI 1.06, 1.23) for participants with v. without antihypertensive treatment; 1.09 (95 % CI 1.00, 1.18) for residents inland v. coastal; 0.89 (95 % CI 0.82, 0.97) and 0.83 (95 % CI 0.74, 0.92) for participants with moderate and high v. low physical activity levels; 1.54 (95 % CI 1.41, 1.68) and 2.47 (95 % CI 2.17, 2.81) for participants with a glomerular filtration rate 60-90 and < 60 v. ≥ 90 ml/min per 1.73 m²; and 1.20 (95 % CI 1.07, 1.35) and 3.81 (95 % CI 3.33, 4.36) for participants with CT and TT v. CC genotype at methylenetetrahydrofolate reductase 677C>T polymorphism, respectively. Furthermore, higher tHcy concentrations were observed in smokers of both sexes (men: geometric mean 12.1 (interquartile range (IQR) 9.2-14.5) v. 11.9 (IQR 9.-14.) μmol/l, P= 0.005; women: geometric mean 10·3 (IQR 8.3-13.0) v. 9.6 (IQR 7.8-11.6) μmol/l, P= 0.010), and only in males with hypertension grade 3 (v. grade 1 or controlled blood pressure) (geometric mean 12.1 (IQR 9.2-14.4) v. 11.7 (IQR 9.2-14.0), P= 0.016) and in male non-drinkers (yes v. no) (geometric mean 12.3 (IQR 9.4-14.8) v. 11.7 (IQR 9.1-13.9), P= 0.014). In conclusion, there was a high prevalence of hyperhomocysteinaemia in Chinese hypertensive adults, particularly in the inlanders, who may benefit greatly from tHcy-lowering strategies, such as folic acid supplementation and lifestyle change.

Efficacy and Tolerability of a Single-Pill Combination of Amlodipine/Valsartan in Asian Hypertensive Patients Not Adequately Controlled with Valsartan Monotherapy

This randomized, double-blind study evaluated efficacy of a single-pill combination of amlodipine/valsartan (Aml/Val) in Asian patients with hypertension not responding to Val 80 mg. Patients with mean sitting diastolic blood pressure (DBP) ≥90 − ≤110 mmHg were randomized to Aml/Val 5/80, Val 80, or Val 160 mg for 8 weeks. At week-8 endpoint, significantly greater reductions in BP were seen with Aml/Val 5/80 mg than valsartan monotherapies (p < 0.0001). The BP control was greater with Aml/Val 5/80 (70.5%) than Val (44.1–58.6%) monotherapies. The combination was well tolerated. In conclusion, single-pill combination with Aml/Val provided significant additional BP reduction and control in hypertensive patients not responding to Val 80 mg.

Folic Acid Therapy Reduces the First Stroke Risk Associated With Hypercholesterolemia Among Hypertensive Patients

Background and Purpose— We sought to determine whether folic acid supplementation can independently reduce the risk of first stroke associated with elevated total cholesterol levels in a subanalysis using data from the CSPPT (China Stroke Primary Prevention Trial), a double-blind, randomized controlled trial. Methods— A total of 20 702 hypertensive adults without a history of major cardiovascular disease were randomly assigned to a double-blind daily treatment of an enalapril 10-mg and a folic acid 0.8-mg tablet or an enalapril 10-mg tablet alone. The primary outcome was first stroke. Results— The median treatment duration was 4.5 years. For participants not receiving folic acid treatment (enalapril-only group), high total cholesterol (≥200 mg/dL) was an independent predictor of first stroke when compared with low total cholesterol (<200 mg/dL; 4.0% versus 2.6%; hazard ratio, 1.52; 95% confidence interval, 1.18–1.97; P=0.001). Folic acid supplementation significantly reduced the risk of first stroke among participants with high total cholesterol (4.0% in the enalapril-only group versus 2.7% in the enalapril–folic acid group; hazard ratio, 0.69; 95% confidence interval, 0.56–0.84; P<0.001; number needed to treat, 78; 95% confidence interval, 52–158), independent of baseline folate levels and other important covariates. By contrast, among participants with low total cholesterol, the risk of stroke was 2.6% in the enalapril-only group versus 2.5% in the enalapril–folic acid group (hazard ratio, 1.00; 95% confidence interval, 0.75–1.30; P=0.982). The effect was greater among participants with elevated total cholesterol (P for interaction=0.024). Conclusions— Elevated total cholesterol levels may modify the benefits of folic acid therapy on first stroke. Folic acid supplementation reduced the risk of first stroke associated with elevated total cholesterol by 31% among hypertensive adults without a history of major cardiovascular diseases. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885.

Distinctive effects of carvedilol in the non-infarct zone: remodelling of the ligated rat heart linked to oxidative stress.

In this study, an experimental rat ligated heart model was used to observe the effect of treatment with carvedilol, metoprolol and metoprolol plus a highly selective α1-adrenergic blocking agent, bunazosin, after acute myocardial infarction (MI). Compared with an untreated MI group, all drug-treated groups demonstrated attenuation of inflammatory mediators, activation of nuclear factor-κB (NF-κB), and increased levels of mRNA and active protein for the collagenases matrix metallopeptidase (MMP)-8 and MMP-13 in the non-infarct zone of the ventricle, as well as inhibition of the increase of left ventricular end-diastolic pressure. Supplementation of metoprolol with bunazosin did not add greatly to the effects of metoprolol alone. Of the three drug treatments, carvedilol showed a uniquely potent antioxidant activity that may strengthen its capacity to inhibit oxidative stress, the release of inflammatory mediators and activation of NF-κB. This study may help provide a mechanistic explanation for the greater benefits shown by carvedilol compared with metoprolol in treating heart failure.

Independent and Joint Effect of Brachial-Ankle Pulse Wave Velocity and Blood Pressure Control on Incident Stroke in Hypertensive Adults

Pulse wave velocity (PWV) has been shown to influence the effects of antihypertensive drugs in the prevention of cardiovascular diseases. Data are limited on whether PWV is an independent predictor of stroke above and beyond hypertension control. This longitudinal analysis examined the independent and joint effect of brachial-ankle PWV (baPWV) with hypertension control on the risk of first stroke. This report included 3310 hypertensive adults, a subset of the China Stroke Primary Prevention Trial (CSPPT) with baseline measurements for baPWV. During a median follow-up of 4.5 years, 111 participants developed first stroke. The risk of stroke was higher among participants with baPWV in the highest quartile than among those in the lower quartiles (6.3% versus 2.4%; hazard ratio, 1.66; 95% confidence interval, 1.06–2.60). Similarly, the participants with inadequate hypertension control had a higher risk of stroke than those with adequate control (5.1% versus 1.8%; hazard ratio, 2.32; 95% confidence interval, 1.49–3.61). When baPWV and hypertension control were examined jointly, participants in the highest baPWV quartile and with inadequate hypertension control had the highest risk of stroke compared with their counterparts (7.5% versus 1.3%; hazard ratio, 3.57; 95% confidence interval, 1.88–6.77). There was a significant and independent effect of high baPWV on stroke as shown among participants with adequate hypertension control (4.2% versus 1.3%; hazard ratio, 2.29, 95% confidence interval, 1.09–4.81). In summary, among hypertensive patients, baPWV and hypertension control were found to independently and jointly affect the risk of first stroke. Participants with high baPWV and inadequate hypertension control had the highest risk of stroke compared with other groups.

Effect of NR3C2 genetic polymorphisms on the blood pressure response to enalapril treatment

AIM The mineralocorticoid receptor (MR; also known as NR3C2) plays important roles in the modulation of blood pressure. The effect of NR3C2 polymorphisms on antihypertensive response to enalapril was investigated. PATIENTS & METHODS Two hundred and seventy nine essential hypertension patients treated with enalapril were genotyped for two NR3C2 tagSNPs, rs5522 and rs2070950, by Sequenom MassArray™ technology. RESULTS The reductions in diastolic blood pressure (DBP) were significantly greater in AA homozygotes compared with AG+GG genotype carriers for the rs5522 polymorphism (p = 0.009), and the reductions in DBP were greater in GG homozygotes compared with GC+CC genotype carriers for the rs2070950 polymorphism, with marginal significance (p = 0.065). Stepwise multiple regression analysis indicated that significant predictors of DBP reduction were baseline DBP (p < 0.001), waist:hip ratio (p = 0.001) and rs5522 genotype (p = 0.003). CONCLUSION NR3C2 rs5522 affects blood pressure response to enalapril treatment and may serve as a useful pharmacogenomic marker of antihypertensive response to enalapril in essential hypertension patients.