David S. Wald

Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis

Abstract Objective: To assess whether the association of serum homocysteine concentration with ischaemic heart disease, deep vein thrombosis and pulmonary embolism, and stroke is causal and, if so, to quantify the effect of homocysteine reduction in preventing them. Design: Meta-analyses of the above three diseases using (a) 72 studies in which the prevalence of a mutation in the MTHFR gene (which increases homocysteine) was determined in cases (n=16 849) and controls, and (b) 20 prospective studies (3820 participants) of serum homocysteine and disease risk. Main outcome measures: Odds ratios of the three diseases for a 5 μmol/l increase in serum homocysteine concentration. Results: There were significant associations between homocysteine and the three diseases. The odds ratios for a 5 μmol/l increase in serum homocysteine were, for ischaemic heart disease, 1.42 (95% confidence interval 1.11 to 1.84) in the genetic studies and 1.32 (1.19 to 1.45) in the prospective studies; for deep vein thrombosis with or without pulmonary embolism, 1.60 (1.15 to 2.22) in the genetic studies (there were no prospective studies); and, for stroke, 1.65 (0.66 to 4.13) in the genetic studies and 1.59 (1.29 to 1.96) in the prospective studies. Conclusions: The genetic studies and the prospective studies do not share the same potential sources of error, but both yield similar highly significant results—strong evidence that the association between homocysteine and cardiovascular disease is causal. On this basis, lowering homocysteine concentrations by 3 μmol/l from current levels (achievable by increasing folic acid intake) would reduce the risk of ischaemic heart disease by 16% (11% to 20%), deep vein thrombosis by 25% (8% to 38%), and stroke by 24% (15% to 33%). What is already known on this topic There is an association between serum homocysteine concentration and cardiovascular disease, but it is not known whether the association is causal A common single gene mutation that reduces the activity of an enzyme involved in folate metabolism (MTHFR) is associated with a moderate (20%) increase in serum homocysteine What this study adds A meta-analysis of MTHFR studies shows a significantly higher risk of both ischaemic heart disease and deep vein thrombosis (with or without pulmonary embolism) in people with the MTHFR mutation A meta-analysis of prospective studies shows a significant association between homocysteine concentration and ischaemic heart disease similar in size to that expected from the results of the MTHFR studies and a significant association with stroke The MTHFR studies and the prospective studies do not share the same potential sources of error but both yield similar results—strong evidence that the association between homocysteine and cardiovascular disease is causal On this basis a decrease in serum homocysteine of 3 μmol/l (achievable by daily intake of about 0.8 mg folic acid) should reduce the risk of ischaemic heart disease by 16%, deep vein thrombosis by 25%, and stroke by 24%

Randomized Trial of Preventive Angioplasty in Myocardial Infarction

BACKGROUND In acute ST-segment elevation myocardial infarction (STEMI), the use of percutaneous coronary intervention (PCI) to treat the artery responsible for the infarct (infarct, or culprit, artery) improves prognosis. The value of PCI in noninfarct coronary arteries with major stenoses (preventive PCI) is unknown. METHODS From 2008 through 2013, at five centers in the United Kingdom, we enrolled 465 patients with acute STEMI (including 3 patients with left bundle-branch block) who were undergoing infarct-artery PCI and randomly assigned them to either preventive PCI (234 patients) or no preventive PCI (231 patients). Subsequent PCI for angina was recommended only for refractory angina with objective evidence of ischemia. The primary outcome was a composite of death from cardiac causes, nonfatal myocardial infarction, or refractory angina. An intention-to-treat analysis was used. RESULTS By January 2013, the results were considered conclusive by the data and safety monitoring committee, which recommended that the trial be stopped early. During a mean follow-up of 23 months, the primary outcome occurred in 21 patients assigned to preventive PCI and in 53 patients assigned to no preventive PCI (infarct-artery-only PCI), which translated into rates of 9 events per 100 patients and 23 per 100, respectively (hazard ratio in the preventive-PCI group, 0.35; 95% confidence interval [CI], 0.21 to 0.58; P<0.001). Hazard ratios for the three components of the primary outcome were 0.34 (95% CI, 0.11 to 1.08) for death from cardiac causes, 0.32 (95% CI, 0.13 to 0.75) for nonfatal myocardial infarction, and 0.35 (95% CI, 0.18 to 0.69) for refractory angina. CONCLUSIONS In patients with STEMI and multivessel coronary artery disease undergoing infarct-artery PCI, preventive PCI in noninfarct coronary arteries with major stenoses significantly reduced the risk of adverse cardiovascular events, as compared with PCI limited to the infarct artery. (Funded by Barts and the London Charity; PRAMI Current Controlled Trials number, ISRCTN73028481.).

Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials.

OBJECTIVE To quantify the incremental effect of combining blood pressure-lowering drugs from any 2 classes of thiazides, beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers over 1 drug alone and to compare the effects of combining drugs with doubling dose. METHODS Meta-analysis of factorial trials in which participants were randomly allocated to 1 drug alone, another drug alone, both drugs together, or a placebo. RESULTS We identified 42 trials (10,968 participants). With a thiazide used alone, the mean placebo-subtracted reduction in systolic blood pressure was 7.3 mm Hg and 14.6 mm Hg combined with a drug from another class. The corresponding reductions were 9.3 mm Hg and 18.9 mm Hg with a beta-blocker, 6.8 mm Hg and 13.9 mm Hg with an angiotensin-converting enzyme, and 8.4 mm Hg and 14.3 mm Hg with a calcium channel blocker. The expected blood pressure reduction from 2 drugs together, assuming an additive effect, closely predicted the observed blood pressure reductions. The ratios of the observed to expected incremental blood pressure reductions from combining each class of drug with any other over that from 1 drug were, respectively, for thiazides, beta-blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers: 1.04 (95% confidence interval [CI], 0.88-1.20), 1.00 (95% CI, 0.76-1.24), 1.16 (95% CI, 0.93-1.39), and 0.89 (95% CI, 0.69-1.09); the overall average was 1.01 (95% CI, 0.90-1.12). Comparison of our results with those of a published meta-analysis of different doses of the same drug showed that doubling the dose of 1 drug had approximately one fifth of the equivalent incremental effect (0.22 [95% CI, 0.19-0.25]). CONCLUSION Blood pressure reduction from combining drugs from these 4 classes can be predicted on the basis of additive effects. The extra blood pressure reduction from combining drugs from 2 different classes is approximately 5 times greater than doubling the dose of 1 drug.

Quantifying the effect of folic acid

BACKGROUND Folic acid is known to prevent neural-tube defects (NTDs) but the size of the effect for a given dose is unclear. We aimed to quantify such an effect. METHODS We used published data from 13 studies of folic acid supplementation on serum folate concentrations and results from a large cohort study of the risk of NTDs according to serum folate, to measure the preventive effect of specified increases in intake of folic acid. FINDINGS Serum folate concentrations increase by 0.94 ng/mL (95% CI 0.77-1.10) for every 0.1 mg/day increase in folic acid intake in women aged 20-35 years, and about double that in people aged 40-65. Every doubling of serum folate concentration roughly halves the risk of an NTD. These two effects can be combined to predict the reduction in risk according to intake of extra folic acid and background serum folate concentration. Such results predict that the preventive effect is greater in women with low serum folate than in those with higher concentrations. The results have also been used to predict direct observations from large randomised trials and the effect of food fortification. From a typical western background serum folate of 5 ng/mL, about 0.2 mg/day (the US level of folic acid fortification) would be expected to reduce NTDs by about 20%; a similar effect can be expected from the current British recommendation (0.24 mg/day). An increase of 0.4 mg/day would reduce risk by about 36%, of 1 mg/day by 57%, and taking a 5-mg tablet daily would reduce risk by about 85%. INTERPRETATION Folic acid fortification levels should be increased. Additionally women planning a pregnancy should take 5 mg folic acid tablets daily, instead of the 0.4 mg dose presently recommended.

Adherence to drugs that prevent cardiovascular disease: meta-analysis on 376,162 patients

OBJECTIVE Combination therapy, specifically with aspirin, cholesterol and blood pressure-lowering drugs, substantially reduces the risk of coronary heart disease, but the full preventive effect is only realized if treatment continues indefinitely. Our objective was to provide a summary estimate of adherence to drugs that prevent coronary heart disease, according to drug class and use in people who have had a myocardial infarction (secondary prevention) and people who have not (primary prevention). METHODS A meta-analysis of data on 376,162 patients from 20 studies assessing adherence using prescription refill frequency for the following 7 drug classes was performed: aspirin, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, calcium-channel blockers, thiazides, and statins. Meta-regression was used to examine the effects of age, payment, and treatment duration. RESULTS The summary estimate for adherence across all studies was 57% (95% confidence interval [CI], 50-64) after a median of 24 months. There were statistically significant differences in adherence between primary and secondary prevention: 50% (CI, 45-56) and 66% (CI, 56-75), respectively (P=.012). Adherence was lower for thiazides (42%) than for angiotensin receptor blockers (61%) in primary prevention (P=.02). There were no other statistically significant differences between any of the drug classes in primary or secondary prevention studies. Adherence decreased by 0.15% points/month (P=.07) and was unrelated to age or whether patients paid for their pills. CONCLUSION Adherence to preventive treatment is poor and little related to class of drug, suggesting that side effects are not the main cause. General, rather than class-specific, measures at improving adherence are needed.

Folic acid, homocysteine, and cardiovascular disease: judging causality in the face of inconclusive trial evidence

Increasing intake of folic acid would be a relatively cheap and simple way of reducing heart disease, if it works. Can we draw a definitive conclusion from the current evidence?

Child-parent screening for familial hypercholesterolaemia: screening strategy based on a meta-analysis

Objective To develop a population screening strategy for familial hypercholesterolaemia. Design Meta-analysis of published data on total and low density lipoprotein (LDL) cholesterol in people with and without familial hypercholesterolaemia according to age. Thirteen studies reporting on 1907 cases and 16 221 controls were used in the analysis. Included studies had at least 10 cases and controls with data on the distribution of cholesterol in affected and unaffected individuals. Main outcome measures Detection rates (sensitivity) for specified false positive rates (0.1%, 0.5%, and 1%) in newborns and in age groups 1-9, 10-19, 20-39, 40-59, and ≥60 years. Results Serum cholesterol concentration discriminated best between people with and without familial hypercholesterolaemia at ages 1-9, when the detection rates with total cholesterol were 88%, 94%, and 96% for false positive rates of 0.1%, 0.5%, and 1%. The results were similar with LDL cholesterol. Screening newborns was much less effective. Once an affected child is identified, measurement of cholesterol would detect about 96% of parents with the disorder, using the simple rule that the parent with the higher serum cholesterol concentration is the affected parent. Conclusions The proposed strategy of screening children and parents for familial hypercholesterolaemia could have considerable impact in preventing the medical consequences of this disorder in two generations simultaneously.

Randomized Polypill Crossover Trial in People Aged 50 and Over

Background A Polypill is proposed for the primary prevention of cardiovascular disease in people judged to be at risk on account of their age alone. Its efficacy in reducing cholesterol and blood pressure is uncertain. Methods We conducted a randomized double-blind placebo-controlled crossover trial of a Polypill among individuals aged 50+ without a history of cardiovascular disease and compared the reductions with those predicted from published estimates of the effects of the individual drugs. Participants took the Polypill (amlodipine 2.5 mg, losartan 25 mg, hydrochlorothiazide 12.5 mg and simvastatin 40 mg) each evening for 12 weeks and a placebo each evening for 12 weeks in random sequence. The mean within-person differences in blood pressure and low density lipoprotein (LDL) cholesterol at the end of each 12 week period were determined. Results 84 out of 86 participants completed both treatment periods. The mean systolic blood pressure was reduced by 17.9 mmHg (95% CI, 15.7–20.1) on the Polypill, diastolic blood pressure by 9.8 mmHg (8.1–11.5), and LDL cholesterol by 1.4 mmol/L (1.2–1.6), reductions of 12%, 11%, and 39% respectively. The results were almost identical to those predicted; 18.4 mmHg, 9.7 mmHg, and 1.4 mmol/L respectively. Conclusion The Polypill resulted in the predicted reductions in blood pressure and LDL cholesterol. Long term reductions of this magnitude would have a substantial effect in preventing heart attacks and strokes. Trial Registration Controlled-Trials.com ISRCTN36672232

Effect of Folic Acid, with or without Other B Vitamins, on Cognitive Decline: Meta-Analysis of Randomized Trials

PURPOSE We aimed to quantify the effect of folic acid supplementation on the prevention of cognitive decline. METHODS We conducted a meta-analysis of 9 placebo-controlled randomized trials (2835 participants, median duration 6 months) of folic acid, with or without other B vitamins, on cognitive function. Standardized mean differences in cognitive function test scores were calculated between folic acid and placebo-treated groups. RESULTS The standardized mean difference in cognitive function test scores was 0.01 (95% confidence interval [95% CI], -0.08 to 0.10), or an increase of 1% (95% CI, -8% to 10%) of 1 standard deviation. The results were similar within each of the 4 categories of cognitive function (memory, speed, language, and executive function); standardized mean differences were 0.01 (95% CI, -0.08 to 0.09), -0.01 (95% CI, -0.10 to 0.13), -0.05 (95% CI, -0.15 to 0.04), and 0.03 (95% CI, -0.13 to 0.19), respectively. CONCLUSION Randomized trials show no effect of folic acid, with or without other B vitamins, on cognitive function within 3 years of the start of treatment. Trials of longer duration, recording the incidence of dementia, as well as cognitive decline, are needed.

Serum homocysteine and dementia: Meta-analysis of eight cohort studies including 8669 participants

Prospective cohort studies have not been consistent in showing an association between serum homocysteine and dementia.