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N J Wald

Publications and source records attributed to N J Wald.

At least 19 recordsLinked to original sources
PubMed2004

The performance of blood pressure and other cardiovascular risk factors as screening tests for ischaemic heart disease and stroke.

This paper summarises the main evidence and conclusions relating to using blood pressure measurement as a screening test to identify people who will develop ischaemic heart disease (IHD) or stroke, as recently published in a Health Technology Assessment report. While blood pressure is recognised as an important cause of stroke and IHD, and lowering blood pressure can substantially lower the risk of these diseases, the measurement of blood pressure is a poor screening test. It is not good in distinguishing those who will and will not develop these diseases. The poor screening performance is illustrated by the findings that in the largest cohort study, persons in the top 10% of the distribution of systolic blood pressure experienced only 21% of all IHD events and 28% of all strokes at a given age. Using several cardiovascular risk factors in combination does not add materially to the poor screening performance of blood pressure alone. Among persons in a specified age group, the 5% at highest risk experience 17% of all heart disease deaths with risk computation based on blood pressure alone, 22% when based on blood pressure and apolipoprotein B (or LDL cholesterol) in combination, and only 28% using these two, smoking and three other cardiovascular risk factors all in combination. Identifying patients at the time of hospital discharge following myocardial infarction or stroke is the most effective screening test to identify those who will die of cardiovascular disease. In patients with a history of myocardial infarction or stroke the cardiovascular death rate in the absence of treatment is about 5% per year, a risk that persists for at least 15 years. In the absence of treatment, about half of all deaths from heart disease in a population occur after hospital discharge following the first infarct. Among persons with no history of cardiovascular disease, age is a better screening test than the reversible risk factors, and the best policy is to offer treatment to all persons above a specified age such as 55 years.

Blood Pressure↗
PubMed2003

A strategy to reduce cardiovascular disease by more than 80%.

OBJECTIVES: To determine the combination of drugs and vitamins, and their doses, for use in a single daily pill to achieve a large effect in preventing cardiovascular disease with minimal adverse effects. The strategy was to simultaneously reduce four cardiovascular risk factors (low density lipoprotein cholesterol, blood pressure, serum homocysteine, and platelet function) regardless of pretreatment levels. DESIGN: We quantified the efficacy and adverse effects of the proposed formulation from published meta-analyses of randomised trials and cohort studies and a meta-analysis of 15 trials of low dose (50-125 mg/day) aspirin. OUTCOME MEASURES: Proportional reduction in ischaemic heart disease (IHD) events and strokes; life years gained; and prevalence of adverse effects. RESULTS: The formulation which met our objectives was: a statin (for example, atorvastatin (daily dose 10 mg) or simvastatin (40 mg)); three blood pressure lowering drugs (for example, a thiazide, a beta blocker, and an angiotensin converting enzyme inhibitor), each at half standard dose; folic acid (0.8 mg); and aspirin (75 mg). We estimate that the combination (which we call the Polypill) reduces IHD events by 88% (95% confidence interval 84% to 91%) and stroke by 80% (71% to 87%). One third of people taking this pill from age 55 would benefit, gaining on average about 11 years of life free from an IHD event or stroke. Summing the adverse effects of the components observed in randomised trials shows that the Polypill would cause symptoms in 8-15% of people (depending on the precise formulation). CONCLUSION: The Polypill strategy could largely prevent heart attacks and stroke if taken by everyone aged 55 and older and everyone with existing cardiovascular disease. It would be acceptably safe and with widespread use would have a greater impact on the prevention of disease in the Western world than any other single intervention.

Adult↗
PubMed2003

Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis.

OBJECTIVES: To determine by how much statins reduce serum concentrations of low density lipoprotein (LDL) cholesterol and incidence of ischaemic heart disease (IHD) events and stroke, according to drug, dose, and duration of treatment. DESIGN: Three meta-analyses: 164 short term randomised placebo controlled trials of six statins and LDL cholesterol reduction; 58 randomised trials of cholesterol lowering by any means and IHD events; and nine cohort studies and the same 58 trials on stoke. MAIN OUTCOME MEASURES: Reductions in LDL cholesterol according to statin and dose; reduction in IHD events and stroke for a specified reduction in LDL cholesterol. RESULTS: Reductions in LDL cholesterol (in the 164 trials) were 2.8 mmol/l (60%) with rosuvastatin 80 mg/day, 2.6 mmol/l (55%) with atorvastatin 80 mg/day, 1.8 mmol/l (40%) with atorvastatin 10 mg/day, lovastatin 40 mg/day, simvastatin 40 mg/day, or rosuvastatin 5 mg/day, all from pretreatment concentrations of 4.8 mmol/l. Pravastatin and fluvastatin achieved smaller reductions. In the 58 trials, for an LDL cholesterol reduction of 1.0 mmol/l the risk of IHD events was reduced by 11% in the first year of treatment, 24% in the second year, 33% in years three to five, and by 36% thereafter (P < 0.001 for trend). IHD events were reduced by 20%, 31%, and 51% in trials grouped by LDL cholesterol reduction (means 0.5 mmol/l, 1.0 mmol/l, and 1.6 mmol/l) after results from first two years of treatment were excluded (P < 0.001 for trend). After several years a reduction of 1.8 mmol/l would reduce IHD events by an estimated 61%. Results from the same 58 trials, corroborated by results from the nine cohort studies, show that lowering LDL cholesterol decreases all stroke by 10% for a 1 mmol/l reduction and 17% for a 1.8 mmol/l reduction. Estimates allow for the fact that trials tended to recruit people with vascular disease, among whom the effect of LDL cholesterol reduction on stroke is greater because of their higher risk of thromboembolic stroke (rather than haemorrhagic stroke) compared with people in the general population. CONCLUSIONS: Statins can lower LDL cholesterol concentration by an average of 1.8 mmol/l which reduces the risk of IHD events by about 60% and stroke by 17%.

Cholesterol, LDL↗
PubMed2003

Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials.

OBJECTIVE: To determine the average reduction in blood pressure, prevalence of adverse effects, and reduction in risk of stroke and ischaemic heart disease events produced by the five main categories of blood pressure lowering drugs according to dose, singly and in combination. DESIGN: Meta-analysis of 354 randomised double blind placebo controlled trials of thiazides, beta blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and calcium channel blockers in fixed dose. SUBJECTS: 40,000 treated patients and 16,000 patients given placebo. MAIN OUTCOME MEASURES: Placebo adjusted reductions in systolic and diastolic blood pressure and prevalence of adverse effects, according to dose expressed as a multiple of the standard (recommended) doses of the drugs. RESULTS: All five categories of drug produced similar reductions in blood pressure. The average reduction was 9.1 mm Hg systolic and 5.5 mm Hg diastolic at standard dose and 7.1 mm Hg systolic and 4.4 mm Hg diastolic (20% lower) at half standard dose. The drugs reduced blood pressure from all pretreatment levels, more so from higher levels; for a 10 mm Hg higher blood pressure the reduction was 1.0 mm Hg systolic and 1.1 mm Hg diastolic greater. The blood pressure lowering effects of different categories of drugs were additive. Symptoms attributable to thiazides, beta blockers, and calcium channel blockers were strongly dose related; symptoms caused by ACE inhibitors (mainly cough) were not dose related. Angiotensin II receptor antagonists caused no excess of symptoms. The prevalence of symptoms with two drugs in combination was less than additive. Adverse metabolic effects (such as changes in cholesterol or potassium) were negligible at half standard dose. CONCLUSIONS: Combination low dose drug treatment increases efficacy and reduces adverse effects. From the average blood pressure in people who have strokes (150/90 mm Hg) three drugs at half standard dose are estimated to lower blood pressure by 20 mm Hg systolic and 11 mm Hg diastolic and thereby reduce the risk of stroke by 63% and ischaemic heart disease events by 46% at age 60-69.

Antihypertensive Agents↗
PubMed2003

Comparison of models of maternal age-specific risk for Down syndrome live births.

OBJECTIVES: To display and compare the different published formulae that specify the association between maternal age and the risk of a Down syndrome live birth. METHODS: Papers published since 1987 on the prevalence of Down syndrome live births in relation to maternal age were located using MEDLINE and the references given in other papers. The data series and the models fitted to them were plotted to obtain a visual idea of their similarities and differences. RESULTS: The observed and modelled age-specific rates for Down syndrome births were remarkably similar in all published series of data for women up to the age of 35, were reasonably similar for women aged 35 to 45, but differed for women older than 45. CONCLUSION: In practice, the overall small differences in age-related risk between the different studies did not materially affect the performance of antenatal screening for Down syndrome. If a choice is to be made, the analysis based on the National Down Syndrome Cytogenetic Register (NDSCR) has marginal advantages since it is based on the largest data set and the corresponding model fits the data well. More data is needed to clarify the pattern of risk with maternal age among women over 45 years of age.

Adult↗
PubMed2003

A new approach to antenatal screening for Fragile X syndrome.

OBJECTIVES: To describe a new approach to antenatal screening for Fragile X syndrome and to evaluate its effectiveness. METHODS: We propose that Fragile X syndrome should be considered as a different disorder in males and in females. We also propose that only male Fragile X syndrome should be screened for, so the initial screening test would be the determination of fetal sex. This can now be performed from eight-weeks gestation using a polymerase chain reaction (PCR) analysis on maternal serum. If this test reveals a male fetus, then the same blood sample can be used to determine the CGG repeat length in the DNA of the mother, again using the PCR technique and a Southern blot analysis where necessary. Mothers with positive results (>58 repeats) would be offered antenatal diagnosis (chorionic villus sampling or amniocentesis) to determine the CGG repeat length in cells from the fetus. The screening performance of this strategy was determined using the performance of the component tests. RESULTS: The proposed strategy for screening for male Fragile X syndrome would have a 99% detection rate and a 0.1% false-positive rate. CONCLUSION: After antenatal screening for Down syndrome, the proposed screening strategy would be the most effective method of preventing the birth of males with severe mental retardation. It would have a higher detection rate and a lower false-positive rate than any other antenatal screening programme currently being undertaken, and there would be virtually no prenatal diagnosis of female Fragile X syndrome, which, because such a high proportion are phenotypically normal, has been a barrier to the introduction of screening.

Adult↗
PubMed2003

Using Down syndrome serum screening results to predict low birthweight.

OBJECTIVE: To investigate the use of prenatal maternal serum screening results for Down syndrome, for the prediction of low (<2500 g) and very low (<1500 g) birthweight. DESIGN: Record linkage of maternal serum screening results with the corresponding birth records. PARTICIPANTS: 42 259 women whose pregnancies had been screened for the risk of Down syndrome. SETTING: Three East London maternity units, between February 1989 and August 1998. RESULTS: Estimates were made of the effectiveness of single markers only for the prediction of low birthweight, and of multiple markers together with mother's weight and smoking habit. As reported previously, high levels of the single markers alpha-fetoprotein and total human chorionic gonadotrophin, inhibin A, and low levels of unconjugated oestriol were associated with low birthweight. However, the best prediction was obtained when multiple serum markers comprising alpha-fetoprotein, unconjugated oestriol, and inhibin A were used in combination together with mother's weight and adjustment for smoking habit. For a false-positive rate of 5%, this combination predicted 23% of low birthweight and 39% of very low birthweight babies, possibly the best method of prediction to date. CONCLUSION: Prediction of low birthweight derived from Down syndrome screening could be used, for little extra cost, to advise on place of delivery or to select candidates for randomised clinical trials of low birthweight prevention.

Adult↗
PubMed2003

Cystic fibrosis: selecting the prenatal screening strategy of choice.

Cystic fibrosis is a serious disorder. Research into the treatment of affected individuals is in progress, but a cure is not expected in the near future. In this review, we demonstrate that prenatal screening for cystic fibrosis meets the requirements for a worthwhile screening programme. We explain the reasons that have led us to conclude that one approach ('couple screening') is the method of choice. The couple-based approach calls for reporting results to the couple as a unit. Only if both parents are found to be carriers is the result designated screen-positive and an amniocentesis or chorionic villus sampling offered. This offers a substantial reduction in the proportion of women with unaffected pregnancies with positive results (the false-positive rate) compared with other methods without reducing the detection of affected pregnancies. It also avoids creating a screen-positive group for which no definitive diagnosis is available. This is a problem with other screening methods. The couple method can achieve a 72% detection rate for a 0.1% false-positive rate. The screening method is simple, non-invasive, reliable, safe and reasonably cost effective. Existing programmes have shown that screening using this method is acceptable to health care professionals and patients. Setting up a national prenatal screening programme for cystic fibrosis is timely and should be implemented using the couple screening method.

Adult↗
PubMed2001

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.

Adult↗
PubMed2001

Randomized trial of folic acid supplementation and serum homocysteine levels.

BACKGROUND: Lowering serum homocysteine levels with folic acid is expected to reduce mortality from ischemic heart disease. Homocysteine reduction is known to be maximal at a folic acid dosage of 1 mg/d, but the effect of lower doses (relevant to food fortification) is unclear. METHODS: We randomized 151 patients with ischemic heart disease to 1 of 5 dosages of folic acid (0.2, 0.4, 0.6, 0.8, and 1.0 mg/d) or placebo. Fasting blood samples for serum homocysteine and serum folate analysis were taken initially, after 3 months of supplementation, and 3 months after folic acid use was discontinued. RESULTS: Median serum homocysteine level decreased with increasing folic acid dosage, to a maximum at 0.8 mg of folic acid per day, when the homocysteine reduction (placebo adjusted) was 2.7 micromol/L (23%), similar to the known effect of folic acid dosages of 1 mg/d and above. The higher a person's initial serum homocysteine level, the greater was the response to folic acid, but there were statistically significant reductions regardless of the initial level. Serum folate level increased approximately linearly (5.5 nmol/L for every 0.1 mg of folic acid). Within-person fluctuations over time in serum homocysteine levels, measured in the placebo group, were large compared with the effect of folic acid, indicating that monitoring of the reduction in an individual is impractical. CONCLUSIONS: A dosage of folic acid of 0.8 mg/d appears necessary to achieve the maximum reduction in serum homocysteine level across the range of homocysteine levels in the population. Current US food fortification levels will achieve only a small proportion of the achievable homocysteine reduction.

Adult↗