Nicholas J. Wald

Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies

Objectives To determine the quantitative efficacy of different classes of blood pressure lowering drugs in preventing coronary heart disease (CHD) and stroke, and who should receive treatment. Design Meta-analysis. Data source Medline (1966-2007). Study selection Randomised trials of blood pressure lowering drugs recording CHD events and strokes. 108 trials studied differences in blood pressure between study drug and placebo (or control group not receiving the study drug) (“blood pressure difference trials”), and 46 trials compared drugs (“drug comparison trials”). Seven trials with three randomised groups fell into both categories. The results were interpreted in the context of those expected from the largest published meta-analysis of cohort studies, totalling 958 000 people. Participants 464 000 people defined into three mutually exclusive categories: participants with no history of vascular disease, a history of CHD, or a history of stroke. Results In the blood pressure difference trials β blockers had a special effect over and above that due to blood pressure reduction in preventing recurrent CHD events in people with a history of CHD: risk reduction 29% (95% confidence interval 22% to 34%) compared with 15% (11% to 19%) in trials of other drugs. The extra effect was limited to a few years after myocardial infarction, with a risk reduction of 31% compared with 13% in people with CHD with no recent infarct (P=0.04). In the other blood pressure difference trials (excluding CHD events in trials of β blockers in people with CHD), there was a 22% reduction in CHD events (17% to 27%) and a 41% (33% to 48%) reduction in stroke for a blood pressure reduction of 10 mm Hg systolic or 5 mm Hg diastolic, similar to the reductions of 25% (CHD) and 36% (stroke) expected for the same difference in blood pressure from the cohort study meta-analysis, indicating that the benefit is explained by blood pressure reduction itself. The five main classes of blood pressure lowering drugs (thiazides, β blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers) were similarly effective (within a few percentage points) in preventing CHD events and strokes, with the exception that calcium channel blockers had a greater preventive effect on stroke (relative risk 0.92, 95% confidence interval 0.85 to 0.98). The percentage reductions in CHD events and stroke were similar in people with and without cardiovascular disease and regardless of blood pressure before treatment (down to 110 mm Hg systolic and 70 mm Hg diastolic). Combining our results with those from two other studies (the meta-analyses of blood pressure cohort studies and of trials determining the blood pressure lowering effects of drugs according to dose) showed that in people aged 60-69 with a diastolic blood pressure before treatment of 90 mm Hg, three drugs at half standard dose in combination reduced the risk of CHD by an estimated 46% and of stroke by 62%; one drug at standard dose had about half this effect. The present meta-analysis also showed that drugs other than calcium channel blockers (with the exception of non-cardioselective β blockers) reduced the incidence of heart failure by 24% (19% to 28%) and calcium channel blockers by 19% (6% to 31%). Conclusions With the exception of the extra protective effect of β blockers given shortly after a myocardial infarction and the minor additional effect of calcium channel blockers in preventing stroke, all the classes of blood pressure lowering drugs have a similar effect in reducing CHD events and stroke for a given reduction in blood pressure so excluding material pleiotropic effects. The proportional reduction in cardiovascular disease events was the same or similar regardless of pretreatment blood pressure and the presence or absence of existing cardiovascular disease. Guidelines on the use of blood pressure lowering drugs can be simplified so that drugs are offered to people with all levels of blood pressure. Our results indicate the importance of lowering blood pressure in everyone over a certain age, rather than measuring it in everyone and treating it in some.

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

Abstract 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%.

A strategy to reduce cardiovascular disease by more than 80

Abstract 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 β 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.

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

Abstract 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, β 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, β 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.

Maternal serum screening for Down's syndrome in early pregnancy.

The possibility of improving the effectiveness of antenatal screening for Downs syndrome by measuring human chorionic gonadotrophin concentrations in maternal serum during the second trimester to select women for diagnostic amniocentesis was examined. The median maternal serum human chorionic gonadotrophin concentration in 77 pregnancies associated with Downs syndrome was twice the median concentration in 385 unaffected pregnancies matched for maternal age, gestational age, and duration of storage of the serum sample. Measuring human chorionic gonadotrophin in maternal serum was an effective screening test, giving a lower false positive rate (3%) at a 30% detection rate than that for maternal age (5%) and the two existing serum screening tests, unconjugated oestriol (7%) and alpha fetoprotein (11%). The most effective screening results were obtained with all four variables combined; at the same 30% detection rate the false positive rate declined to 0.5%. The new screening method would detect over 60% of affected pregnancies, more than double that achievable with the same amniocentesis rate in existing programmes (5%), and could reduce the number of children born with Downs syndrome in the United Kingdom from about 900 a year to about 350 a year.

The accumulated evidence on lung cancer and environmental tobacco smoke

Abstract Objective: To estimate the risk of lung cancer in lifelong non-smokers exposed to environmental tobacco smoke. Design: Analysis of 37 published epidemiological studies of the risk of lung cancer (4626 cases) in non-smokers who did and did not live with a smoker. The risk estimate was compared with that from linear extrapolation of the risk in smokers using seven studies of biochemical markers of tobacco smoke intake. Main outcome measure: Relative risk of lung cancer in lifelong non-smokers according to whether the spouse currently smoked or had never smoked. Results: The excess risk of lung cancer was 24% (95% confidence interval 13% to 36%) in non-smokers who lived with a smoker (P<0.001). Adjustment for the effects of bias (positive and negative) and dietary confounding had little overall effect; the adjusted excess risk was 26% (7% to 47%). The dose-response relation of the risk of lung cancer with both the number of cigarettes smoked by the spouse and the duration of exposure was significant. The excess risk derived by linear extrapolation from that in smokers was 19%, similar to the direct estimate of 26%. Conclusion: The epidemiological and biochemical evidence on exposure to environmental tobacco smoke, with the supporting evidence of tobacco specific carcinogens in the blood and urine of non-smokers exposed to environmental tobacco smoke, provides compelling confirmation that breathing other peoples tobacco smoke is a cause of lung cancer. Key messages A woman who has never smoked has an estimated 24% greater risk of lung cancer if she lives with a smoker Neither bias nor confounding accounted for the association There is a dose-response relation between a non-smokers risk of lung cancer and the number of cigarettes and years of exposure to the smoker The increased risk was consistent with that expected from extrapolation of the risk in smokers using biochemical markers Tobacco specific carcinogens are found in the blood and urine of non-smokers exposed to environmental tobacco smoke All the available evidence confirms that exposure to environmental tobacco smoke causes lung cancer

Environmental tobacco smoke exposure and ischaemic heart disease: an evaluation of the evidence

Abstract Objectives: To estimate the risk of ischaemic heart disease caused by exposure to environmental tobacco smoke and to explain why the associated excess risk is almost half that of smoking 20 cigarettes per day when the exposure is only about 1% that of smoking. Design: Meta-analysis of all 19 acceptable published studies of risk of ischaemic heart disease in lifelong non-smokers who live with a smoker and in those who live with a non-smoker, five large prospective studies of smoking and ischaemic heart disease, and studies of platelet aggregation and studies of diet according to exposure to tobacco smoke. Results: The relative risk of ischaemic heart disease associated with exposure to environmental tobacco smoke was 1.30 (95% confidence interval 1.22 to 1.38) at age 65. At the same age the estimated relative risk associated with smoking one cigarette per day was similar (1.39 (1.18 to 1.64)), while for 20 per day it was 1.78 (1.31 to 2.44). Two separate analyses indicated that non-smokers who live with smokers eat a diet that places them at a 6% higher risk of ischaemic heart disease, so the direct effect of environmental tobacco smoke is to increase risk by 23% (14% to 33%), since 1.30/1.06=1.23. Platelet aggregation provides a plausible and quantitatively consistent mechanism for the low dose effect. The increase in platelet aggregation produced experimentally by exposure to environmental tobacco smoke would be expected to have acute effects increasing the risk of ischaemic heart disease by 34%. Conclusion: Breathing other peoples smoke is an important and avoidable cause of ischaemic heart disease, increasing a persons risk by a quarter. Key messages Analysis of 19 epidemiological studies shows that people who have never smoked have an estimated 30% greater risk of ischaemic heart disease if they live with a smoker (P<0.001) This is surprisingly large—almost half the risk of smoking 20 cigarettes per day even though the exposure is only 1% of that of a smoker The excess risk from smoking one cigarette per day is 39%—similar to the risk in a non-smoker living with a smoker The effect is mainly explained by a non-linear dose-response relation between expsoure to tobacco smoke and risk of heart disease Detailed analysis shows no significant bias; dietary confounding can account for an excess risk of only 6%, so revising the excess risk from 30% to 23%

Estimating a woman's risk of having a pregnancy associated with Down's syndrome using her age and serum alpha-fetoprotein level.

The risk of an individual woman having a pregnancy associated with Downs syndrome was estimated from her age and her serum alpha‐fetoprotein (AFP) level at 14–20 weeks gestation. The estimates were made using published data on the risk of Downs syndrome in relation to maternal age from 4528 affected and over 5 million unaffected pregnancies, and on the risk in relation to serum AFP from 68 affected and 36 645 unaffected pregnancies. Separate estimates were derived for AFP levels using gestational age based (i) on the time since the first day of the last menstrual period and (ii) on an ultrasound biparietal diameter measurement. In each case this was done with and without adjusting AFP levels to take account of maternal weight. The same sources of data were also used to construct six Downs syndrome screening policies, each combining information on maternal age and serum AFP. For example with one policy the detection rate would be 28% and would involve selecting 2·8% of unaffected pregnancies for amniocentesis; using age alone the same detection rate could only be achieved by selecting 4·3% of unaffected pregnancies for amniocentesis—an increase of 50%. In general, screening for Downs syndrome using both maternal age and serum AFP is more efficient than either alone.

First and Second Trimester Antenatal Screening for Down's Syndrome: The Results of the Serum, Urine and Ultrasound Screening Study (SURUSS):

Objectives To identify the most effective, safe and cost-effective method of antenatal screening for Downs syndrome using nuchal translucency (NT), maternal serum and urine markers in the first and second trimesters of pregnancy, and maternal age in various combinations.Design A prospective study of women who booked for their antenatal care at about 8-14 weeks of gestation, with follow-up to identify pregnancies with Downs syndrome ascertained through second trimester screening or at birth.Setting Twenty-five maternity units (24 in the UK and one in Austria) offering second trimester Downs syndrome serum screening that agreed to collect observational data in the first trimester.Participants The results were based on 47,053 singleton pregnancies, including 101 pregnancies with Downs syndrome.Measurements and tests NT measurements were included if obtained between 9 and 13 weeks of pregnancy; serum and urine samples were also taken and stored. Another pair of serum and urine samples was collected in the second trimester and included if obtained between 14 and 20 weeks. Urine and serum samples from each affected pregnancy and five matched controls were tested for:Serum:alphafetoprotein (AFP)total human chorionic gonadotrophin (hCG)unconjugated oestriol (uE(3))pregnancy associated plasma protein A (PAPP-A)free beta-hCG.dimeric inhibin-A.Urine:invasive trophoblast antigen (ITA)beta-core fragmenttotal hCGfree beta-hCG.The matching criteria were gestation (using an ultrasound crown-rump length or biparietal diameter measurement), duration of storage, and centre. Screening performance of the individual markers and combinations of markers together with maternal age was assessed using standard methods. In addition pairs of first and second trimester serum samples from 600 controls were tested to secure a larger set in which screening performance could be determined using distribution parameters based on dates (time since first day of the last menstrual period).Main outcome measures The following were determined for different combinations of markers:efficacy (by assessing screening performance, focusing on the false-positive rate (FPR) for an 85% detection rate (DR))safety (focusing on the number of fetal losses due to amniocentesis (or chorionic villus sampling) in 100,000 women screened)cost-effectiveness (focusing on the cost of screening 100,000 women and the cost per Downs syndrome pregnancy diagnosed).Results Efficacy (screening performance) The false-positive rates for an 85% detection rate for the main screening tests are shown in the above table, in decreasing order of screening performance:With the serum integrated test, 10 weeks is the preferred time in pregnancy for the PAPP-A measurement. For the integrated test and the combined test, the timing of the measurement of the first trimester markers is less critical.Safety The lower false-positive rate with the integrated test compared with other tests means that at an 85% detection rate there would be nine diagnostic procedure-related unaffected fetal losses per 100,000 women screened compared with 44 using the combined test or 45 with the quadruple test.Cost-effectiveness Screening using the integrated test is less costly than might be expected because the extra screening costs tend to be offset by savings in the cost of diagnosis arising from the low false-positive rate. It was estimated that to achieve an 85% detection rate the cost to the UK NHS would be pound15,300 per Downs syndrome pregnancy detected. The corresponding cost using the second trimester quadruple test would be pound16,800 and using the first trimester combined test it would be pound19,000.Conclusions Implications for healthcare The results showed that screening performance in the first trimester of pregnancy was virtually the same as that in the second trimester, and in either it was much less effective than integrating screening measurements from both trimesters into a single test. In applying these results to screening practice several conclusions can be drawn. The following tests offer the most effective and safe method of screening:overall: the integrated testif an NT measurement is not available: the serum integrated testfor women who do not attend for antenatal care until the second trimester of pregnancy: the quadruple testfor women who choose to have a screening test in the first trimester: the combined test.At a constant detection rate, the cost-effectiveness of these four tests is broadly similar, any extra screening costs tending to be offset by fewer diagnostic costs. The evidence presented in this report does not support retaining the double test, the triple test, or NT measurements on their own (with or without maternal age) because each would lead to many more women having invasive diagnostic tests, without increasing the proportion of Downs syndrome pregnancies detected.

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.).