Use of Repeated Blood Pressure and Cholesterol Measurements to Improve Cardiovascular Disease Risk Prediction: An Individual-Participant-Data Meta-Analysis.

The added value of incorporating information from repeated blood pressure and cholesterol measurements to predict cardiovascular disease (CVD) risk has not been rigorously assessed. We used data on 191,445 adults from the Emerging Risk Factors Collaboration (38 cohorts from 17 countries with data encompassing 1962-2014) with more than 1 million measurements of systolic blood pressure, total cholesterol, and high-density lipoprotein cholesterol. Over a median 12 years of follow-up, 21,170 CVD events occurred. Risk prediction models using cumulative mean values of repeated measurements and summary measures from longitudinal modeling of the repeated measurements were compared with models using measurements from a single time point. Risk discrimination (C-index) and net reclassification were calculated, and changes in C-indices were meta-analyzed across studies. Compared with the single-time-point model, the cumulative means and longitudinal models increased the C-index by 0.0040 (95% confidence interval (CI): 0.0023, 0.0057) and 0.0023 (95% CI: 0.0005, 0.0042), respectively. Reclassification was also improved in both models; compared with the single-time-point model, overall net reclassification improvements were 0.0369 (95% CI: 0.0303, 0.0436) for the cumulative-means model and 0.0177 (95% CI: 0.0110, 0.0243) for the longitudinal model. In conclusion, incorporating repeated measurements of blood pressure and cholesterol into CVD risk prediction models slightly improves risk prediction.

Distinguishing between those dying suddenly or not suddenly from coronary heart disease: long-term prospective results from the Northwick Park Heart Study.

AIM: To establish whether ECG findings are associated with subsequent risk of sudden death from coronary heart disease (CHD). METHODS AND RESULTS: Potential risk factors for CHD were measured at entry to the first Northwick Park Heart Study of 2167 men. ECG findings were coded as high or low risk for CHD according to definitions in the Minnesota code. Sudden or non-sudden deaths were defined as occurring in less than or more than 24 hours, respectively. The only factor independently associated with sudden death among the 262 men dying of CHD was high-risk ECG. Of 184 sudden CHD deaths, 34 men (18.5%) had had high-risk ECGs at entry to the study compared with 5 (6.4%) of 78 men who experienced non-sudden deaths (adjusted OR 3.94 (95% CI 1.33 to 11.67)) (p=0.006). Findings were also compared among all 2167 men, where high-risk ECGs were again associated with sudden death. T-wave changes were the main abnormalities associated with a high risk of sudden death. CONCLUSIONS: In a group of men who had not previously experienced major episodes of CHD but who subsequently died from it, there was strong evidence that high-risk ECG changes, mainly T-wave abnormalities, differentiated between those who later died sudden deaths and those who survived for >24 hours.

Peak flow rate and death due to coronary heart disease: 30-year results from the Northwick Park Heart cohort study.

OBJECTIVE: Numerous studies have reported that chronic obstructive pulmonary disease or impaired lung function are associated with later coronary heart disease (CHD). However, it is unclear if lung function is an independent risk factor, as many of these studies have included only limited measures of other factors associated with CHD. METHODS: In total 2167 men of all ages in the first Northwick Park Heart Study were followed for a median of 30 years. Cox regression models were used to assess the relationship between peak flow rate (PFR) and CHD mortality adjusted for potential confounders measured at baseline. Analyses allowed for missing data, and secondary analyses for repeat measures on some men and competing risks of CHD death. RESULTS: There were 254 CHD deaths with some evidence of an association between PFR and CHD mortality. The adjusted HRs (95% CIs) from the lowest to the highest of four PFR quartiles were 1.53 (1.04 to 2.25), <430 L/min; 1.43 (0.99 to 2.08), 430 - <490 L/min; and 1.31 (0.93 to 1.86), 490 - <550 L/min; compared with the reference group of ≥550 L/min (trend test p=0.025). Other associations with CHD mortality were observed for systolic blood pressure (p<0.0001), body mass index (p=0.0002), smoking status (p=0.015), blood cholesterol (p=0.005), plasma fibrinogen (p=0.001) and high-risk ECG (p=0.021). There were no strong associations for factors V and VIII or platelet count. CONCLUSIONS: After allowing for a range of other risk factors associated with CHD, there was only limited evidence of a relation between PFR and CHD mortality.

Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data.

OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies. PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)). CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.

C-reactive protein, fibrinogen, and cardiovascular disease prediction.

BACKGROUND: There is debate about the value of assessing levels of C-reactive protein (CRP) and other biomarkers of inflammation for the prediction of first cardiovascular events. METHODS: We analyzed data from 52 prospective studies that included 246,669 participants without a history of cardiovascular disease to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk. We calculated measures of discrimination and reclassification during follow-up and modeled the clinical implications of initiation of statin therapy after the assessment of CRP or fibrinogen. RESULTS: The addition of information on high-density lipoprotein cholesterol to a prognostic model for cardiovascular disease that included age, sex, smoking status, blood pressure, history of diabetes, and total cholesterol level increased the C-index, a measure of risk discrimination, by 0.0050. The further addition to this model of information on CRP or fibrinogen increased the C-index by 0.0039 and 0.0027, respectively (P<0.001), and yielded a net reclassification improvement of 1.52% and 0.83%, respectively, for the predicted 10-year risk categories of "low" (<10%), "intermediate" (10% to <20%), and "high" (≥20%) (P<0.02 for both comparisons). We estimated that among 100,000 adults 40 years of age or older, 15,025 persons would initially be classified as being at intermediate risk for a cardiovascular event if conventional risk factors alone were used to calculate risk. Assuming that statin therapy would be initiated in accordance with Adult Treatment Panel III guidelines (i.e., for persons with a predicted risk of ≥20% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), additional targeted assessment of CRP or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years. CONCLUSIONS: In a study of people without known cardiovascular disease, we estimated that under current treatment guidelines, assessment of the CRP or fibrinogen level in people at intermediate risk for a cardiovascular event could help prevent one additional event over a period of 10 years for every 400 to 500 people screened. (Funded by the British Heart Foundation and others.).

Primary prevention of ischaemic cardiovascular disorders with antiplatelet agents.

In those who have already survived myocardial infarction (MI) or stroke, or have had a transient ischaemic episode (TIA), daily low dose aspirin (ASA) reduces the risk of recurrences by an amount that greatly exceeds the risk of serious bleeding (secondary prevention). ASA is therefore recommended for these people. However, in primary prevention-reducing risk in those so far free of clinically manifest episodes-the benefit is of the same order as the bleeding hazard, (which is much the same in both primary and secondary prevention contexts). The use of other effective agents such as statins further emphasises the even balance between benefit and hazard in primary prevention. Six primary prevention trials are reviewed, first singly and then in a meta-analysis based on individual patient data. ASA reduced non-fatal myocardial infarction by about 25%. However, death from coronary heart disease (CHD) was not significantly reduced (by 5%), nor was any vascular death (3%). There was a non- significant reduction in strokes of 5%, this being the net result of an 8% reduction in non-fatal stroke and a 21% increase in stroke death (mainly from haemorrhagic events), both effects being non-significant. Serious vascular events (MI, stroke or vascular death) were significantly reduced by 12%, mainly due to the large effect on non-fatal MI. About 1650 people would need to be treated with ASA for a year to avoid one serious vascular event, which contrasts with the 10-20 events avoided in secondary prevention by treating 1,000 patients for a year. Other primary prevention trials not included in the meta-analysis have also reported no benefits in MI or stroke, but the findings of still unpublished trials are awaited. Recently, however, encouraging results have come from meta-analyses of the effects of ASA on cancer incidence and mortality and on its effects on cancer metastasis, particularly for adenocarcinomas. Typically, reductions in these measures have been around 30% following treatment for four or five years, but more in several instances. These results alter the balance in primary prevention between benefit and hazard as it appears for arterial events alone, tipping it towards the use of ASA. Consequently, new guidelines on advice and decisions on ASA in primary prevention are now needed. Low dose ASA, eg. 75 mg daily is as effective as higher doses for all the vascular and cancer benefits established in the meta-analyses, and it causes less serious bleeding than higher doses.

Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials.

BACKGROUND: Daily aspirin reduces the long-term risk of death due to cancer. However, the short-term effect is less certain, especially in women, effects on cancer incidence are largely unknown, and the time course of risk and benefit in primary prevention is unclear. We studied cancer deaths in all trials of daily aspirin versus control and the time course of effects of low-dose aspirin on cancer incidence and other outcomes in trials in primary prevention. METHODS: We studied individual patient data from randomised trials of daily aspirin versus no aspirin in prevention of vascular events. Death due to cancer, all non-vascular death, vascular death, and all deaths were assessed in all eligible trials. In trials of low-dose aspirin in primary prevention, we also established the time course of effects on incident cancer, major vascular events, and major extracranial bleeds, with stratification by age, sex, and smoking status. RESULTS: Allocation to aspirin reduced cancer deaths (562 vs 664 deaths; odds ratio [OR] 0·85, 95% CI 0·76-0·96, p=0·008; 34 trials, 69,224 participants), particularly from 5 years onwards (92 vs 145; OR 0·63, 95% CI 0·49-0·82, p=0·0005), resulting in fewer non-vascular deaths overall (1021 vs 1173; OR 0·88, 95% CI 0·78-0·96, p=0·003; 51 trials, 77,549 participants). In trials in primary prevention, the reduction in non-vascular deaths accounted for 87 (91%) of 96 deaths prevented. In six trials of daily low-dose aspirin in primary prevention (35,535 participants), aspirin reduced cancer incidence from 3 years onwards (324 vs 421 cases; OR 0·76, 95% CI 0·66-0·88, p=0·0003) in women (132 vs 176; OR 0·75, 95% CI 0·59-0·94, p=0·01) and in men (192 vs 245; OR 0·77, 95% CI 0·63-0·93, p=0·008). The reduced risk of major vascular events on aspirin was initially offset by an increased risk of major bleeding, but effects on both outcomes diminished with increasing follow-up, leaving only the reduced risk of cancer (absolute reduction 3·13 [95% CI 1·44-4·82] per 1000 patients per year) from 3 years onwards. Case-fatality from major extracranial bleeds was also lower on aspirin than on control (8/203 vs 15/132; OR 0·32, 95% CI 0·12-0·83, p=0·009). INTERPRETATION: Alongside the previously reported reduction by aspirin of the long-term risk of cancer death, the short-term reductions in cancer incidence and mortality and the decrease in risk of major extracranial bleeds with extended use, and their low case-fatality, add to the case for daily aspirin in prevention of cancer. FUNDING: None.

Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials.

BACKGROUND: Daily aspirin reduces the long-term incidence of some adenocarcinomas, but effects on mortality due to some cancers appear after only a few years, suggesting that it might also reduce growth or metastasis. We established the frequency of distant metastasis in patients who developed cancer during trials of daily aspirin versus control. METHODS: Our analysis included all five large randomised trials of daily aspirin (≥75 mg daily) versus control for the prevention of vascular events in the UK. Electronic and paper records were reviewed for all patients with incident cancer. The effect of aspirin on risk of metastases at presentation or on subsequent follow-up (including post-trial follow-up of in-trial cancers) was stratified by tumour histology (adenocarcinoma vs other) and clinical characteristics. FINDINGS: Of 17,285 trial participants, 987 had a new solid cancer diagnosed during mean in-trial follow-up of 6·5 years (SD 2·0). Allocation to aspirin reduced risk of cancer with distant metastasis (all cancers, hazard ratio [HR] 0·64, 95% CI 0·48-0·84, p=0·001; adenocarcinoma, HR 0·54, 95% CI 0·38-0·77, p=0·0007; other solid cancers, HR 0·82, 95% CI 0·53-1·28, p=0·39), due mainly to a reduction in proportion of adenocarcinomas that had metastatic versus local disease (odds ratio 0·52, 95% CI 0·35-0·75, p=0·0006). Aspirin reduced risk of adenocarcinoma with metastasis at initial diagnosis (HR 0·69, 95% CI 0·50-0·95, p=0·02) and risk of metastasis on subsequent follow-up in patients without metastasis initially (HR 0·45, 95% CI 0·28-0·72, p=0·0009), particularly in patients with colorectal cancer (HR 0·26, 95% CI 0·11-0·57, p=0·0008) and in patients who remained on trial treatment up to or after diagnosis (HR 0·31, 95% CI 0·15-0·62, p=0·0009). Allocation to aspirin reduced death due to cancer in patients who developed adenocarcinoma, particularly in those without metastasis at diagnosis (HR 0·50, 95% CI 0·34-0·74, p=0·0006). Consequently, aspirin reduced the overall risk of fatal adenocarcinoma in the trial populations (HR 0·65, 95% CI 0·53-0·82, p=0·0002), but not the risk of other fatal cancers (HR 1·06, 95% CI 0·84-1·32, p=0·64; difference, p=0·003). Effects were independent of age and sex, but absolute benefit was greatest in smokers. A low-dose, slow-release formulation of aspirin designed to inhibit platelets but to have little systemic bioavailability was as effective as higher doses. INTERPRETATION: That aspirin prevents distant metastasis could account for the early reduction in cancer deaths in trials of daily aspirin versus control. This finding suggests that aspirin might help in treatment of some cancers and provides proof of principle for pharmacological intervention specifically to prevent distant metastasis. FUNDING: None.

Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies.

BACKGROUND: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. METHODS: In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125,222 participants. We also compared the frequency of Asp358Ala in 51,441 patients with coronary heart disease and in 136,226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. FINDINGS: The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4-38·2) and of interleukin 6 by 14·6% (10·7-18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9-9·1) and of fibrinogen by 1·0% (0·7-1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8-5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. INTERPRETATION: Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. FUNDING: British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.

Recent respiratory infection and risk of venous thromboembolism: case-control study through a general practice database.

BACKGROUND: The association between respiratory infection and risk of heart attacks and strokes is well established. However, less evidence exists for an association between respiratory infection and venous thromboembolism (VTE). In this article, we describe the associations between respiratory infection and VTE. METHODS: All cases aged ≥18 years of first-time diagnosis of deep-vein thrombosis (DVT) or pulmonary embolism (PE) were identified together with single-matched controls from a primary care general practice database. In addition to the matching characteristics, information was collected on other potentially important confounding factors. RESULTS: There were 457/11,557 (4.0%) DVT cases with respiratory infection in the year before the index date (73 in the preceding month) compared with 262/11,557 (2.3%) controls (24 in the preceding month). There was an increased risk of DVT in the month following infection [adjusted odds ratio (OR) = 2.64, 95% confidence interval (95% CI) 1.62-4.29] which persisted up to a year. There were 180/5162 (3.5%) PE cases with respiratory infection in the year before the index date compared with 94/5162 (1.8%) controls excluding those in the preceding month to avoid the possible misdiagnosis of early PE. There was an increased risk of PE in the 3 months following infection (adjusted OR = 2.50, 95% CI 1.33-4.72) which may have persisted up to a year. CONCLUSIONS: There are strong associations between recent respiratory infection and VTE. There should be less distinction between venous and arterial events in decisions about preventing or aborting infections, especially in high-risk patients.

Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials.

BACKGROUND: Treatment with daily aspirin for 5 years or longer reduces subsequent risk of colorectal cancer. Several lines of evidence suggest that aspirin might also reduce risk of other cancers, particularly of the gastrointestinal tract, but proof in man is lacking. We studied deaths due to cancer during and after randomised trials of daily aspirin versus control done originally for prevention of vascular events. METHODS: We used individual patient data from all randomised trials of daily aspirin versus no aspirin with mean duration of scheduled trial treatment of 4 years or longer to determine the effect of allocation to aspirin on risk of cancer death in relation to scheduled duration of trial treatment for gastrointestinal and non-gastrointestinal cancers. In three large UK trials, long-term post-trial follow-up of individual patients was obtained from death certificates and cancer registries. RESULTS: In eight eligible trials (25 570 patients, 674 cancer deaths), allocation to aspirin reduced death due to cancer (pooled odds ratio [OR] 0·79, 95% CI 0·68-0·92, p=0·003). On analysis of individual patient data, which were available from seven trials (23 535 patients, 657 cancer deaths), benefit was apparent only after 5 years' follow-up (all cancers, hazard ratio [HR] 0·66, 0·50-0·87; gastrointestinal cancers, 0·46, 0·27-0·77; both p=0·003). The 20-year risk of cancer death (1634 deaths in 12 659 patients in three trials) remained lower in the aspirin groups than in the control groups (all solid cancers, HR 0·80, 0·72-0·88, p<0·0001; gastrointestinal cancers, 0·65, 0·54-0·78, p<0·0001), and benefit increased (interaction p=0·01) with scheduled duration of trial treatment (≥7·5 years: all solid cancers, 0·69, 0·54-0·88, p=0·003; gastrointestinal cancers, 0·41, 0·26-0·66, p=0·0001). The latent period before an effect on deaths was about 5 years for oesophageal, pancreatic, brain, and lung cancer, but was more delayed for stomach, colorectal, and prostate cancer. For lung and oesophageal cancer, benefit was confined to adenocarcinomas, and the overall effect on 20-year risk of cancer death was greatest for adenocarcinomas (HR 0·66, 0·56-0·77, p<0·0001). Benefit was unrelated to aspirin dose (75 mg upwards), sex, or smoking, but increased with age-the absolute reduction in 20-year risk of cancer death reaching 7·08% (2·42-11·74) at age 65 years and older. INTERPRETATION: Daily aspirin reduced deaths due to several common cancers during and after the trials. Benefit increased with duration of treatment and was consistent across the different study populations. These findings have implications for guidelines on use of aspirin and for understanding of carcinogenesis and its susceptibility to drug intervention. FUNDING: None.

Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials.

BACKGROUND: High-dose aspirin (≥500 mg daily) reduces long-term incidence of colorectal cancer, but adverse effects might limit its potential for long-term prevention. The long-term effectiveness of lower doses (75-300 mg daily) is unknown. We assessed the effects of aspirin on incidence and mortality due to colorectal cancer in relation to dose, duration of treatment, and site of tumour. METHODS: We followed up four randomised trials of aspirin versus control in primary (Thrombosis Prevention Trial, British Doctors Aspirin Trial) and secondary (Swedish Aspirin Low Dose Trial, UK-TIA Aspirin Trial) prevention of vascular events and one trial of different doses of aspirin (Dutch TIA Aspirin Trial) and established the effect of aspirin on risk of colorectal cancer over 20 years during and after the trials by analysis of pooled individual patient data. RESULTS: In the four trials of aspirin versus control (mean duration of scheduled treatment 6·0 years), 391 (2·8%) of 14 033 patients had colorectal cancer during a median follow-up of 18·3 years. Allocation to aspirin reduced the 20-year risk of colon cancer (incidence hazard ratio [HR] 0·76, 0·60-0·96, p=0·02; mortality HR 0·65, 0·48-0·88, p=0·005), but not rectal cancer (0·90, 0·63-1·30, p=0·58; 0·80, 0·50-1·28, p=0·35). Where subsite data were available, aspirin reduced risk of cancer of the proximal colon (0·45, 0·28-0·74, p=0·001; 0·34, 0·18-0·66, p=0·001), but not the distal colon (1·10, 0·73-1·64, p=0·66; 1·21, 0·66-2·24, p=0·54; for incidence difference p=0·04, for mortality difference p=0·01). However, benefit increased with scheduled duration of treatment, such that allocation to aspirin of 5 years or longer reduced risk of proximal colon cancer by about 70% (0·35, 0·20-0·63; 0·24, 0·11-0·52; both p<0·0001) and also reduced risk of rectal cancer (0·58, 0·36-0·92, p=0·02; 0·47, 0·26-0·87, p=0·01). There was no increase in benefit at doses of aspirin greater than 75 mg daily, with an absolute reduction of 1·76% (0·61-2·91; p=0·001) in 20-year risk of any fatal colorectal cancer after 5-years scheduled treatment with 75-300 mg daily. However, risk of fatal colorectal cancer was higher on 30 mg versus 283 mg daily on long-term follow-up of the Dutch TIA trial (odds ratio 2·02, 0·70-6·05, p=0·15). INTERPRETATION: Aspirin taken for several years at doses of at least 75 mg daily reduced long-term incidence and mortality due to colorectal cancer. Benefit was greatest for cancers of the proximal colon, which are not otherwise prevented effectively by screening with sigmoidoscopy or colonoscopy. FUNDING: None.

Review: Plasma renin and the incidence of cardiovascular disease.

Whether renin is involved in the onset of coronary heart disease (CHD) remains unclear. A case-control study in 1972, suggesting a causal association between renin and CHD, has now been followed by three prospective studies. One was based on 1,717 hypertensive subjects in a Work-Site Program in New York. The main results showed an increased risk of CHD the higher the renin level. A second study in occupational groups in North West London, UK, recruited 803 white men not selected according to blood pressure, and found no association. A possible exception was in the minority of those with similar blood pressure levels to participants in the Work-Site Program, in whom the incidence of CHD was higher according to the renin level, but not significantly so. The third study was in Framingham Offspring and included 3,532 participants also not selected according to blood pressure. As in the UK study, there was no clear association between renin and risk of CHD in all participants, or in this study in those with raised blood pressure. The authors considered their results consistent with those of the UK study in finding "no association of renin with overall risk of CHD". Besides the three epidemiological studies, dealing explicitly with renin, other studies in which it has been one of several variables considered have also not found convincing evidence of its involvement in CHD. There is, therefore, little support for the hypothesis that high renin levels increase the risk of CHD, with the possible but uncertain exception of those with raised blood pressure.

Circulating levels of coagulation and inflammation markers and cancer risks: individual participant analysis of data from three long-term cohorts.

BACKGROUND: Basic and clinical research support the hypothesis that activation of the coagulation and inflammation pathways may affect cancer onset, but there is limited epidemiological data to support this. METHODS: We examined a large range of haemostatic and inflammation markers, including fibrinogen, in 19 303 male participants from three English cohorts followed for up to 30 years. After excluding the first 3 years of follow-up, 2908 incident cancers were accrued. Competing risk models were fitted to estimate rate ratios (RRs) for cancer incidence, adjusting for age and other confounders. RESULTS: Baseline white blood cell (WBC) count and circulating levels of fibrinogen, C-reactive protein (CRP), factor VII antigen (VIIa) and prothrombin fragment F1.2 were positively associated with risk of smoking-related cancers, particularly lung cancer. The magnitude of these associations was highest for persistently raised fibrinogen levels. There was, however, substantial confounding by smoking with risk being fully (WBC, CRP and VIIa) or partially (fibrinogen) removed after adjustment. The pooled RRs (95% confidence interval) per one standard deviation increase in fibrinogen levels before and after adjustment for smoking habits were 1.23 (1.12, 1.36) and 1.12 (1.05, 1.20), respectively. The fibrinogen associations were present only among current smokers at entry. The effect of smoking on smoking-related cancers was partly mediated by fibrinogen levels. CONCLUSIONS: Our results are consistent with elevated circulating levels of fibrinogen and F1.2 being predictors of risk of smoking-related cancers. Further research is necessary to clarify whether elevated levels of fibrinogen and F1.2 are causally relevant or simply correlates of the smoking-cancer association.

Long-term association of routine blood count (Coulter) variables on fatal coronary heart disease: 30-year results from the first prospective Northwick Park Heart Study (NPHS-I).

BACKGROUND: Since evidence of a long-term association between routine blood count (Coulter) variables and coronary heart disease (CHD) is inconsistent, the authors analysed white blood cell count (WBC), red blood cell count (RBC), haemoglobin (Hgb), packed cell volume (PCV) and platelet count for their long-term associations with CHD mortality in the first Northwick Park Heart Study (NPHS-I). NPHS-I has follow-up information for >30 years on 2167 White men and 941 White women and holds entry and follow-up data on haematological variables and other known CHD risk factors. METHODS: Proportional hazards Cox models were fitted to estimate rate ratios (RRs) for the separate and joint effects of entry and follow-up Coulter variables. RESULTS: Entry RBC, PCV and Hgb were significant risk factors for CHD mortality after adjustment for gender but only PCV remained significant after adjustment for potential confounders [RR per 1 standard deviation (SD) increase = 1.17, 95% confidence interval (CI) 1.00-1.37]. This effect was partly reduced when the values of 6 years were analysed (RR per 1 SD increase = 1.10, 95% CI 0.93-1.30). No significant gender, smoking or age/time interactions were identified. PCV was the only significant predictor when all Coulter variables were studied jointly. CONCLUSION: PCV was found to predict CHD mortality even after controlling for classical risk factors. This may give some insight into possible mechanisms, such as an influence on thrombin production.

Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.

BACKGROUND: Low-dose aspirin is of definite and substantial net benefit for many people who already have occlusive vascular disease. We have assessed the benefits and risks in primary prevention. METHODS: We undertook meta-analyses of serious vascular events (myocardial infarction, stroke, or vascular death) and major bleeds in six primary prevention trials (95,000 individuals at low average risk, 660,000 person-years, 3554 serious vascular events) and 16 secondary prevention trials (17,000 individuals at high average risk, 43,000 person-years, 3306 serious vascular events) that compared long-term aspirin versus control. We report intention-to-treat analyses of first events during the scheduled treatment period. FINDINGS: In the primary prevention trials, aspirin allocation yielded a 12% proportional reduction in serious vascular events (0.51% aspirin vs 0.57% control per year, p=0.0001), due mainly to a reduction of about a fifth in non-fatal myocardial infarction (0.18%vs 0.23% per year, p<0.0001). The net effect on stroke was not significant (0.20%vs 0.21% per year, p=0.4: haemorrhagic stroke 0.04%vs 0.03%, p=0.05; other stroke 0.16%vs 0.18% per year, p=0.08). Vascular mortality did not differ significantly (0.19%vs 0.19% per year, p=0.7). Aspirin allocation increased major gastrointestinal and extracranial bleeds (0.10%vs 0.07% per year, p<0.0001), and the main risk factors for coronary disease were also risk factors for bleeding. In the secondary prevention trials, aspirin allocation yielded a greater absolute reduction in serious vascular events (6.7%vs 8.2% per year, p<0.0001), with a non-significant increase in haemorrhagic stroke but reductions of about a fifth in total stroke (2.08%vs 2.54% per year, p=0.002) and in coronary events (4.3%vs 5.3% per year, p<0.0001). In both primary and secondary prevention trials, the proportional reductions in the aggregate of all serious vascular events seemed similar for men and women. INTERPRETATION: In primary prevention without previous disease, aspirin is of uncertain net value as the reduction in occlusive events needs to be weighed against any increase in major bleeds. Further trials are in progress. FUNDING: UK Medical Research Council, British Heart Foundation, Cancer Research UK, and the European Community Biomed Programme.

Health related quality of life after combined hormone replacement therapy: randomised controlled trial.

OBJECTIVE: To assess the effect of combined hormone replacement therapy (HRT) on health related quality of life. DESIGN: Randomised placebo controlled double blind trial. SETTING: General practices in United Kingdom (384), Australia (94), and New Zealand (24). PARTICIPANTS: Postmenopausal women aged 50-69 at randomisation; 3721 women with a uterus were randomised to combined oestrogen and progestogen (n=1862) or placebo (n=1859). Data on health related quality of life at one year were available from 1043 and 1087 women, respectively. INTERVENTIONS: Conjugated equine oestrogen 0.625 mg plus medroxyprogesterone acetate 2.5/5.0 mg or matched placebo orally daily for one year. MAIN OUTCOME MEASURES: Health related quality of life and psychological wellbeing as measured by the women's health questionnaire. Changes in emotional and physical menopausal symptoms as measured by a symptoms questionnaire and depression by the Centre for Epidemiological Studies depression scale (CES-D). Overall health related quality of life and overall quality of life as measured by the European quality of life instrument (EuroQol) and visual analogue scale, respectively. RESULTS: After one year small but significant improvements were observed in three of nine components of the women's health questionnaire for those taking combined HRT compared with those taking placebo: vasomotor symptoms (P<0.001), sexual functioning (P<0.001), and sleep problems (P<0.001). Significantly fewer women in the combined HRT group reported hot flushes (P<0.001), night sweats (P<0.001), aching joints and muscles (P=0.001), insomnia (P<0.001), and vaginal dryness (P<0.001) than in the placebo group, but greater proportions reported breast tenderness (P<0.001) or vaginal discharge (P<0.001). Hot flushes were experienced in the combined HRT and placebo groups by 30% and 29% at trial entry and 9% and 25% at one year, respectively. No significant differences in other menopausal symptoms, depression, or overall quality of life were observed at one year. CONCLUSIONS: Combined HRT started many years after the menopause can improve health related quality of life. TRIAL REGISTRATION: ISRCTN 63718836.

Recent respiratory infection and risk of cardiovascular disease: case-control study through a general practice database.

AIMS: Respiratory infection may be associated with an increased risk of major cardiovascular events. This case-control study describes associations with these events of respiratory infection. METHODS AND RESULTS: The IMS Disease Analyzer Mediplus primary care database was used to identify all cases of first-time diagnosis of myocardial infarction (MI) or stroke and single matched controls. Details were extracted on visits for respiratory infection over the preceding year. A total of 11 155 MI cases and 9208 stroke cases were identified. For MI and stroke respectively, there were 326 and 260 respiratory infections during the month preceding the index date. There was strong evidence of an increased risk of both events in the 7 days following infection, for MI adjusted odds ratio (OR) 2.10 (95% confidence interval 1.38-3.21), for stroke OR 1.92 (95% confidence interval 1.24-2.97). The strength of these associations fell over time. The associations for MI occurred at all levels of initial underlying cardiovascular risk. CONCLUSIONS: There are strong associations between recent respiratory infection and major cardiovascular events, for MI at all levels of underlying risk. The benefits of reducing respiratory infection either through immunization or treating or preventing infection may be substantial.

Model for estimating the population prevalence of chronic obstructive pulmonary disease: cross sectional data from the Health Survey for England.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major but neglected public health problem. Currently 1.4% of the England population has a clinical diagnosis of COPD, but the true burden of the disease has not been known with certainty, as many cases remain undiagnosed. METHODS: A mathematical model based on cross sectional data from a representative sample of the population in England (the Heath Survey for England 2001, n = 10,750) was developed allowing estimates on the prevalence of COPD (defined based on the presence of airflow obstruction) to be obtained. Logistic regression analysis was used to investigate and choose risk factors for inclusion in the model and to derive the prevalence estimates based on the strength of association between selected risk factors and the outcome COPD. The model allows the prevalence to be estimated in populations at national level and also at regional and large local areas, based on their compositions according to age, sex, smoking and ethnicity, and on area degrees of urbanisation and deprivation. We applied the model to measure the prevalence of COPD in England and in some sub-groups of the population within the country. RESULTS: The prevalence of COPD in England is estimated as 3.1% (3.9% in men and 2.4% in women) in the population over 15 years of age, and 5.3% (6.8% in men and 3.9% in women) in 45 year-olds and over. There was a 7-fold variation in the prevalence across subgroups of the population, with lowest values in Asian women from wealthy rural areas (1.7%), and highest in black men from deprived urban areas (12.5%). CONCLUSION: The model can be used to estimate population prevalence of COPD from large general practices to national level, and as a tool to identify areas of high levels of unmet needs for COPD priority health actions. The results from the model highlight the importance of including variables other than age, sex and smoking, i.e. levels of deprivation, urbanisation and ethnicity, when estimating population prevalence of COPD. The model should be validated at local level and incorporated into case-finding strategies.

Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women.

OBJECTIVE: To assess the long term risks and benefits of hormone replacement therapy (combined hormone therapy versus placebo, and oestrogen alone versus combined hormone therapy). DESIGN: Multicentre, randomised, placebo controlled, double blind trial. SETTING: General practices in UK (384), Australia (91), and New Zealand (24). PARTICIPANTS: Postmenopausal women aged 50-69 years at randomisation. At early closure of the trial, 56,583 had been screened, 8980 entered run-in, and 5692 (26% of target of 22,300) started treatment. INTERVENTIONS: Oestrogen only therapy (conjugated equine oestrogens 0.625 mg orally daily) or combined hormone therapy (conjugated equine oestrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily). Ten years of treatment planned. PRIMARY OUTCOMES: major cardiovascular disease, osteoporotic fractures, and breast cancer. SECONDARY OUTCOMES: other cancers, death from all causes, venous thromboembolism, cerebrovascular disease, dementia, and quality of life. RESULTS: The trial was prematurely closed during recruitment, after a median follow-up of 11.9 months (interquartile range 7.1-19.6, total 6498 women years) in those enrolled, after the publication of early results from the women's health initiative study. The mean age of randomised women was 62.8 (SD 4.8) years. When combined hormone therapy (n=2196) was compared with placebo (n=2189), there was a significant increase in the number of major cardiovascular events (7 v 0, P=0.016) and venous thromboembolisms (22 v 3, hazard ratio 7.36 (95% CI 2.20 to 24.60)). There were no statistically significant differences in numbers of breast or other cancers (22 v 25, hazard ratio 0.88 (0.49 to 1.56)), cerebrovascular events (14 v 19, 0.73 (0.37 to 1.46)), fractures (40 v 58, 0.69 (0.46 to 1.03)), and overall deaths (8 v 5, 1.60 (0.52 to 4.89)). Comparison of combined hormone therapy (n=815) versus oestrogen therapy (n=826) outcomes revealed no significant differences. CONCLUSIONS: Hormone replacement therapy increases cardiovascular and thromboembolic risk when started many years after the menopause. The results are consistent with the findings of the women's health initiative study and secondary prevention studies. Research is needed to assess the long term risks and benefits of starting hormone replacement therapy near the menopause, when the effect may be different. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 63718836.