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Objective: We sought to determine the association of dietary factors and risk of cognitive decline in a population at high risk of cardiovascular disease. Methods: Baseline dietary intake and measures of the Mini-Mental State Examination were recorded in 27,860 men and women who were enrolled in 2 international parallel trials of the ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) and TRANSCEND (Telmisartan Randomised Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease) studies. We measured diet quality using the modified Alternative Healthy Eating Index. Cox proportional hazards regression was used to determine the association between diet quality and risk of ≥3-point decline in Mini-Mental State Examination score, and reported as hazard ratio with 95% confidence intervals with adjustment for covariates. Results: During 56 months of follow-up, 4,699 cases of cognitive decline occurred. We observed lower risk of cognitive decline among those in the healthiest dietary quintile of modified Alternative Healthy Eating Index compared with lowest quintile (hazard ratio 0.76, 95% confidence interval 0.66–0.86, Q5 vs Q1). Lower risk of cognitive decline was consistent regardless of baseline cognitive level. Conclusion: We found that higher diet quality was associated with a reduced risk of cognitive decline. Improved diet quality represents an important potential target for reducing the global burden of cognitive decline.

This position statement addresses issues in revascularization for multivessel coronary artery disease (CAD) from the perspective of both cardiologists and cardiac surgeons. Recommendations are made based on evidence from clinical trials and observational studies, with an emphasis on the increasing number of individuals with significant comorbid disease burden and functional debilitation who are being referred for definitive management of their multivessel CAD in the context of routine clinical practice. These types of individuals have traditionally not been included in the many clinical trials that have been the basis for guidelines and recommendations, and the objective of the proposed medical intervention or revascularization (or both) would not necessarily be to improve prognosis but to improve quality of life. One purpose of this document is to propose practical multidisciplinary approaches to the management of these patients. Recommendations are made for revascularization in acute coronary syndromes and stable CAD, with specific considerations for individuals with left ventricular dysfunction and heart failure, chronic renal failure, and chronic obstructive pulmonary disease. We also consider the use of various risk scores, including the Society of Thoracic Surgeons score, the EuroSCORE, and the SYNTAX II score. The importance of a heart team approach is also emphasized. The complementary role of coronary bypass surgery and percutaneous coronary intervention is highlighted, along with the importance of optimal medical therapy.

The aim was to determine the effects of dulaglutide, a synthetic once-weekly, injectable human glucagon-like peptide 1 analogue that lowers blood glucose, body weight, appetite and blood pressure, on cardiovascular outcomes. People with type 2 diabetes, aged ≥50 years, with glycated haemoglobin (HbA1c) ≤9.5%, and either a previous cardiovascular event, evidence of cardiovascular disease or ≥2 cardiovascular risk factors were randomly allocated to a weekly subcutaneous injection of either dulaglutide (1.5 mg) or placebo and followed within the ongoing Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial every 3 to 6 months. The primary cardiovascular outcome is the first occurrence of the composite of cardiovascular death or non-fatal myocardial infarction or non-fatal stroke. Secondary outcomes include each component of the primary composite cardiovascular outcome, a composite clinical microvascular outcome comprising retinal or renal disease, hospitalization for unstable angina, heart failure requiring hospitalization or an urgent heart failure visit, and all-cause mortality. Follow-up will continue until the accrual of 1200 confirmed primary outcomes. Recruitment of 9901 participants (mean age 66 years, 46% women) occurred in 370 sites located in 24 countries over a period of 2 years. The mean duration of diabetes was 10 years, mean baseline HbA1c was 7.3%, and 31% had prior cardiovascular disease. The REWIND trial's international scope, high proportion of women, high proportion of people without prior cardiovascular disease and inclusion of participants whose mean baseline HbA1c was 7.3% suggests that its cardiovascular and safety findings will be directly relevant to the typical middle-aged patient seen in general practice throughout the world.

Although 24-h urinary measure to estimate sodium and potassium excretion is the gold standard, it is not practical for large studies. We compared estimates of 24-h sodium and potassium excretion from a single morning fasting urine (MFU) using three different formulae in healthy individuals.We studied 1083 individuals aged 35-70 years from the general population in 11 countries. A 24-h urine and MFU specimen were obtained from each individual. A subset of 448 individuals repeated the measures after 30-90 days. The Kawasaki, Tanaka, and INTERSALT formulae were used to estimate urinary excretion from a MFU specimen.The intraclass correlation coefficient (ICC) between estimated and measured sodium excretion was higher with Kawasaki (0.71; 95% confidence interval, CI: 0.65-0.76) compared with INTERSALT (0.49; 95% CI: 0.29-0.62) and Tanaka (0.54; 95% CI: 0.42-0.62) formulae (P 0.001). For potassium, the ICC was higher with the Kawasaki (0.55; 95% CI: 0.31-0.69) than the Tanaka (0.36; 95% CI: -0.07 to 0.60; P 0.05) formula (no INTERSALT formula exists for potassium). The degree of bias (vs. the 24-h urine) for sodium was smaller with Kawasaki (+313 mg/day; 95% CI: +182 to +444) compared with INTERSALT (-872 mg/day; 95% CI: -728 to -1016) and Tanaka (-548 mg/day; 95% CI: -408 to -688) formulae (P 0.001 and P = 0.02, respectively). Similarly for potassium, the Kawasaki formula provided the best agreement and least bias. Blood pressure correlated most closely and similarly with the 24-h and Kawasaki estimates for sodium compared with the other two formulae.In a diverse population, the Kawasaki formula is the most valid and least biased method of estimating 24-h sodium excretion from a single MFU and is suitable for population studies.

OBJECTIVE Epidemiologic studies linking insulin glargine and glucose-lowering therapies to cancers and n-3 fatty acids to cancer prevention have not been confirmed. We aimed to assess the effect of insulin glargine and n-3 fatty acids on incident cancers within the context of the ORIGIN (Outcome Reduction with Initial Glargine Intervention) trial. RESEARCH DESIGN AND METHODS The ORIGIN trial is an international, long-term, randomized two-by-two factorial study comparing insulin glargine with standard care and n-3 fatty acids with placebo (double blind) in people with dysglycemia at high risk for cardiovascular events. The primary outcome measure (cancer substudy) was the occurrence of any new or recurrent adjudicated cancer. Cancer mortality and cancer subtypes were also analyzed. RESULTS Among 12,537 people (mean age 63.5 years, SD 7.8; 4,388 females), 953 developed a cancer event during the median follow-up of 6.2 years. In the glargine and standard care groups, the incidence of cancers was 1.32 and 1.32 per 100 person-years, respectively (P = 0.97), and in the n-3 fatty acid and placebo groups, it was 1.28 and 1.36 per 100 person-years, respectively (P = 0.39). No difference in the effect of either intervention was noted within predefined subgroups (P for all interactions ≥0.17). Cancer-related mortality and cancer-specific outcomes also did not differ between groups. Postrandomization HbA1c levels, glucose-lowering therapies (including metformin), and BMI did not affect cancer outcomes. CONCLUSIONS Insulin glargine and n-3 fatty acids have a neutral association with overall and cancer-specific outcomes, including cancer-specific mortality. Exposure to glucose-lowering therapies, including metformin, and HbA1c level during the study did not alter cancer risk.

In the Ongoing Telmisartan Alone and in Combination with Ramipril Trial (ONTARGET), dual agent renin-angiotensin-aldosterone system (RAAS) blockade with angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) did not reduce the risk of renal and cardiovascular outcomes compared with the single use of either agent. Dual therapy however increased the incidence of hyperkalemia. We examined risk factors for hyper- and hyokalemia and hypothesized that both would be associated with worse cardiovascular and renal outcomes.A post-hoc analysis of the ONTARGET trial comparing dual therapy (ramipril and telmisartan) vs monotherapy (ramipril or telmisartan) was performed. The association between serum potassium at week 6 on cardiovascular and renal outcomes during the 56 months follow-up was assessed by multivariate Cox analysis. The main cardiovascular outcome was the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. The renal outcome was defined as the composite of a doubling of serum creatinine or chronic dialysis.Six weeks after randomization, hyperkalemia developed in 210 (2.7%) patients on dual therapy vs. 264 (1.6%) patients on monotherapy (p 0.001 vs. dual therapy). Hypokalemia developed in 87 (1.1%) patients on dual therapy vs. 200 (1.2%)patients on monotherapy. Serum potassium was nonlinearly associated with cardiovascular and renal events with a nadir between 4.0-5.0 mmol/l for cardiovascular and 4.0-4.5 mmol/l for renal events such that subjects above or below these values exhibited higher risks. This association was independent of age, gender, diabetes, estimated glomerular filtration rate, systolic blood pressure and diuretic use.With the precautions stipulated by the protocol of the ONTARGET trial, hypokalemia and hyperkalemia were infrequent events. Nevertheless, both high and low serum potassium were associated with an increased risk of cardiovascular and renal disease.

BACKGROUND & AIMS: Proton pump inhibitors (PPIs) are effective at treating acid-related disorders. These drugs are well tolerated in the short term, but long-term treatment was associated with adverse events in observational studies. We aimed to confirm these findings in an adequately powered randomized trial.METHODS: We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease randomly assigned to groups given pantoprazole (40 mg daily, n = 8791) or placebo (n = 8807). Participants were also randomly assigned to groups that received rivaroxaban (2.5 mg twice daily) with aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg) alone. We collected data on development of pneumonia, Clostridium difficile infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, cancer, hospitalizations, and all-cause mortality every 6 months. Patients were followed up for a median of 3.01 years, with 53,152 patient-years of follow-up.RESULTS: There was no statistically significant difference between the pantoprazole and placebo groups in safety events except for enteric infections (1.4% vs 1.0% in the placebo group; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). For all other safety outcomes, proportions were similar between groups except for C difficile infection, which was approximately twice as common in the pantoprazole vs the placebo group, although there were only 13 events, so this difference was not statistically significant.CONCLUSIONS: In a large placebo-controlled randomized trial, we found that pantoprazole is not associated with any adverse event when used for 3 years, with the possible exception of an increased risk of enteric infections. ClinicalTrials.gov Number: NCT01776424.

Objectives The purpose of this analysis was to assess in patients with type 2 diabetes and stable coronary artery disease (CAD) whether the risk of all-cause mortality and cardiovascular events varied according to the presence or absence of angina and angina equivalent symptoms. Background Data on the prognostic value of symptoms in these patients are limited. Methods Post-hoc analysis was performed in 2,364 patients with type 2 diabetes and documented CAD enrolled in the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial to determine the occurrence of death and composite of death, myocardial infarction, and stroke during a 5-year follow-up according to cardiac symptoms at baseline. Results There were 1,434 patients with angina (A), 506 with angina equivalents (E), and 424 with neither of these (N). The cumulative death rates (total 316) were 12% in A, 14% in E, and 10% in N (p = 0.3), and cardiovascular composite rates (total 548) were 24% in A, 24% in E, and 21% in N (p = 0.5). Compared with N, the hazard ratios adjusted for confounders were not different for death in A (1.11; 99% CI: 0.81 to 1.53) and E (1.17; 99% CI: 0.81 to 1.68) or for cardiovascular events in A (1.17; 99% CI: 0.92 to 1.50) and E (1.11; 99% CI: 0.84 to 1.48). Conclusions Whatever their symptom status, patients with type 2 diabetes and stable CAD were at similar risk of cardiovascular events and death. These findings suggest that these patients may be similarly managed in terms of risk stratification and preventive therapies. (Bypass Angioplasty Revascularization Investigation 2 Diabetes [BARI 2D]; NCT00006305)

Objectives This study was designed to examine the prognostic value of systemic arterial compliance (SAC) by Doppler-echocardiography in patients with type 2 diabetes mellitus (T2D). Background Reduced SAC has been shown to predict outcomes in patients with hypertension. T2D is associated with accelerated arterial stiffening and increased cardiovascular events. We hypothesized that SAC measured by Doppler-echocardiography would independently predict mortality in patients with T2D. Methods Since 2001, SAC calculated as the ratio of stroke volume index to arterial pulse pressure by sphygmomanometer is routinely performed in our laboratory. Data from 505 consecutive patients with T2D were retrospectively analyzed. Based on a previously validated cut-off value of SAC 2 /mmHg, patients were divided into Group 1, reduced SAC, 255 patients (50%) and Group 2, preserved SAC, 250 patients (50%). The primary endpoint was overall mortality. Results Patients with reduced SAC had significantly lower 5-year survival than those with preserved SAC (66 ± 5 vs. 82 ± 5%, p = 0.02) and a 1.57-fold (95% CI: 1.04–2.43; p = 0.03) increased risk of mortality after adjusting for other risk factors. Blood pressure did not predict mortality and pseudo-normalized blood pressures related to LV dysfunction and low cardiac output were found in 75 patients (15%). Conclusion Reduced SAC is encountered frequently in T2D, is an independent predictor of mortality and allows identification of patients who, despite a normal blood pressure, are at increased risk. Future studies are necessary to further evaluate the clinical utility of this simple echocardiographic parameter and therapies are needed to alter vascular stiffness to improve clinical outcomes in these high-risk patients.

12 p., Background: Several studies reported a U-shaped association between urinary sodium excretion and cardiovascular disease events and mortality. Whether these associations vary between those individuals with and without hypertension is uncertain. We aimed to explore whether the association between sodium intake and cardiovascular disease events and all-cause mortality is modified by hypertension status. Methods: In this pooled analysis, we studied 133118 individuals (63559 with hypertension and 69559 without hypertension), median age of 55 years (IQR 45–63), from 49 countries in four large prospective studies and estimated 24-h urinary sodium excretion (as group-level measure of intake). We related this to the composite outcome of death and major cardiovascular disease events over a median of 4·2 years (IQR 3·0–5·0) and blood pressure. Findings: Increased sodium intake was associated with greater increases in systolic blood pressure in individuals with hypertension (2·08 mm Hg change per g sodium increase) compared with individuals without hypertension (1·22 mm Hg change per g; pinteraction

12 p., BACKGROUND Elevated blood pressure and elevated low-density lipoprotein (LDL) cholesterol increase the risk of cardiovascular disease. Lowering both should reduce the risk of cardiovascular events substantially. METHODS In a trial with 2-by-2 factorial design, we randomly assigned 12,705 participants at intermediate risk who did not have cardiovascular disease to rosuvastatin (10 mg perday) or placebo and to candesartan (16 mg per day) plus hydrochlorothiazide (12.5 mg per day) or placebo. In the analyses reported here, we compared the 3180 participants assigned to combined therapy (with rosuvastatin and the two antihypertensive agents) with the 3168 participants assigned to dual placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, and the second coprimary outcome additionally included heart failure, cardiac arrest, or revascularization. The median follow-up was 5.6 years. RESULTS The decrease in the LDL cholesterol level was 33.7 mg per deciliter (0.87 mmol per liter) greater in the combined-therapy group than in the dual-placebo group, and the decrease in systolic blood pressure was 6.2 mm Hg greater with combined therapy than with dual placebo. The first coprimary outcome occurred in 113 participants (3.6%) in the combined-therapy group and in 157 (5.0%) in the dual-placebo group (hazard ratio, 0.71; 95% confidence interval [CI], 0.56 to 0.90; P=0.005). The second coprimary outcome occurred in 136 participants (4.3%) and 187 participants (5.9%), respectively (hazard ratio, 0.72; 95% CI, 0.57 to 0.89; P=0.003). Muscle weakness and dizziness were more common in the combined-therapy group than in the dual-placebo group, but the overall rate of discontinuation of the trial regimen was similar in the two groups. CONCLUSIONS The combination of rosuvastatin (10 mg per day), candesartan (16 mg per day), and hydrochlorothiazide (12.5 mg per day) was associated with a significantly lower rate of cardiovascular events than dual placebo among persons at intermediate risk who did not have cardiovascular disease. (Funded by the Canadian Institutes of Health Research and AstraZeneca; ClinicalTrials.gov number, NCT00468923.)

Background: The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain. Methods: We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual-participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies. Results: For people born between 1900 and 1960, mean adult height increased 0.5-1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96-0.99) for death from any cause, 0.94 (0.93-0.96) for death from vascular causes, 1.04 (1.03-1.06) for death from cancer and 0.92 (0.90-0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12-1.42) for risk of melanoma death to 0.84 (0.80-0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators. Conclusion: Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases. Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2012; all rights reserved.

Context The value of assessing various emerging lipid-related markers for prediction of first cardiovascular events is debated. Objective To determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A(2) to total cholesterol and high-density lipoprotein cholesterol (HDL-C) improves cardiovascular disease (CVD) risk prediction. Design, Setting, and Participants Individual records were available for 165 544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15 126 incident fatal or nonfatal CVD outcomes (10 132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years). Main Outcome Measures Discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low ( = 20%) risk. Results The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model's discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A(2) mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100 000 adults aged 40 years or older, 15 436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A(2) mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines. Conclusion In a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A(2) mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction. JAMA. 2012; 307(23):2499-2506 www.jama.com

OBJECTIVES To examine whether the psychometric properties of the effort-reward imbalance (ERI) at work scales could be replicated with post-myocardial infarction (post-MI) patients and to measure the criterion validity through its association with psychological distress. METHODS A cross-sectional survey was conducted among 814 patients (739 men and 75 women) who had returned to work after their first MI and who were followed up by telephone at an average of 2.2 years after their baseline interview (1998-2000). The psychological demands scale of the Karasek Job Content Questionnaire was used to measure effort. Reward was measured with nine items from the original reward scale by Siegrist plus two proxy items. Exploratory and confirmatory factor analyses were used to test the theoretical structure of ERI. Using log-binomial regression models, we evaluated the association between ERI scales and psychological distress measured with the 14-item Psychiatric Symptom Index. RESULTS ERI scales and subscales demonstrated adequate internal consistencies. Exploratory factor analysis using oblique (promax) rotation yielded a three-factor solution with items representative of extrinsic effort (Factor 1) and reward subscales (Factors 2 and 3). Confirmatory factor analysis demonstrated a good fit with the data. The internal consistencies and discriminant validities of the ERI scales were satisfactory. Furthermore, effort, reward, and ERI ratio were significantly associated with psychological distress (adjusted prevalence ratio [PR] = 1.71, 95% confidence interval [CI] = 1.26-2.31; PR = 1.63, 95% CI = 1.16-2.29; and PR = 1.70, 95% CI = 1.17-2.47, respectively). CONCLUSIONS The psychometric properties of the ERI scales were generally reproduced among post-MI patients. The associations with psychological distress supported the criterion validity of the ERI scales in this population.

OBJECTIVE: Prospective studies have shown that effort-reward imbalance (ERI) at work is associated with the incidence of a first coronary heart disease (CHD) event. However, it is unknown whether ERI at work increases the risk of recurrent CHD events. The objective of this study was to determine whether ERI at work and its components (effort and reward) increase the risk of recurrent CHD in post-myocardial infarction (post-MI) workers. METHODS: We carried out a prospective cohort study of 669 men and 69 women who returned to work after a first MI. ERI at work was assessed by telephone interview using validated scales of reward and psychological demands. The outcome was a composite of fatal CHD, nonfatal MI, and unstable angina. CHD risk factors were documented in medical files and by interview. The participants were followed up for a mean period of 4.0 years (1998-2005). RESULTS: During the follow-up, 96 CHD events were documented. High ERI and low reward were associated with recurrent CHD (respective adjusted hazard ratios [HRs] = 1.75, 95% confidence interval [CI] = 0.99-3.08, and HR = 1.77, 95% CI = 1.16-2.71). There was a gender interaction showing stronger effects among women (respective adjusted HRs for high ERI and low reward: HR = 3.95, 95% CI = 0.93-16.79, and HR = 9.53, 95% CI = 1.15-78.68). CONCLUSIONS: Post-MI workers holding jobs that involved ERI or low reward had increased risk of recurrent CHD.

OBJECTIVE To examine the impact of withdrawing rosiglitazone and ramipril medication on diabetes incidence after closeout of the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial. RESEARCH DESIGN AND METHODS The 3,366 DREAM subjects at trial end who had not developed diabetes while taking double-blind study medication were transferred to single-blind placebo for 2 to 3 months before undergoing an oral glucose tolerance test. Glycemic status was analyzed for the trial plus washout period and for the washout period alone. RESULTS Following median (interquartile range) 71 (63–86) days drug withdrawal, overall glycemic status remained modestly improved in those allocated ramipril during the trial with an 11% increase in regression to normoglycemia, compared with placebo. In those previously allocated rosiglitazone, glycemic status remained substantially improved with a 49% reduction of new-onset diabetes or death and a 22% increase in regression to normoglycemia, compared with placebo. However, during the washout phase alone the incidence of diabetes or death was identical for those allocated previously to ramipril or placebo, or to rosiglitazone or placebo. CONCLUSIONS In people allocated to ramipril compared with those not allocated ramipril during the trial, the postwashout normoglycemia incidence was higher. In people allocated to rosiglitazone compared with those not allocated rosiglitazone during the trial, the postwashout incidence of diabetes was significantly lower and the incidence of normoglycemia was higher. During the washout period, diabetes incidence was the same for ramipril versus placebo and for rosiglitazone versus placebo. Rosiglitazone delays disease progression during treatment but the process resumes at the placebo rate when the drug is stopped.

The CANadian Network and Centre for Trials INternationally (CANNeCTIN) was jointly funded by the Canadian Institutes of Health Research and the Canadian Foundation for Innovation in April 2008 to provide infrastructure for clinical studies of cardiovascular diseases and diabetes mellitus. Its functional components include a national coordinating centre at the Population Health Research Institute (PHRI) in Hamilton (Ontario), a collaborative Canadian network and an affiliated international network of hospitals and clinics. The rationales for CANNeCTIN include the global health burden of cardiovascular diseases and diabetes, the strengths of randomized controlled trials – particularly large, multicentre and international – and the track record of success of the PHRI. CANNeCTIN will provide investigators from across Canada with opportunities to become the principal investigators of national and international trials coordinated by the PHRI. CANNeCTIN will support priority pilot studies, and successful investigators will be encouraged and assisted to apply for peer review and industrial funding for full studies to be conducted within the network and coordinated by the PHRI. An extensive education program offers hands-on experience in organizing and leading large national/international clinical trials led by accomplished researchers, distance learning courses in clinical research methodology, biostatistics and study coordination, and ‘cutting-edge’ workshops. A knowledge translation program seeks opportunities arising from clinical trials and encourages research into this paradigm for understanding how best to close the gaps between knowledge and effective practice. The five-year goals are to enhance the capacity of Canadian investigators to lead major clinical studies, facilitate knowledge translation and exchange, and augment Canada’s capacity to train the next generation of leaders in cardiovascular and diabetes clinical research.

We previously observed an attenuation of exercise-induced myocardial ischemia on the ergocycle during a ramp protocol compared to the standard Bruce protocol treadmill test in patients with coronary heart disease. However, it was uncertain whether decreased ischemia on the ergocycle resulted from the warm-up effect of the more gradual ramp protocol or from the mode of exercise itself (cycling vs running). Sixteen stable patients, aged 64 +/- 5 years, with documented coronary heart disease (or =70% coronary artery stenosis and/or reversible myocardial perfusion defects) performed 3 symptom-limited exercise tests: the standard Bruce protocol treadmill test and 2 individualized ramp protocols (treadmill and ergocycle). We measured the ischemic threshold (heart rate x systolic blood pressure product at 1-mm ST-segment depression) and oxygen consumption (VO(2)). The ischemic threshold was higher during cycling (ergocycle ramp, 24,009 +/- 5,769 beats/min x mm Hg) compared to running (Bruce treadmill, 20,429 +/- 3,508 beats/min x mm Hg; and ramp treadmill, 19,451 +/- 3,392 beats/min x mm Hg; p0.001), independently of exercise intensity (VO(2)). The peak VO(2) did not significantly differ among all tests (p = 0.25) despite a greater peak rate-pressure product achieved with the ergocycle (29,378 +/- 6,291 beats/min x mm Hg) compared to either treadmill protocol (Bruce, 26,202 +/- 5,831 beats/min x mm Hg; ramp, 25,654 +/- 6,492 beats/min x mm Hg; p0.001). In conclusion, the mode of exercise (ergocycle vs treadmill), rather than the type of protocol (ramp vs Bruce), is associated with an attenuation of electrocardiographic parameters of myocardial ischemia, independently of exercise intensity (VO(2)) and myocardial demand (rate-pressure product).

Background The natural history of intermittent claudication, from its risk factors to its cardiovascular prognosis, has been reported in few prospective studies. Objective To assess incident intermittent claudication, as well as its risk factors and long-term prognosis in men. Methods A random sample of 4376 men 35 to 64 years of age from Quebec City (Quebec), who were free of cardiovascular disease (CVD), was evaluated in 1974 for CVD risk factors and followed until 1998. To assess the prognosis, the event rates between 1985 and 1998 were computed among men with incident claudication without other CVD, incident survivors of a first myocardial infarction (MI) without other CVD and men free of CVD between 1974 and 1985. Results From 1974 to 1998, 300 men developed intermittent claudication. Tobacco consumption, high systolic blood pressure and diabetes at least doubled the adjusted RR (aRR) of intermittent claudication. In 1985, there were 80 claudicants, 2868 men free of CVD and 68 survivors of a first MI. During the 13-year follow-up, a new CVD occurred in 48.8% of the claudicants, in 18.9% of men without CVD (aRR 2.08; 95% CI 1.48 to 2.90) and in 45.6% of MI survivors (aRR compared with claudicants 1.12; 95% CI 0.69 to 1.79). There was also no significant difference between claudicants and MI survivors for fatal CVD, nonfatal CVD and total mortality. Conclusions Men with intermittent claudication are at high risk for CVD that may be equivalent to men with previous MI.

The ONTARGET Trial Programme includes the ONTARGET and TRANSCEND studies. In both studies, participants were at high cardiovascular risk because they had vascular disease without heart failure, or diabetes with end-organ damage. Participants also received proven therapies for cardiovascular risk reduction. In ONTARGET, telmisartan 80 mg was compared with ramipril 10 mg, and the combination of telmisartan and ramipril was compared with ramipril alone. Telmisartan was as effective as ramipril on the primary outcome and other cardiovascular events and was better tolerated, with fewer treatment discontinuations. In TRANSCEND, telmisartan and placebo, both added to background therapy, were compared in high-risk patients intolerant to angiotensin-converting enzyme-inhibitors. There was a lower incidence of cardiovascular events than assumed in power calculations probably due to higher use of background therapy than expected based upon the HOPE trial. This may explain why the reduction in the primary outcome associated with telmisartan was not statistically significant. Nevertheless, the results of TRANSCEND were consistent with the outcome of the HOPE trial, and the secondary endpoint in TRANSCEND, which was equal to the HOPE primary endpoint (cardiovascular death, myocardial infarction, and stroke), was indeed significant. Telmisartan plus ramipril did not reduce the primary outcome compared with ramipril alone and was associated with a greater likelihood of adverse events. The combination is not recommended for the prevention of cardiovascular events in this patient population. In summary, telmisartan was as effective as ramipril on major vascular events in high-risk patients in ONTARGET but showed a non-significant benefit in TRANSCEND. In both studies, the lower rate of treatment discontinuations with telmisartan is important life-long adherence to therapy.

Background— The presence of moderate saphenous vein graft (SVG) lesions is a major predictor of cardiac events late after coronary artery bypass grafting. We determined the effects of sealing moderate nonsignificant SVG lesions with paclitaxel-eluting stents (PES) on the prevention of SVG atherosclerosis progression. Methods and Results— Patients with at least 1 moderate SVG lesion (30% to 60% diameter stenosis) were randomized either to stenting the moderate SVG lesion with a PES (n=30, PES group) or to medical treatment alone (n=27, medical treatment group). Patients had an angiographic and intravascular ultrasound evaluation of the SVG at baseline and at 12-month follow-up. The primary end points were (1) the ultrasound SVG minimal lumen area at follow-up and (2) the changes in ultrasound atheroma volume in an angiographically nondiseased SVG segment. Mean time from coronary artery bypass grafting was 12±6 years, and mean low-density lipoprotein cholesterol level was 73±31 mg/dL. A total of 70 moderate SVG lesions (39±7% diameter stenosis) were evaluated. Significant disease progression occurred in the medical treatment group at the level of the moderate SVG lesion (decrease in minimal lumen area from 6.3±3.0 to 5.6±3.1 mm 2 ; P P =0.014). In the PES group, mean minimal lumen area increased ( P 2 at follow-up ( P =0.001 compared with the medical treatment group at 12 months). There were no cases of restenosis or stent thrombosis. No significant atherosclerosis progression occurred at the nonstented SVG segments. At 12-month follow-up, the cumulative incidence of major adverse cardiac events related to the target SVG was 19% in the medical treatment group versus 3% in the PES group ( P =0.091). Conclusions— Stenting moderate nonsignificant lesions in old SVGs with PES was associated with a lower rate of SVG disease progression and a trend toward a lower incidence of major adverse cardiac events at 1-year follow-up compared with medical treatment alone, despite very low low-density lipoprotein cholesterol values. This pilot study supports further investigation into the role of plaque sealing in SVGs. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT002289835.

Despite its widespread use, limited data on the validity of the Canadian Cardiovascular Society angina (CCSA) classification relative to other measures of functional status have been reported.To assess the validity of the CCSA classification by comparing it with the Duke Activity Status Index (DASI) and evaluate its prognostic significance with respect to long-term mortality.The study population consisted of 1407 patients who underwent cardiac catheterization between 1992 and 1996. The median follow-up period was 9.7 years (interquartile range 6.1 to 11.1 years) and the mortality status as of December 31, 2004 was available for all patients.The first three CCSA classes were inversely related to the DASI. The mean (+/- SD) scores were as follows: class I, 31.4+/-16.7; class II, 22.5+/-15.4; class III, 14.7+/-14.3; and class IV, 15.5+/-14.9 (P0.01). Increasing CCSA class was associated with increased long-term mortality, even after adjusting for baseline characteristics. Chest pain course was also an important modulator of mortality among class III and IV patients; one-year mortality rates were 8.1% among unstable patients compared with 4.8% among patients with stable or progressing course.CCSA classes I to III were inversely related to DASI scores and linearly associated with mortality. The similarity in outcomes among class III and IV patients is probably explained by the confounding effect of the stability of the patients' symptoms. The higher mortality risk among class III and IV patients with an unstable course provides impetus for a revised CCSA definition incorporating this information.

Objectives The aim of this study was to evaluate effects of the angiotensin-converting enzyme (ACE) inhibitor ramipril and the thiazolidinedione (TZD) rosiglitazone on carotid intima-media thickness (CIMT) in people with impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG). Background People with IGT and/or IFG are at increased long-term risk for cardiovascular disease. Effects of ACE inhibitors and of TZDs on vascular disease in this population are unknown. Methods One thousand four hundred twenty-five people with IGT and/or IFG but without cardiovascular disease or diabetes were randomized to ramipril 15 mg/day or its placebo and to rosiglitazone 8 mg/day or its placebo with a 2 × 2 factorial design. The primary study outcome was the annualized change of the aggregate maximum CIMT, computed as the average of the maximum CIMTs across 12 carotid arterial segments. The secondary study outcome was the annualized change of the mean far wall left and right common CIMT. Median follow-up was 3 years and carotid ultrasound examinations were obtained at baseline and yearly thereafter. Results There were no differences in the primary and secondary outcomes between the ramipril and placebo groups. Compared with placebo, rosiglitazone reduced the primary CIMT outcome, but the difference was not statistically significant (difference = 0.0027 ± 0.0015 mm/year; p = 0.08) and significantly reduced the secondary CIMT outcome (difference = 0.0043 ± 0.0017 mm/year; p = 0.01). Conclusions In people with IGT and/or IFG without cardiovascular disease and diabetes, treatment with ramipril had a neutral effect on CIMT, whereas rosiglitazone modestly reduced CIMT progression. (The Study of Atherosclerosis With Ramipril and Rosiglitazone; NCT00140647 ).

Many measures have been proposed to summarize the prognostic ability of the Cox proportional hazards (CPH) survival model, although none is universally accepted for general use. By contrast, little work has been done to summarize the prognostic ability of the stratified CPH model; such measures would be useful in analyses of individual participant data from multiple studies, data from multi-centre studies, and in single study analysis where stratification is used to avoid making assumptions of proportional hazards. We have chosen three measures developed for the unstratified CPH model (Schemper and Henderson's V , Harrell's C-index and Royston and Sauerbrei's D), adapted them for use with the stratified CPH model and demonstrated how their values can be represented over time. Although each of these measures is promising in principle, we found the measure of explained variation V very difficult to apply when data are combined from several studies with differing durations of participant follow-up. The two other measures considered, D and the C-index, were more applicable under such circumstances. We illustrate the methods using individual participant data from several prospective epidemiological studies of chronic disease outcomes.

Objectives This study was designed to prospectively determine, in patients with an acute coronary syndrome, whether the inflammatory marker, C-reactive protein (CRP), measured at hospital admission, discharge, and 1 month later has incremental value to predict outcomes at 1 year. Background The clinical utility of CRP measurements in patients with acute coronary syndromes remains uncertain. Limitations of previous studies have been retrospective design and incomplete adjustment for readily available clinical prognosticators. Methods The CRP marker was measured at admission, hospital discharge, and 1 month later in consecutive patients hospitalized for acute coronary syndromes in 8 tertiary and secondary hospitals. The primary outcome was a composite of death, nonfatal myocardial infarction (MI), and unstable angina (UA) with electrocardiogram (ECG) changes at 1 year. Results A total of 1,210 patients, age 62 ± 12 years, 64% with acute myocardial infarction (MI) and 36% with unstable angina (UA), were recruited. At 1 year, the primary outcome occurred in 142 patients (11.7%) and included 58 deaths (4.8%), 79 nonfatal MIs (6.5%), and 26 UA episodes with ECG changes (2.1%). The unadjusted odds ratios (ORs) (95% confidence intervals) of CRP values at admission, hospital discharge, and 1 month later for the occurrence of the primary outcome were 1.20 (1.06 to 1.36), 0.98 (0.85 to 1.14), and 1.23 (1.00 to 1.50), respectively. After multivariate adjustment, ORs were 1.04 (0.91 to 1.20), 0.90 (0.77 to 1.06), and 1.12 (0.93 to 1.34), respectively. The individual components of the primary outcome were also not independently associated with any of the 3 CRP measurements. Conclusions The modest predictive ability of CRP following admission for an acute coronary syndrome disappeared after adjusting for common clinical variables. This large prospective study does not support the incremental value of measuring CRP in this clinical setting.

PurposeThe purpose of this paper is to docoment a randomized controlled trial, with follow‐up at three and six months, to determine the impact of a coronary risk factor modification program for employees.Design/methodology/approachIntervention participants received a 12‐week health promotion program involving exercise, education seminars, nutritional analysis and smoking cessation counselling. Outcome measures included differences in coronary risk factors of control and intervention participants between baseline and three and six‐month follow‐up visits.FindingsThe participants included 566 individuals employed in the Halifax area, Nova Scotia, Canada. They were between 19 and 66 years old with at least two modifiable coronary risk factors. There were statistically significant differences at three months in coronary risk score improvement, smoking cessation, physical activity level increases, body mass index reductions and serum cholesterol. At six months, improvements remained significant except for cholesterol. Reduction in blood pressure was not significantly different. Intervention participants compared to control participants showed significant differences in both cardiac and stroke risk at three and six‐month visits.Practical implicationsThis study demonstrates that employees had a significant coronary disease risk reduction as a result of a relatively short health promotion intervention. Benefits three months post‐intervention were not sustained to the same extent as during the intervention. This underscores the need for long‐term commitment with lifestyle changes and raises the issue of the need for a comprehensive approach that also addresses environmental factors.Originality/valueThis paper contributes to the current research base on this topic as there are few well‐designed studies to reduce coronary risk factors for employees.

Aims Cardiovascular (CV) disease is the leading cause of death in the elderly. The use of ACE-inhibitors in elderly patients with chronic stable vascular disease has not been previously reported. Methods and results The HOPE trial evaluated the effects of ramipril and vitamin E in high-risk vascular disease patients. We report the effects of ramipril in the elderly HOPE study patients, defined as those � 70 years of age. A total of 2755 elderly patients with vascular disease or diabetes and at least one additional CV risk factor and without heart failure or low ejection fraction were randomized to ramipril 10 mg daily or placebo. Those assigned to ramipril had fewer major vascular events compared to those assigned to placebo [18.6 vs. 24.0%, hazard ratio (HR) ¼ 0.75, P ¼ 0.0006], CV deaths (9.3 vs. 13.0%, HR ¼ 0.71, P ¼ 0.003), myocardial infarctions (12.0 vs. 15.6%, HR ¼ 0.75, P ¼ 0.006), and strokes (5.4 vs. 7.7%, HR ¼ 0.69, P ¼ 0.013). Treatment was safe and generally well tolerated. Conclusion Ramipril reduces the risk of major vascular events in elderly patients with vascular disease and is safe and well tolerated by most.

Summary Background WHO has targeted that medicines to prevent recurrent cardiovascular disease be available in 80% of communities and used by 50% of eligible individuals by 2025. We have previously reported that use of these medicines is very low, but now aim to assess how such low use relates to their lack of availability or poor affordability. Methods We analysed information about availability and costs of cardiovascular disease medicines (aspirin, β blockers, angiotensin-converting enzyme inhibitors, and statins) in pharmacies gathered from 596 communities in 18 countries participating in the Prospective Urban Rural Epidemiology (PURE) study. Medicines were considered available if present at the pharmacy when surveyed, and affordable if their combined cost was less than 20% of household capacity-to-pay. We compared results from high-income, upper middle-income, lower middle-income, and low-income countries. Data from India were presented separately given its large, generic pharmaceutical industry. Findings Communities were recruited between Jan 1, 2003, and Dec 31, 2013. All four cardiovascular disease medicines were available in 61 (95%) of 64 urban and 27 (90%) of 30 rural communities in high-income countries, 53 (80%) of 66 urban and 43 (73%) of 59 rural communities in upper middle-income countries, 69 (62%) of 111 urban and 42 (37%) of 114 rural communities in lower middle-income countries, eight (25%) of 32 urban and one (3%) of 30 rural communities in low-income countries (excluding India), and 34 (89%) of 38 urban and 42 (81%) of 52 rural communities in India. The four cardiovascular disease medicines were potentially unaffordable for 0·14% of households in high-income countries (14 of 9934 households), 25% of upper middle-income countries (6299 of 24 776), 33% of lower middle-income countries (13 253 of 40 023), 60% of low-income countries (excluding India; 1976 of 3312), and 59% households in India (9939 of 16 874). In low-income and middle-income countries, patients with previous cardiovascular disease were less likely to use all four medicines if fewer than four were available (odds ratio [OR] 0·16, 95% CI 0·04–0·57). In communities in which all four medicines were available, patients were less likely to use medicines if the household potentially could not afford them (0·16, 0·04–0·55). Interpretation Secondary prevention medicines are unavailable and unaffordable for a large proportion of communities and households in upper middle-income, lower middle-income, and low-income countries, which have very low use of these medicines. Improvements to the availability and affordability of key medicines is likely to enhance their use and help towards achieving WHO's targets of 50% use of key medicines by 2025. Funding Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, AstraZeneca (Canada), Sanofi-Aventis (France and Canada), Boehringer Ingelheim (Germany and Canada), Servier, GlaxoSmithKline, Novartis, King Pharma, and national or local organisations in participating countries.

10 p., Background Alcohol consumption is proposed to be the third most important modifiable risk factor for death and disability. However, alcohol consumption has been associated with both benefits and harms, and previous studies were mostly done in high-income countries. We investigated associations between alcohol consumption and outcomes in a prospective cohort of countries at different economic levels in five continents. Methods We included information from 12 countries participating in the Prospective Urban Rural Epidemiological (PURE) study, a prospective cohort study of individuals aged 35–70 years. We used Cox proportional hazards regression to study associations with mortality (n=2723), cardiovascular disease (n=2742), myocardial infarction (n=979), stroke (n=817), alcohol-related cancer (n=764), injury (n=824), admission to hospital (n=8786), and for a composite of these outcomes (n=11 963). Findings We included 114 970 adults, of whom 12 904 (11%) were from high-income countries (HICs), 24 408 (21%) were from upper-middle-income countries (UMICs), 48 845 (43%) were from lower-middle-income countries (LMICs), and 28 813 (25%) were from low-income countries (LICs). Median follow-up was 4·3 years (IQR 3·0–6·0). Current drinking was reported by 36 030 (31%) individuals, and was associated with reduced myocardial infarction (hazard ratio [HR] 0·76 [95% CI 0·63–0·93]), but increased alcohol-related cancers (HR 1·51 [1·22–1·89]) and injury (HR 1·29 [1·04–1·61]). High intake was associated with increased mortality (HR 1·31 [1·04–1·66]). Compared with never drinkers, we identified significantly reduced hazards for the composite outcome for current drinkers in HICs and UMICs (HR 0·84 [0·77–0·92]), but not in LMICs and LICs, for which we identified no reductions in this outcome (HR 1·07 [0·95–1·21]; pinteraction

IMPORTANCE: The prevalence of cardiometabolic multimorbidity is increasing. OBJECTIVE: To estimate reductions in life expectancy associated with cardiometabolic multimorbidity. DESIGN, SETTING, AND PARTICIPANTS: Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689 300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128 843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499 808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. EXPOSURES: A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI). MAIN OUTCOMES AND MEASURES: All-cause mortality and estimated reductions in life expectancy. RESULTS: In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy. CONCLUSIONS AND RELEVANCE: Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

Background.Research has shown less aggressive treatment and poorer control of cardiovascular disease (CVD) risk factors in women than men.Methods.We analyzed sex differences in pharmacotherapy strategies and attainment of goals for hemoglobin A1c (HbA1c), blood pressure (BP), and low density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes and established coronary artery disease enrolled into the BARI 2D trial.Results.Similar numbers of drugs were prescribed in both women and men. Women were less frequent on metformin or sulfonylurea and more likely to take insulin and to be on higher doses of hydroxymethylglutaryl-CoA reductase inhibitors (statins) than men. After adjusting for baseline differences and treatment prescribed, women were less likely to achieve goals for HbA1c (OR = 0.71, 95% CI 0.57, 0.88) and LDL-C (OR = 0.64, 95% CI 0.53, 0.78). More antihypertensives were prescribed to women, and yet BP ≤ 130/80 mmHg did not differ by sex.Conclusions.Women entering the BARI 2D trial were as aggressively treated with drugs as men. Despite equivalent treatment, women less frequently met targets for HbA1c and LDL-C. Our findings suggest that there may be sex differences in response to drug therapies used to treat diabetes, hypertension, and hyperlipidemia.

Angiotensin-converting-enzyme (ACE) inhibitors reduce cardiovascular mortality and morbidity in patients with heart failure or left ventricular systolic dysfunction (LVSD). Three large trials have assessed the effect of ACE inhibitors in stable patients without these conditions but with atherosclerosis. We undertook a systematic review of the Heart Outcomes Prevention Evaluation (HOPE), the European trial on Reduction Of cardiac events with Perindopril among patients with stable coronary Artery disease (EUROPA), and the Prevention of Events with ACE inhibition (PEACE) studies to determine the consistency with which ACE inhibitors reduce total mortality and fatal and non-fatal cardiovascular events.We computed cardiovascular outcomes and total mortality in the 29,805 patients of these three trials, randomly assigned an ACE inhibitor or placebo and followed up for a mean of about 4.5 years. The results were also analysed within the context of five large trials of ACE inhibitors in patients with heart failure or LVSD.When the findings of the HOPE, EUROPA, and PEACE trials were combined, ACE inhibitors significantly reduced all-cause mortality (7.8 vs 8.9%, p=0.0004), cardiovascular mortality (4.3 vs 5.2%, p=0.0002), non-fatal myocardial infarction (5.3 vs 6.4%, p=0.0001), all stroke (2.2 vs 2.8%, p=0.0004), heart failure (2.1 vs 2.7%, p=0.0007), coronary-artery bypass surgery (6.0 vs 6.9%, p=0.0036) but not percutaneous coronary intervention (7.4 vs 7.6%, p=0.481). The composite outcomes of cardiovascular mortality, non-fatal myocardial infarction, or stroke occurred in 1599 (10.7%) of the patients allocated ACE inhibitor and in 1910 (12.8%) of those allocated placebo (odds ratio, 0.82; 95% CIs 0.76-0.88; p0.0001). Except for stroke and revascularisation, these results were similar to those of the five trials in patients with heart failure or LVSD.ACE inhibitors reduce serious vascular events in patients with atherosclerosis without known evidence of LVSD or heart failure. Results showing these benefits in intermediate-risk patients complement existing evidence of similar benefit in higher-risk patients with LVSD or heart failure. Therefore, use of ACE inhibitors should be considered in all patients with atherosclerosis.

We tested the hypothesis that elevated plasma interleukin-6 (IL-6), C-reactive protein (CRP) and fibrinogen concentrations are independent risk factors and interact in increasing the long-term risk of ischemic heart disease (IHD) in men. A total of 1982 IHD-free men from the Quebec Cardiovascular Study were followed over a period of 13 years during which 210 first fatal IHD events and non-fatal myocardial infarctions were recorded. Increased CRP levels (4th versus 1st quartile) were not associated with an increased risk of IHD after adjustment for non-lipid risk factors (age, body mass index, systolic blood pressure, diabetes, smoking and medication use at baseline), lipid risk factors (LDL and HDL cholesterol and triglyceride levels) and for IL-6 and fibrinogen (RR=0.70, 95% CI=0.43–1.13). High plasma IL-6 levels (4th versus 1st quartile) were associated with a 70% greater risk of IHD independent of confounding risk factors and of the other 2 inflammatory markers (RR=1.71, 95% CI=1.07–2.75). The relationship between high fibrinogen levels (4th versus 1st quartile) and IHD risk was borderline significant in multivariate analyses (RR=1.53, 95% CI=0.97–2.43). An inflammation score based on plasma IL-6 and fibrinogen levels improved the IHD risk predictive value of a multivariate model of traditional risk factors ( p =0.03). Including plasma CRP levels into the inflammatory score provided no additional predictive value. In conclusion, elevated plasma IL-6 concentrations are more strongly related to IHD risk than CRP and fibrinogen. An inflammation score based on high plasma IL-6 and fibrinogen levels used in combination with traditional risk factors may improve our ability to adequately identify high risk individuals.

Background: Many people who are not obese according to standard height and weight criteria may still display features of insulin resistance syndrome and thus be at high risk of ischemic heart disease. We sought to investigate the effect of cumulative features of insulin resistance syndrome on the risk of ischemic heart disease associated with variations in body mass index (BMI) among men who participated in the Quebec Cardiovascular Study. Methods: A cohort of 1824 nondiabetic men free of ischemic heart disease was evaluated at the 1985 baseline evaluation and followed for a period of 13 years, during which 284 first ischemic heart disease events were recorded. Relative hazards (RHs) of ischemic heart disease in 3 BMI groups (normal weight, overweight and obese) were estimated using Cox proportional hazards regression. Results: Although obese men (BMI ≥ 30 kg/m 2 ) were the most likely to accumulate features of insulin resistance syndrome, the univariate risk of ischemic heart disease in this group was not significantly increased compared with normal-weight men (BMI 2 ) (RH 1.26, 95% confidence interval [CI] 0.88–1.80). However, obese men who accumulated more than 4 features of insulin resistance syndrome were at increased risk of ischemic heart disease (RH 1.81, 95% CI 1.02–3.19) compared with normal-weight men who had fewer than 3 features of the syndrome. Conversely, having more than 4 features of insulin resistance syndrome was associated with a 3-fold increase in the risk of ischemic heart disease among normal-weight men (RH 3.01, 95% CI 1.70–5.32). Interpretation: Although obesity is an important risk factor for ischemic heart disease, variations in BMI alone poorly reflect the risk of ischemic heart disease associated with features of insulin resistance syndrome.

Increased body mass index (BMI) and abdominal adiposity increase the risk of cardiovascular disease (CVD) in persons free of these diseases, but their independent prognostic impact in persons with CVD has not been well defined.BMI, waist-to-hip ratio (WHR), and waist circumference (WC) were measured in 6620 men and 2182 women with a mean age of 66 and stable CVD without congestive heart failure (CHF) participating in the Heart Outcomes Prevention Evaluation (HOPE) study. The main outcomes were CVD death, myocardial infarction, stroke, hospitalization for CHF, and all-cause mortality.During the 4.5-year follow-up, 658 had a CVD death, 1018 a myocardial infarction, 364 a stroke, 297 a CHF event, and 1034 died. When compared with the first tertile, the third tertile of BMI increased the adjusted relative risk (RR) of myocardial infarction by 20% (P.02). Patients in the third tertile of WC had an increased adjusted RR of 23% for myocardial infarction (P.01), 38% for heart failure (P.03), and 17% for total mortality (P.05). For WHR, there was an increased adjusted RR of 24% for CVD death (P.03), 20% for myocardial infarction (P.01), and 32% for total mortality (P.001).Obesity, particularly abdominal adiposity, worsens the prognosis of patients with CVD; weight reduction program should be integrated in the active management of these patients.

OBJECTIVE To assess the prevalence of psychologic distress in women and men returning to work after a myocardial infarction (MI) and to compare this prevalence with the prevalence observed among men and women of the general working population. METHODS The study population was composed of 990 post-MI patients (106 women and 884 men) recruited in 30 hospitals who had returned to work after their first MI. Psychologic distress was measured with the French version of the Psychiatric Symptom Index (PSI). Adjusted mean PSI score and prevalence of psychologic distress were compared with those observed in 8829 other workers (3823 women and 5006 men), representative of the general working population. RESULTS Mean PSI score was higher in post-MI women (30.3) than in post-MI men (20.3). This score was also higher in the post-MI population than in the general working population, both for women (30.3 compared with 17.0) and men (20.3 compared with 14.1). Psychologic distress was more prevalent in post-MI women than in post-MI men (prevalence ratio [PR], 1.62; confidence interval [CI], 1.27-2.07). This score was also higher in post-MI women and post-MI men than in the general working population (PR, 2.18; CI, 1.75-2.71 and 1.76; CI, 1.48-2.08, respectively). CONCLUSIONS Among the presumably fittest post-MI patients, namely those who had returned to work, psychologic distress was significantly more prevalent than in the general working population, particularly among women. Further research is needed to shed light on prognosis in post-MI workers experiencing psychologic distress and on adequate intervention before and after their return to work.

Background Hypertension is a well-established risk factor for myocardial infarction (MI), but its prognostic importance in survivors of an acute MI is less clear. Methods We used Cox proportional hazards models to examine the risk of any major cardiovascular event (cardiovascular death, heart failure, recurrent MI, or stroke)—combined or individual components—and all-cause death and evaluate the efficacy of captopril in 906 patients with hypertension and 1325 patients without hypertension in the Survival and Ventricular Enlargement (SAVE) clinical trial. All patients had survived an acute MI with resultant left ventricular (LV) systolic dysfunction, but without overt heart failure, and were randomized within 3 to 16 days after the index MI to receive either captopril or placebo. The mean (± SD) follow-up period was 42 ± 10 months. Results After adjustment for known risk factors, medication use at enrollment, and baseline systolic blood pressure, patients with hypertension had a significant increase in the risk of experiencing a combined cardiovascular event (47.7% vs 31.3%; hazard ratio [HR], 1.49; 95% CI, 1.28–1.74), cardiovascular death (23.4% vs 15.9%; HR, 1.40; 95% CI, 1.12–1.74), heart failure (27.7% vs 15.5%; HR, 1.64; 95% CI, 1.34–2.02), and all-cause death (27.4 vs 19.3%; HR, 1.25; 95% CI, 1.02–1.53), and a similar but statistically non-significant increase in the risk of non-fatal or fatal recurrent MI (17.4% vs 10.9%; HR, 1.27; 95% CI, 0.98–1.65), and non-fatal or fatal stroke (5.0% vs 3.6%; HR, 1.31; 95% CI, 0.81–2.09). Captopril resulted in similar benefits for both patients with and patients without hypertension. The number of combined cardiovascular events prevented for every 100 patients treated with captopril was 7.0 (95% CI, 0.5–13.5) in patients with hypertension and 7.5 (95% CI, 2.6–12.5) in patients without hypertension. Conclusions In survivors of an acute MI with LV systolic dysfunction, antecedent hypertension was associated with a greater risk of subsequent adverse cardiovascular events, not directly explained by elevated blood pressure levels. Captopril use was beneficial in both patients with and patients without hypertenson.

This study investigated the relevance of using the plasma triglyceride to high-density lipoprotein cholesterol ratio (Log TG/HDL-C) for the prediction of the small dense lowdensity lipoprotein (LDL) phenotype and the risk of ischemic heart disease (IHD). Analyses were based on data from the Quebec Cardiovascular Study in a cohort of 2072 men free of IHD at baseline, among whom 262 had a first IHD event (coronary death, non fatal myocardial infarction and unstable angina) during a 13-year follow-up period. LDL particle size phenotype was characterized using 2-16% polyacrylamide gradient gel electrophoresis (PAGGE) of whole plasma. There were significant associations between the Log TG/HDL-C ratio and features of LDL size phenotype such as the proportion of LDL with a diameter255A (r = 0.43, p0.001) and LDL peak particle size (r = -20.55, p0.001). However, the Log TG/HDL-C ratio brought no additional value (p â yen 0.1) in predicting the small dense LDL phenotype (area under the receiver operating curve (AUROC = 71.9%) compared to TG alone (AUROC = 71.2%) or to a combination of Log TG and HDL-C (AUROC = 72.4%) after multivariate adjustment for non lipid risk factors. Finally, elevations in the Log TG/HDL-C ratio did not improve the discrimination of incident IHD cases from non IHD cases compared to the use of plasma TG levels alone (p = 0.5) or a combination of the individual TG and HDL-C values (p = 0.5). The Log TG/HDL-C ratio does not improve our ability to identify individuals with the small dense LDL phenotype compared to plasma TG levels alone. The Log TG/HDLC is also not superior to plasma TG levels alone in predicting IHD risk in men of the QuA(c)bec Cardiovascular Study.

This purpose of this study was to investigate how plasma C-reactive protein (CRP), a nonspecific acute-phase reactant, modulates the risk of coronary heart disease (CHD) associated with the small, dense, low-density lipoprotein (LDL) phenotype. LDL particle size and plasma CRP were measured in the Quebec Cardiovascular Study cohort of 2,025 men free of CHD at baseline, among whom 103 had a first CHD event during a 5-year follow-up period. Plasma CRP levels were measured using the Behring Latex-Enhanced (highly sensitive) CRP assay. LDL particle size phenotype was characterized using 2% to 16% polyacrylamide gradient gel electrophoresis. There were weak but significant associations between plasma CRP levels and features of LDL size, such as the proportion of LDL with a diameter

OBJECTIVES—Experimental and observational studies suggest that vitamin E may reduce the risk of cardiovascular (CV) events and of microvascular complications in people with diabetes. However, data from randomized clinical trials are limited. Therefore, we evaluated the effects of vitamin E supplementation on major CV outcomes and on the development of nephropathy in people with diabetes. RESEARCH DESIGN AND METHODS—The Heart Outcomes Prevention Evaluation (HOPE) trial is a randomized clinical trial with a 2 × 2 factorial design, which evaluated the effects of vitamin E and of ramipril in patients at high risk for CV events. Patients were eligible for the study if they were 55 years or older and if they had CV disease or diabetes with at least one additional coronary risk factor. The study was designed to recruit a large number of people with diabetes, and the analyses of the effects of vitamin E in this group were preplanned. Patients were randomly allocated to daily treatment with 400 IU vitamin E and with 10 mg ramipril or their respective placebos and were followed for an average of 4.5 years. The primary study outcome was the composite of myocardial infarction, stroke, or CV death. Secondary outcomes included total mortality, hospitalizations for heart failure, hospitalizations for unstable angina, revascularizations, and overt nephropathy. RESULTS—There were 3,654 people with diabetes. Vitamin E had a neutral effect on the primary study outcome (relative risk = 1.03, 95% CI 0.88–1.21; P = 0.70), on each component of the composite primary outcome, and on all predefined secondary outcomes. CONCLUSIONS—The daily administration of 400 IU vitamin E for an average of 4.5 years to middle-aged and elderly people with diabetes and CV disease and/or additional coronary risk factor(s) has no effect on CV outcomes or nephropathy.

10 p., Background: Previous research has shown that environments with features that encourage walking are associated with increased physical activity. Existing methods to assess the built environment using geographical information systems (GIS) data, direct audit or large surveys of the residents face constraints, such as data availability and comparability, when used to study communities in countries in diverse parts of the world. The aim of this study was to develop a method to evaluate features of the built environment of communities using a standard set of photos. In this report we describe the method of photo collection, photo analysis instrument development and inter-rater reliability of the instrument. Methods/Principal Findings: A minimum of 5 photos were taken per community in 86 communities in 5 countries according to a standard set of instructions from a designated central point of each community by researchers at each site. A standard pro forma derived from reviewing existing instruments to assess the built environment was developed and used to score the characteristics of each community. Photo sets from each community were assessed independently by three observers in the central research office according to the pro forma and the inter-rater reliability was compared by intra-class correlation (ICC). Overall 87% (53 of 60) items had an ICC of $0.70, 7% (4 of 60) had an ICC between 0.60 and 0.70 and 5% (3 of 60) items had an ICC #0.50. Conclusions/Significance: Analysis of photos using a standardized protocol as described in this study offers a means to obtain reliable and reproducible information on the built environment in communities in very diverse locations around the world. The collection of the photographic data required minimal training and the analysis demonstrated high reliability for the majority of items of interest.

Background and Purpose—Incidental magnetic resonance diffusion-weighted imaging (DWI)–positive lesions, considered to represent small acute infarcts, have been detected in patients with cerebral small vessel diseases or cognitive impairment, but the prevalence in the community population is unknown.Methods—DWI sequences collected in 793 participants in the Prospective Urban Rural Epidemiological (PURE) study were reviewed for DWI lesions consistent with small acute infarcts.Results—No DWI-positive lesions were detected (0%, 95% confidence interval, 0–0.5).Conclusions—DWI-positive lesions are rare in an asymptomatic community population. The prevalence of DWI-positive lesions in the community seems to be lower than in patients with cerebral amyloid angiopathy, intracerebral hemorrhage, or cognitive impairment.

Aims: We studied the unclear question whether blood pressure (BP) lowering reduces cardiovascular disease (CVD) in elderly individuals with systolic BP

Background —At one end of the clinical spectrum of coronary artery disease (CAD) are subjects who have had repeated acute ischemic events, and at the other end are those with long-standing angina who have never been unstable. This study tests the hypothesis that a specific biological profile can distinguish these 2 extreme groups and predict acute coronary events. Methods and Results —Blood levels of lipoprotein(a), homocysteine, tissue plasminogen activator, plasminogen activator inhibitor-1, C-reactive protein (CRP), fibrinogen, and von Willebrand factor were compared in 3 groups of 50 subjects each: (1) those with previous multiple acute coronary events, (2) age-matched subjects with ≥3 years of stable angina and no prior acute coronary events, and (3) matched controls without evidence of atherosclerotic disease and a normal coronary angiogram. All subjects were followed for 4.0 years. Lipoprotein(a), homocysteine, tissue plasminogen activator, and plasminogen activator inhibitor-1 were similar in both CAD groups and significantly higher than in the control group. However, compared with subjects with long-standing stable angina, those with previous multiple coronary events had higher values of CRP (5.7±5.4 versus 3.0±5.2 mg/L, P =0.012), fibrinogen (3.38±0.75 versus 2.92±0.64 g/L, P =0.001), and von Willebrand factor (1.60±0.55 versus 1.25±0.36 U/mL, P =0.0003). On follow-up, myocardial infarction and unstable angina occurred in 42% of the group with multiple events, 4% of the stable angina group ( P P P =0.002). A baseline CRP >3.5 mg/L had a relative risk of 7.6 (2.6 to 21.7, P =0.0002) for subsequent acute events. Conclusions —An inflammatory biological profile distinguished patients with previous multiple acute coronary events from those with long-standing stable angina and predicted acute coronary instability.

Background: Primary as well as secondary prevention trials have shown the relevance of lowering LDL-cholesterol to reduce coronary heart disease (CHD) risk. However, although the association between LDL-cholesterol and CHD is well recognized, there is a considerable overlap in the distribution of plasma LDL-cholesterol levels between CHD patients and healthy subjects. The objective of the present review article is to use data from the Quebec cardiovascular study to demonstrate that in men, a low HDL-cholesterol may be even more of a risk factor and a target for therapy than a high LDL-cholesterol. Methods and results: Results of the Quebec cardiovascular study, a prospective study of 2103 middle-aged men followed for a period of 5 years, have confirmed results of previous studies in showing that plasma HDL-cholesterol concentration was an independent predictor of a first ischemic heart disease (IHD) event which included typical effort angina, coronary insufficiency, nonfatal myocardial infarction and coronary death. In addition, a reduced plasma HDL-cholesterol concentration was found to have a greater impact than raised LDL-cholesterol on the atherogenic index (total cholesterol/HDL-cholesterol ratio), this ratio being the best variable of the traditional lipid profile for the prediction of IHD events in the Quebec cardiovascular study. However, a low HDL-cholesterol concentration is not often observed as an isolated disorder but also includes hypertriglyceridemia, elevated apo B concentration, and an increased proportion of small, dense LDL particles. These abnormalities are features of an insulin resistant-hyperinsulinemic state resulting from abdominal obesity. Conclusions: It is therefore recommended that we need to go beyond LDL-cholesterol measurement lowering therapy for the optimal management of CHD risk. Raising plasma HDL-cholesterol through weight loss and a healthy diet, by an increased physical activity and, if required, by proper pharmacotherapy is therefore a legitimate therapeutic target for the optimal prevention of CHD in a large proportion of high risk patients.

A sample of 2,103 men aged 47 to 76 years from the Québec Cardiovascular Study cohort was examined to quantify the influence of plasma triglyceride (TG) levels on the relationship between plasma lipoprotein cholesterol and either apolipoprotein A-I (apo A-I) or apo B concentrations. Regression analyses between high-density lipoprotein cholesterol (HDL-C) and apo A-I through TG tertiles showed highly significant correlations (.62or = ror = .75, P.0001) in all TG tertiles between these 2 variables. The associations for plasma apo B versus low-density lipoprotein cholesterol (LDL-C) and non-HDL-C levels were also studied on the basis of TG concentrations, and correlation coefficients between either LDL-C or non-HDL-C and apo B were essentially similar among TG tertiles (.78or = ror = .85 and .83or = ror = .86 for LDL-C and non-HDL-C, respectively, P.0001). Regression analyses also showed that lower HDL-C levels were found for any given apo A-I concentration among men in the 2 upper TG tertiles, whereas lower LDL-C concentrations were observed at any given apo B level among subjects in the upper TG tertile. We further investigated whether there were synergistic alterations in the HDL-C/apo A-I and LDL-C/apo B ratios as a function of increasing plasma TG. A significant association was noted between these 2 ratios (r = .37; P.0001). Mean HDL-C/apo A-I and LDL-C/apo B ratios were then calculated across quintiles of plasma TG concentrations. Increased TG concentrations were first associated with a reduced HDL-C/apo A-I ratio, followed by a decreased LDL-C/apo B ratio. These results suggest that a relatively modest increase in TG may rapidly alter the relative cholesterol content of HDL particles. Finally, the cholesterol content of the non-HDL fraction appears to be influenced less by TG levels than HDL-C and LDL-C fractions. Thus, the plasma apo B-containing lipoprotein cholesterol level may provide a better index of number of atherogenic particles than the LDL-C concentration, particularly in the presence of hypertriglyceridemia (HTG).

Background We assessed the relationship between psychological stress and ischaemic heart disease (IHD) incidence in a population of 868 men over a 10-year follow-up period. Methods In 1981, 869 men aged 42‐60, free from IHD and living around Quebec City completed a questionnaire assessing the presence of psychological stress in different areas of their life. They also underwent a medical examination and provided information on IHD risk factors. From 1981 to 1991, the incidence of IHD events was ascertained. The relationship between 13 stress dimensions and IHD incidence was investigated using Cox regression while controlling for important IHD risk factors. Cross-sectional analyses were also performed to investigate the relationship between stress dimensions and IHD risk factors. Results Between 1981 and 1991, 79 men (9%) experienced a first IHD event. The following risk factors were associated with the risk of IHD: age, (rate ratio (RR) = 1.93, 95% CI : 1.21‐3.09), hypertension (RR = 1.90, 95% CI : 1.22‐2.98), triglycerides (RR = 1.87, 95% CI : 1.19‐2.95) and high density lipoprotein (HDL) cholesterol (RR = 1.64, 95% CI : 1.05‐2.55). After controlling for risk factors, not one of the psychological stress dimensions significantly altered the risk of IHD. Conclusions While confirming the influence of hypertension, age, triglycerides and HDL cholesterol on IHD incidence, this study suggests that there is no important connection between the explored stress dimensions and IHD incidence. It is unlikely that this lack of association is due to the stress questionnaire since the 13 stress dimensions were rigorously developed through independent evaluation of the questions by three specialists and many statistically significant relationships were observed between stress dimensions and IHD risk factors.

To the Editor: Madsen et al1 compared an invasive strategy of coronary arteriography and revascularization with a conservative strategy in patients with inducible myocardial ischemia after thrombolysis for a first myocardial infarction. Just over 500 patients aged ≤69 years and able to perform an exercise test were randomized to each strategy. The invasive-strategy patients underwent 266 angioplasty procedures and 147 bypass operations. There was no significant difference in mortality between the 2 groups at a median of 2.4 years. Rates of reinfarction and of readmission for unstable angina were 5.6% and 17.9%, respectively, for the invasive strategy and 10.5% and 29.5%, respectively, for the conservative strategy. From this, Madsen et al conclude that all subjects with inducible ischemia after a thrombolyzed first myocardial infarction should be revascularized and then extend this sweeping recommendation, without any analysis of costs, days hospitalized, and quality of life, to all postinfarction patients with inducible ischemia. It is unclear why in this study the invasive strategy’s absolute reduction of only 4.9% in the occurrence of myocardial infarction and of 11.6% in the number of admissions for unstable angina …

Summary There is no doubt that visceral obesity increases thesusceptibility to IHD, emphasizing the need to consider this condition in the risk management of IHD. The use of CT or MRI as clinical tools to assess visceral adipose tissue accumulation does not appear to be justified, however, mostly because of the costs of the procedures and the limited availability of the necessary apparatus. The waist:hip ratio has been used extensively as an indicator of body fat distribution. However, it has been shown that the waist:hip ratio is less accurate than the waist circumference alone or the sagittal diameter in predicting - visceral adipose tissue accumulation, particularly when monitoring changes in visceral adipose tissue mass over time. Also, the prediction of visceral adipose tissue levels by the waist circumference alone, as opposed to the waist:hip ratio, does not appear to be affected by gender or by the degree of obesity. For these reasons we have proposed that the waist circumference should be systematically measured in managing the risk of IHD. It is a simple and inexpensive measurement to perform, while providing potentially critical information on the risk profile of both men and women. We believe that identification of viscerally obese patients, a high-risk population for IHD, should be considered as a critical step in the risk management of IHD.

Objectives. This study was undertaken to determine whether lipoprotein(a) [Lp(a)] is an independent risk factor for ischemic heart disease (IHD) and to establish the relation of Lp(a) to the other lipid fractions. Background. Several, but not all, studies have shown that elevated Lp(a) concentrations may be associated with IHD; very few have been prospective. Methods. A 5-year prospective follow-up study was conducted in 2,156 French Canadian men 47 to 76 years old, without clinical evidence of IHD. Lipid measurements obtained at baseline included total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, apoprotein B and Lp(a). During the follow-up period, there were 116 first IHD events (myocardial infarction, angina, death). Adjusted proportional hazards models were used to estimate the relative risk for the different variables. The cohort was also classified according to Lp(a) levels and other lipid risk factor tertiles to evaluate the relation of elevated Lp(a) levels to these risk factors. A cutoff value of 30 mg/dl was used for Lp(a). Risk ratios were calculated using the group with low Lp(a) levels and the first tertile of lipid measures as a reference. Results. Lp(a) was not an independent risk factor for IHD but seemed to increase the deleterious effects of mildly elevated LDL cholesterol and elevated total cholesterol and apoprotein B levels and seemed to counteract the beneficial effects associated with elevated HDL cholesterol levels. Conclusions. In this cohort, Lp(a) was not an independent risk factor for IHD but appeared to increase the risk associated with other lipid risk factors.