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Background: To quantify the association between effects of interventions on carotid intima-media thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk., Methods: We systematically collated data from randomized, controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were used. The primary outcome was a combined CVD end point defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the 2 using a Bayesian meta-regression approach., Results: We analyzed data of 119 randomized, controlled trials involving 100 667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12 038 patients developed the combined CVD end point. Across all interventions, each 10 μm/y reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% Credible Interval, 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 μm/y would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74), respectively. Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients., Conclusions: The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials.

Background: Individual markers of inflammation may add incremental predictive value in the context of conventionally available risk factors. We evaluated the ability of 9 inflammatory biomarkers, microalbuminuria, and N-terminal pro-brain natriuretic peptide (Nt-proBNP) to improve cardiovascular risk prediction beyond that obtained from traditional risk factors in a secondary-prevention population., Methods and Results: We measured biomarkers representing the acute-phase reaction (C-reactive protein, fibrinogen, and interleukin-6), proinflammatory pathways (soluble tumor necrosis factor receptor-1 and -2, soluble interleukin-1 receptor antagonist, and interleukin-18), endothelial activation (soluble vascular adhesion molecule-1 and soluble intercellular adhesion molecule-1), Nt-proBNP, and microalbuminuria in 3199 study individuals of the Heart Outcomes Prevention Evaluation (HOPE) Study and assessed their association with risk of myocardial infarction, stroke, or cardiovascular death (primary outcome, n=501) over 4.5 years of follow-up. In a backward Cox regression procedure that included risk factors and biomarkers, Nt-proBNP (hazard ratio [HR] 1.72 per increment SD, 95% CI 1.39 to 2.12; P<0.0001), soluble intercellular adhesion molecule-1 (HR 1.46, 95% CI 1.19 to 1.80; P=0.0003), microalbuminuria (HR 1.55, 95% CI 1.22 to 1.98; P=0.0004), soluble interleukin-1 receptor antagonist (HR 1.30, 95% CI 1.05 to 1.61; P=0.02), and fibrinogen (HR 1.31, 95% CI 1.05 to 1.62; P=0.02) remained significantly related to the primary outcome. Only inclusion of Nt-proBNP provided incremental information above that obtained by models of traditional risk factors., Conclusions: Although levels of various inflammatory biomarkers are significantly related to future cardiovascular risk, their incremental predictive value is modest. A model consisting of simple traditional risk factors and Nt-proBNP provided the best clinical prediction in the secondary-prevention population.

Background: We have previously demonstrated that ramipril reduces vascular events and new diagnoses of diabetes when given for a 4.5-year period. However, it is not known whether the benefits are observed in subgroups of patients at varying risk or on other proven therapies and whether the benefits are sustained beyond the current trial. The 2 aims of this investigation were to assess whether the benefits observed during the HOPE trial were (1) maintained after trial cessation during an additional 2.6 years of follow-up and (2) observed in subgroups based on risk and ancillary treatments., Methods and Results: Of the initial 267 study centers and 9297 patients, 174 centers and 4528 patients agreed to further follow-up. The rates of use of angiotensin-converting-enzyme inhibitors (ACEIs) in the 2 groups (72% ramipril versus 68% placebo) were similar after the end of the trial. During the posttrial follow-up, patients allocated to ramipril had a 19% further lower relative risk (RR) of myocardial infarction (95% confidence interval [CI], 0.65 to 1.01), a 16% lower RR (95% CI, 0.70 to 0.99) of revascularization, and a 34% lower RR of a new diagnosis of diabetes (95% CI, 0.46 to 0.95). Similar RR reductions in vascular events were observed during and after the active phase of the trial, regardless of baseline risk (RR of 0.76, 0.89, and 0.83 for low-, medium-, and high-risk patients, respectively) or ancillary treatments (RR of 0.90 for aspirin, 0.76 for beta-blockers, and 0.84 for lipid-lowering medication)., Conclusions: The benefits of ramipril observed during the active period of the HOPE trial were maintained during posttrial follow-up for cardiovascular death, stroke, and hospitalization for heart failure. Additional reductions in myocardial infarction, revascularization, and the development of diabetes were observed during the follow-up phase despite similar rates of ACEI use in the 2 randomized groups. These benefits were consistent regardless of patient risk or ancillary treatments.

Background: The clustering of impaired glucose metabolism, elevated triglycerides, low HDL cholesterol, and abdominal obesity is known as the metabolic syndrome. Individuals with this syndrome suffer an excess of cardiovascular disease (CVD) for reasons that are unclear., Methods and Results: We randomly sampled 1276 adults of South Asian, Chinese, European, and Native Indian ancestry from 4 communities in Canada. Participants provided fasting blood samples for glucose, lipids, and fibrinolytic measurements; had an oral glucose tolerance test; and underwent a B-mode carotid ultrasound examination. CVD was determined by history and ECG. The prevalence of the metabolic syndrome was 25.8% (95% CI, 23.5 to 28.2) and varied substantially by ethnic group: 41.6% among Native Indians, 25.9% among South Asians, and 22.0% among Europeans, compared with 11.0% among the Chinese (overall, P=0.0001). People with the metabolic syndrome had more atherosclerosis (maximum intimal medial thickness, 0.78+/-0.18 versus 0.74+/-0.18 mm; P=0.0005), CVD (17.2% versus 7.0%; P=0.0001), and elevated plasminogen activator inhibitor-1 (24.2 versus 14.6 U/mL; P=0.001) compared with levels among people without the metabolic syndrome. For the same amount of atherosclerosis, people with the metabolic syndrome had a greater prevalence of CVD, even among nondiabetic individuals. This difference in CVD prevalence among the groups was attenuated after adjustment for plasminogen activator inhibitor-1 levels, suggesting that fibrinolytic dysfunction mediates the increased risk of CVD in individuals with the metabolic syndrome., Conclusions: CVD among people with the metabolic syndrome is explained by their excess of atherosclerosis and impaired fibrinolysis. Interventions to prevent atherosclerosis progression and improve fibrinolytic function require evaluation in this high-risk group.

Background: Previous trials in the prevention of heart failure have been restricted to patients with low ejection fraction or hypertension. We assessed an angiotensin-converting enzyme (ACE) inhibitor, ramipril, to prevent the development of heart failure in high-risk patients without known low ejection fraction or heart failure., Methods and Results: We randomly assigned 9297 patients to receive double-blind ramipril (10 mg daily) or matching placebo for 4.5 years. Death attributable to heart failure, hospitalization for heart failure, initiation of open-label ACE inhibitor for heart failure, or development of typical signs or symptoms of heart failure developed in 951 patients and was associated with a 4.01-fold increase in the risk of death (P<0.0001). The rate of developing heart failure was significantly increased with coronary disease (risk ratio, 2.17), microalbuminuria (1.82), left ventricular hypertrophy (1.47), increasing age (by decade, 1.37), and diabetes (1.36). Ramipril reduced new-onset heart failure rate from 11.5% to 9.0% (relative risk, 0.77; 95% CI, 0.68 to 0.87; P<0.0001). Ramipril consistently reduced heart failure rate both in those with (relative risk, 0.87) and those without an interim myocardial infarction (relative risk, 0.78). Ramipril also reduced the heart failure rate more in patients with baseline systolic pressure above the median (139 mm Hg) (relative risk, 0.67) compared with those below the median (relative risk, 0.91; P=0.024 for interaction of group by treatment)., Conclusion: Ramipril significantly reduces the rate of development of heart failure in patients at high risk of cardiovascular events.

Background: Limited prospective epidemiological data are available on the relation between exposure to Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus (CMV), and hepatitis A virus (HAV), individually or as a total pathogen score, and human cardiovascular (CV) disease., Methods and Results: We analyzed enrollment sera from 3168 Canadian patients in the Heart Outcomes Prevention Evaluation (HOPE) study for antibodies to C pneumoniae, H pylori, CMV, and HAV and measured the relation between serostatus and 494 adjudicated trial outcomes of myocardial infarction, stroke, or CV death over 4.5 years of follow-up. CV events were associated with CMV serostatus (covariate-adjusted hazard ratio [HR], 1.24; 95% CI, 1.01, 1.53). Neither C pneumoniae IgG (adjusted HR, 0.87; 95% CI, 0.68, 1.10), C pneumonia IgA (adjusted HR, 1.10; 95% CI, 0.90, 1.34), H pylori IgG (HR, 0.99; 95% CI, 0.82, 1.19), nor HAV IgG (HR, 1.01; 95% CI, 0.83, 1.24) predicted CV events. Total pathogen score was associated with CV events (adjusted HR for 4 versus 1 or 0=1.41; 95% CI, 1.02, 1.96)., Conclusions: Exposure to CMV but not to C pneumoniae, H pylori, or HAV was associated with a slight excess risk of subsequent myocardial infarction, stroke, or CV death in HOPE study patients, and total pathogen score based on these infections predicted a small increased hazard of CV events.

Background: Electrocardiographic markers of left ventricular hypertrophy (LVH) predict poor prognosis. We determined whether the ACE inhibitor ramipril prevents the development and causes regression of ECG-LVH and whether these changes are associated with improved prognosis independent of blood pressure reduction., Methods and Results: In the Heart Outcomes Prevention Evaluation (HOPE) study, patients at high risk were randomly assigned to ramipril or placebo and followed for 4.5years. ECGs were recorded at baseline and at study end. We compared prevention/regression and development/persistence of ECG-LVH in the two groups and related these changes to outcomes. At baseline, 676 patients had LVH (321 in the ramipril group and 355 in the placebo group) and 7605 patients did not have LVH (3814 in the ramipril group and 3791 in the placebo group). By study end, 336 patients in the ramipril group (8.1%) compared with 406 in the placebo group (9.8%) had development/persistence of LVH; in contrast, 3799 patients in the ramipril group (91.9%) compared with 3740 in the placebo group (90.2%) had regression/prevention of LVH (P=0.007). The effect of ramipril on LVH was independent of blood pressure changes. Patients who had regression/prevention of LVH had a lower risk of the predefined primary outcome (cardiovascular death, myocardial infarction, or stroke) compared with those who had development/persistence of LVH (12.3% versus 15.8%, P=0.006) and of congestive heart failure (9.3% versus 15.4%, P<0.0001)., Conclusions: The ACE inhibitor ramipril decreases the development and causes regression of ECG-LVH independent of blood pressure reduction, and these changes are associated with reduced risk of death, myocardial infarction, stroke, and congestive heart failure.

Background: Activation of the renin-angiotensin-aldosterone system and oxidative modification of LDL cholesterol play important roles in atherosclerosis. The Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E (SECURE), a substudy of the Heart Outcomes Prevention Evaluation (HOPE) trial, was a prospective, double-blind, 3x2 factorial design trial that evaluated the effects of long-term treatment with the angiotensin-converting enzyme inhibitor ramipril and vitamin E on atherosclerosis progression in high-risk patients., Methods and Results: A total of 732 patients >/=55 years of age who had vascular disease or diabetes and at least one other risk factor and who did not have heart failure or a low left ventricular ejection fraction were randomly assigned to receive ramipril 2.5 mg/d or 10 mg/d and vitamin E (RRR-alpha-tocopheryl acetate) 400 IU/d or their matching placebos. Average follow-up was 4.5 years. Atherosclerosis progression was evaluated by B-mode carotid ultrasound. The progression slope of the mean maximum carotid intimal medial thickness was 0.0217 mm/year in the placebo group, 0.0180 mm/year in the ramipril 2.5 mg/d group, and 0.0137 mm/year in the ramipril 10 mg/d group (P=0.033). There were no differences in atherosclerosis progression rates between patients on vitamin E and those on placebo., Conclusions: Long-term treatment with ramipril had a beneficial effect on atherosclerosis progression. Vitamin E had a neutral effect on atherosclerosis progression.