BACKGROUND: Epidemiological studies suggest that mild to moderate elevation in plasma homocysteine concentration is associated with increased risk of atherothrombotic cardiovascular (CV) disease. Simple, inexpensive and nontoxic therapy with folic acid and vitamins B-6 and B-12 reduces plasma homocysteine levels by approximately 25% to 30% and may reduce CV events. Therefore, a large, randomized clinical trial - the Heart Outcomes Prevention Evaluation (HOPE)-2 study - is being conducted to evaluate this therapy in patients at high risk for CV events.OBJECTIVES: To evaluate whether long-term therapy with folic acid and vitamins B-6 and B-12 reduces the risk of major CV events in a high-risk population. The primary study outcome is the composite of death from CV causes, myocardial infarction and stroke.METHODS: A total of 5522 patients aged 55 years or older with preexisting CV disease or with diabetes and additional risk factor(s) at 145 centres in 13 countries were randomly assigned to daily therapy with combined folic acid 2.5 mg, vitamin B-6 50 mg and vitamin B-12 1 mg, or to placebo. Follow-up will average five years, to be completed by the end of 2005.RESULTS: The patients' baseline characteristics confirmed their high-risk status. Baseline homocysteine levels varied between countries and regions. HOPE-2 is one of the largest trials of folate and vitamins B-6 and B-12 and is expected to significantly contribute to the evaluation of the role of homocysteine lowering in CV prevention.

Aims The aim of this study was to assess the prognostic importance of peripheral arterial disease (PAD) as evaluated by ankle blood pressure index (ABI), and the impact of ramipril on the prevention of major cardiovascular events in PAD patients included in the Heart Outcomes Prevention Evaluation (HOPE) study. Methods and results Patients were randomized to treatment with ramipril or placebo and followed for 4.5 years. Ankle brachial blood pressure index was measured, mainly by digital palpation of the foot pulse, at baseline in 8986 patients. The ABI was subnormal (≤0.9) in 3099 patients and normal in 5887 patients. A low ABI was a strong predictor of morbidity and mortality during the follow-up even in patients with no clinical symptoms of PAD ( n =6769). This was so for the primary outcome of the study; ABI>0.9:13.1%, 0.6 – 0.9: 18.2% and <0.6: 18.0% ( P <0.0001) and for mortality from all causes: in those with a normal ABI it was 8.5%, in those with ABI >0.6 – 0.9, 12.4% and 14.2% in those with an ABI lower than 0.6 ( P <0.0001). Ramipril reduced the risk of clinical outcomes in those with a clinical history of PAD as well as in the patients with subclinical PAD. if measured simply by palpation of the foot arteries is a strong predictor for future cardiovascular events and for all-cause mortality. Ramipril prevented major cardiovascular events in patients with clinical as well as subclinical PAD.©2003 Published by Elsevier Ltd on behalf of The European Society of Cardiology.

Background Diabetes mellitus is a strong risk factor for cardiovascular and renal disease. We investigated whether the angiotensin-converting-enzyme (ACE) inhibitor ramipril can lower these risks in patients with diabetes.Methods 3577 people with diabetes included in the Heart Outcomes Prevention Evaluation study, aged 55 years or older, who had a previous cardiovascular event or at least one other cardiovascular risk factor, no clinical proteinuria, heart failure, or low ejection fraction, and who were not taking ACE inhibitors, were randomly assigned ramipril (10 mg/day) or placebo, and Vitamin E or placebo, according to a two-by-two factorial design. The combined primary outcome was myocardial infarction, stroke, or cardiovascular death. Overt nephropathy was a main outcome in a substudy.Findings The study was stopped 6 months early (after 4.5 years) by the independent data safety and monitoring board because of a consistent benefit of ramipril compared with placebo. Ramipril lowered the risk of the combined primary outcome by 25% (95% CI 12-36, p=0.0004), myocardial infarction by 22% (6-36), stroke by 33% (10-50), cardiovascular death by 37% (21-51), total mortality by 24% (8-37), revascularisation by 17% (2-30), and overt nephropathy by 24% (3-40, p=0.027). After adjustment for the changes in systolic (2.4 mm Hg) and diastolic (1.0 mm Hg) brood pressures, ramipril stilt lowered the risk of the combined primary outcome by 25% (12-36, p=0.0004).Interpretation Ramipril was beneficial for cardiovascular events and overt nephropathy in people with diabetes. The cardiovascular benefit was greater than that attributable to the decrease in blood pressure. This treatment represents a vasculoprotective and renoprotective effect for people with diabetes.

Background. Metoprolol can improve haemodynamics in chronic heart failure, but survival benefit has, not been proven. We investigated whether metoprolol controlled release/extended release (CR/XL) once daily, in addition to standard therapy, would lower mortality in patients with decreased ejection fraction and symptoms of heart failure.Methods. We enrolled 3991 patients with chronic heart failure in New York Heart Association (NYHA) functional class II-IV and with ejection fraction of 0.40 or less, stabilised with optimum standard therapy, in a double-blind randomised controlled study. Randomisation was preceded by a 2-week single-blind placebo run-in period. 1990 patients were randomly assigned metoprolol CR/XL 12.5 mg (NYHA III-IV) or 25.0 mg once daily (NYHA II) and 2001 were assigned placebo. The target dose was 200 mg once daily and doses were up-titrated over 8 weeks. Our primary endpoint was all-cause mortality, analysed by intention to treat.Findings. The study was stopped early on the recommendation of the independent safety committee. Mean follow-up time was 1 year. All-cause mortality was lower in the metoprolol CR/XL group than in the placebo group (145 [7.2%, per patient-year of follow-up]) vs 217 deaths [11.0%], relative risk 0.66 [95% Cl 0.53-0.81]; p = 0.00009 or adjusted for interim analyses p = 0.0062). There were fewer sudden deaths in the metoprolol CR/XL group than in the placebo group (79 vs 132, 0.59 [0.45-0.78]; p = 0.0002) and deaths from worsening heart failure (30 vs 58, 0.51 [0.33-0.79]; p = 0.0023).Interpretation. Metoprolol CR/XL once daily in addition to optimum standard therapy improved survival. The drug was well tolerated.

BACKGROUND:Left ventricular ejection fraction (EF) is a valuable prognostic index in patients with congestive heart failure (CHF). Although EF can be readily measured, many clinicians use roentgenographic heart size as a clue to differentiate systolic from diastolic dysfunction, even in the absence of solid supportive data.OBJECTIVE:To test the hypothesis that the cardiothoracic ratio (CTR) measured from the chest roentgenogram can be used to estimate left ventricular EF in individuals with CHF.METHODS:To answer this question, the database of the Digitalis Investigation Group trial was used. The CTR, determined using the Danzer method, and quantitative EF, measured locally using angiographic, radionuclide, or 2-dimensional echocardiographic techniques, were compared in 7476 patients with clinical CHF (New York Heart Association functional classes I-IV) due to acquired left-sided cardiac disease of ischemic, hypertensive, idiopathic, and alcohol-related causes.RESULTS:Mean (+/-SD) CTR for the cohort was 0.53+/-.07. Mean (+/-SD) EF was 31.7%+/-12.2%. A weak, negative correlation between CTR and EF was observed (r=-0.176). Similar findings were obtained when the results were stratified by cause of CHF, presence of clinically defined right ventricular dysfunction, and method of EF measurement. Categorical analysis failed to yield a CTR cutoff point that facilitated useful segregation of individuals with an EF greater than 35% or 35% and below; greater than 40% or 40% and below; and greater than 45% or 45% and below in any patient group.CONCLUSIONS:Although a weak, negative correlation exists between CTR and EF, this relationship does not allow for accurate determination of systolic function in individual patients with CHF. Considering the morbidity and mortality associated with CHF, and the clinical implications of systolic function in this syndrome, direct measurement of EF is recommended.

Background The role of cardiac glycosides in treating patients with chronic heart failure and normal sinus rhythm remains controversial. We studied the effect of digoxin on mortality and hospitalization in a randomized, double-blind clinical trial.Methods In the main trial, patients with left ventricular ejection fractions of 0.45 or less were randomly assigned to digoxin (3397 patients) or placebo (3403 patients) in addition to diuretics and angiotensin-converting-enzyme inhibitors (median dose of digoxin, 0.25 mg per day; average follow-up, 37 months). In an ancillary trial of patients with ejection fractions greater than 0.45, 492 patients were randomly assigned to digoxin and 496 to placebo.Results In the main trial, mortality was unaffected. There were 1181 deaths (34.8 percent) with digoxin and 1194 deaths (35.1 percent) with placebo (risk ratio when digoxin was compared with placebo, 0.99; 95 percent confidence interval, 0.91 to 1.07; P = 0.80). In the digoxin group, there was a trend toward a decrease in the risk of death attributed to worsening heart failure (risk ratio, 0.88; 95 percent confidence interval, 0.77 to 1.01; P = 0.06). There were 6 percent fewer hospitalizations overall in that group than in the placebo group, and fewer patients were hospitalized for worsening heart failure (26.8 percent vs. 34.7 percent; risk ratio, 0.72; 95 percent confidence interval, 0.66 to 0.79; P < 0.001). In the ancillary trial, the findings regarding the primary combined outcome of death or hospitalization due to worsening heart failure were consistent with the results of the main trial.Conclusions Digoxin did not reduce overall mortality, but it reduced the rate of hospitalization both overall and for worsening heart failure. These findings define more precisely the role of digoxin in the management of chronic heart failure. (C) 1997, Massachusetts Medical Society.

This article provides a detailed overview of the rationale for key aspects of the protocol of the Digitalis Investigation Group (DIG) trial. It also highlights unusual aspects of the study implementation and the baseline characteristics. The DIG trial is a large, simple, international placebo-controlled trial whose primary objective is to determine the effect of digoxin on all cause mortality in patients with clinical heart failure who are in sinus rhythm and whose ejection fraction is less than or equal to 0.45. An ancillary study examines the effect in those with an ejection fraction > 0.45. Key aspects of the trial include the simplicity of the design, broad eligibility criteria, essential data collection, and inclusion of various types of centers. A total of 302 centers in the United States and Canada enrolled 7788 patients between February 1991 and September 1993. Follow-up continued until December 1995 with the results available in Spring 1996.

OBJECTIVE: To describe the design of the HOPE (Heart Outcomes Prevention Evaluation) Study.DESIGN: Description of the key design features of HOPE, a large, simple randomized trial of two widely applicable treatments - ramipril, an angiotensin-converting enzyme inhibitor; and vitamin E, a naturally occurring antioxidant vitamin - in the prevention of myocardial infarction, stroke or cardiovascular death.SETTING: Two-hundred and sixty-seven hospitals, physician offices and clinics in Canada, the United States, Mexico, Europe and South America.PATIENTS: Over 9000 women and men aged 55 years and above at high risk for cardiovascular events such as myocardial infarction and stroke were recruited over 18 months.INTERVENTIONS: A 2x2 factorial design with ramipril and vitamin E with follow-up for up to four years.CONCLUSIONS: HOPE will be one of the largest trials of two new interventions to prevent myocardial infarction, stroke or cardiovascular death in high risk patients. The results of HOPE will have direct public health impact and are likely to be readily incorporated into clinical practice. Key design features of HOPE are inclusion of individuals at high risk of cardiovascular disease, inclusion of a substantial proportion of patients with diabetes (36%) and women (27%), and detailed substudies to provide data on mechanisms of benefit.