The EUROPA trial: design, baseline demography and status of the substudies

BACKGROUND: Angiotensin-converting enzyme inhibitors do reduce both mortality and morbidity in patients with left ventricular dysfunction, recent myocardial infarction and hypertension. However, the long-term effects in patients with coronary artery disease have not been established. The EUROPA study is designed to assess the long-term (3-4 years) effects of perindopril on the reduction of cardiac events in patients with proven stable coronary artery disease but with no evidence of heart failure. STUDY DESIGN AND METHODS: EUROPA is a 12236 patient, randomised, double-blind, placebo-controlled and multicentre trial. EUROPA had an initial run-in period of 4 weeks during which patients received 4 and then 8 mg of perindopril daily to assess tolerance to maximum dose. This was followed by a double-blind randomisation to either perindopril or placebo. Patients were followed-up at 3 and 6 months and then 6 monthly until the last patient included in the main study completes the 3-year follow-up. EUROPA includes five sub-studies. Each of these sub-studies investigates the effects of perindopril on a different aspect of coronary artery disease: endothelial dysfunction, atherosclerosis progression regression, diabetes mellitus, inflammation, thrombosis, neurohormonal activation. Patients are characterised genetically to assess characteristics associated with improved or unfavourable outcome. The final results of EUROPA will be available in 2002

Effects of perindopril on long-term clinical outcome of patients with coronary artery disease and preserved left ventricular function

BACKGROUND: The EUROPA trial has demonstrated that an ACE inhibitor perindopril, was able to significantly decrease the risk of major cardiac events in patients with stable coronary heart disease without apparent heart failure. AIM: To assess the long-term clinical outcome of patients with stable coronary heart disease and preserved left ventricular function (left ventricular ejection fraction (LVEF> or =40%). METHODS: A retrospective evaluation of LVEF was performed in the EUROPA study population. Among the 12,218 patients of EUROPA, we identified 7096 (58%) patients who had LVEF measurement before randomization. The measurements were obtained mainly by echocardiography in 5214 cases (73%) or by angiography in 1470 cases (21%). Two groups of patients were studied: 6878 (97 %) patients with LVEF> or =40% (3429 received 8 mg of perindopril and 3449 received a placebo) and 218 patients (3%) with a LVEF or =40%), there was a significant relative risk reduction of 16% of the primary endpoint (a composite of cardiovascular death, non-fatal myocardial infarction and resuscitated cardiac arrest) in the group treated with perindopril (8.3%) in comparison to the group treated with placebo (9.8%): Hazard ratio (HR)=0.84 [95% CI: 0.72-0.99] p=0.033). Similar results were obtained for the first secondary endpoint (total mortality, non-fatal myocardial infarction, hospital admission for unstable angina and cardiac arrest with successful resuscitation): HR=0.85 [95% CI: 0.76-0.96] p=0.008, for cardiovascular mortality and non-fatal MI: HR=0.84 [95% CI: 0.72-0.99] p=0.036. Similar benefits were observed in patients with an LVEF> or =40% and a history of previous myocardial infarction and in patients with an LVEF<40%. CONCLUSIONS: LVEF was documented in 58% of the EUROPA study population and only 3% had an impaired LV function, confirming that EUROPA patients did not have asymptomatic LV dysfunction. Results in patients with preserved LV function are consistent with those of the whole EUROPA study population and perindopril 8 mg is beneficial in the broad spectrum of patients with stable coronary artery disease without evidence of heart failure

Logistics and quality control for DNA sampling in large multicenter studies

To study associations between genetic variation and disease, large bio-banks need to be created in multicenter studies. Therefore, we studied the effects of storage time and temperature on DNA quality and quantity in a simulation experiment with storage up to 28 days frozen, at 4 degrees C and at room temperature. In the simulation experiment, the conditions did not influence the amount or quality of DNA to an unsatisfactory level. However, the amount of extracted DNA was decreased in frozen samples and in samples that were stored for > 7 days at room temperature. In a sample of patients from 24 countries of the EUROPA trial obtained by mail with transport times up to 1 month DNA yield and quality were adequate. From these results we conclude that transport of non-frozen blood by ordinary mail is usable and practical for DNA isolation for polymerase chain reaction in clinical and epidemiological studies

Efficacy of perindopril in reducing risk of cardiac events in patients with revascularized coronary artery disease

BACKGROUND: The aim of the study was to assess the effect on cardiac events of adding perindopril 8 mg once daily to standard preventive therapy in the subgroup of EUROPA patients with previous revascularization and without previous myocardial infarction (MI). METHODS: We conducted a subgroup analysis of the EUROPA study patients according to their revascularization and previous MI history. Among the 12,218 patients of EUROPA, we identified 6709 (54.9%) patients who had a previous revascularization. Approximately equal proportions had undergone percutaneous coronary intervention (3122) or coronary artery bypass grafting (3136). Of the revascularized patients, 3047 (24.9%) patients had not experienced a previous MI. RESULTS: Out of the 6709 revascularized patients, 3340 were treated with perindopril and 3369 with placebo. Baseline characteristics were similar to the whole EUROPA population in terms of demographics, medical history, physical examination (heart rate, blood pressure), and medications at screening. The mean patient age was 60 years, and 85% were men. The relative risk reduction with perindopril 8 mg was 17.3% (95% CI 1.3%-30.8%, P = .035) for the composite primary end point of cardiovascular death, nonfatal MI, and resuscitated cardiac arrest and was 23% (95% CI 4.9%-37.6%, P = .015) for fatal and nonfatal MI. In the 3047 revascularized patients without a history of MI, perindopril was associated with a relative risk reduction of 31.7% for fatal and nonfatal MI (95% CI 4.4%-51.2%, P = .026). CONCLUSION: Perindopril 8 mg daily is beneficial for primary and secondary prevention of cardiac events in patients with coronary artery disease without clinical evidence of heart failure including those with previous revascularization

The effect of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: results from the PERSUADE substudy

AIMS: The aim of this study was to assess the effect of the angiotensin converting enzyme inhibitor perindopril on cardiovascular events in diabetic patients with coronary artery disease. METHODS AND RESULTS: A total of 1502 diabetic patients with known coronary artery disease and without heart failure of 12 218 overall in the EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery (EUROPA) disease were randomized in a double-blinded manner to perindopril 8 mg once daily or placebo. Follow-up was for a median of 4.3 years. The primary end point was cardiovascular death, non-fatal myocardial infarction, and resuscitated cardiac arrest. Perindopril treatment was associated with a non-significant reduction in the primary endpoint in the diabetic population, 12.6 vs. 15.5%, relative risk reduction 19% [(95% CI, -7 to 38%), P=0.13]. This was of similar relative magnitude to the 20% risk reduction observed in the main EUROPA population. CONCLUSION: Perindopril tends to reduce major cardiovascular events in diabetic patients with coronary disease in addition to other preventive treatments and the trend towards reduction was of a similar relative magnitude to that observed the general population with coronary artery disease

Adverse prognosis associated with the metabolic syndrome in established coronary artery disease: data from the EUROPA trial

OBJECTIVE: To assess the prevalence of metabolic syndrome, and its effect on cardiovascular morbidity and mortality in patients with established coronary disease and to explore the inter-relationships between metabolic syndrome, diabetes, obesity and cardiovascular risk. METHODS: The presence of metabolic syndrome was determined in 8397 patients with stable coronary disease from the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease, with mean follow-up of 4.2 years. Metabolic syndrome was defined using a modified version of the National Cholesterol Education Programme criteria. RESULTS: Metabolic syndrome was present in 1964/8397 (23.4%) of the population and significantly predicted outcome; relative risk (RR) of cardiovascular mortality = 1.82 (95% CI 1.40 to 2.39); and fatal and non-fatal myocardial infarction RR = 1.50 (95% CI 1.24 to 1.80). The association with adverse outcomes remained significant after adjustment, RR of cardiovascular mortality after adjustment for conventional risks and diabetes = 1.39 (95% CI 1.03 to 1.86). In comparison with normal weight subjects without diabetes or metabolic syndrome, normal weight dysmetabolic subjects (with either diabetes or metabolic syndrome) were at substantially increased risk of cardiovascular death (RR = 4.05 (95% CI 2.38 to 6.89)). The relative risks of cardiovascular death for overweight and obese patients with dysmetabolic status were nominally lower (RR = 3.01 (95% CI 1.94 to 4.69) and RR = 2.35 (95% CI 1.50 to 3.68), respectively). CONCLUSIONS: Metabolic syndrome is associated with adverse cardiovascular outcome, independently of its associations with diabetes and obesity. A metabolic profile should form part of the risk assessment in all patients with coronary disease, not just those who are obese

The cardioprotective effects of the angiotensin-converting enzyme inhibitor perindopril in patients with stable coronary artery disease are not modified by mild to moderate renal insufficiency: insights from the EUROPA trial

OBJECTIVES: This study sought to examine whether the cardioprotective effects of angiotensin-converting enzyme (ACE) inhibitor therapy by perindopril are modified by renal function in patients with stable coronary artery disease. BACKGROUND: A recent study reported that an impaired renal function identified a subgroup of patients with stable coronary artery disease more likely to benefit from ACE inhibition therapy. In light of the growing interest in tailored therapy for targeting medications to specific subgroups, remarks on the consistency of the treatment effect by ACE inhibitors are highly important. METHODS: The present study involved 12,056 patients with stable coronary artery disease without heart failure randomized to perindopril or placebo. Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease equation. Cox regression analysis was used to estimate multivariable-adjusted hazard ratios. RESULTS: The mean eGFR was 76.2 (+/-18.1) ml/min/1.73 m2. During follow-up, the primary end point (cardiovascular death, nonfatal myocardial infarction, or resuscitated cardiac arrest) occurred in 454 of 5,761 patients (7.9%) with eGFR > or =75 and in 631 of 6,295 patients (10.0%) with eGFR or =75 (hazard ratio 0.77; 95% confidence interval 0.64 to 0.93) or eGFR <75 (hazard ratio 0.84; 95% confidence interval 0.72 to 0.98). We observed no significant interaction between renal function and treatment benefit (p = 0.47). Using different cutoff points of eGFR at the level of 60 or 90 resulted in similar trends. CONCLUSIONS: The treatment benefit of perindopril is consistent and not modified by mild to moderate renal insufficiency

Genetic determinants of treatment benefit of the angiotensin-converting enzyme-inhibitor perindopril in patients with stable coronary artery disease

Aims The efficacy of angiotensin-converting enzyme (ACE)-inhibitors in stable coronary artery disease (CAD) may be increased by targeting the therapy to those patients most likely to benefit. However, these patients cannot be identified by clinical characteristics. We developed a genetic profile to predict the treatment benefit of ACE-inhibitors exist and to optimize therapy with ACE-inhibitors. Methods and resultsIn 8907 stable CAD patients participating in the randomized placebo-controlled EUROPA-trial, we analysed 12 candidate genes within the pharmacodynamic pathway of ACE-inhibitors, using 52 haplotype-tagging-single nucleotide polymorphisms (SNPs). The primary outcome was the reduction in cardiovascular mortality, non-fatal myocardial infarction, and resuscitated cardiac arrest during 4.2 years of follow-up. Multivariate Cox regression was performed with multiple testing corrections using permutation analysis. Three polymorphisms, located in the angiotensin-II type I receptor and bradykinin type I receptor genes, were significantly associated with the treatment benefit of perindopril after multivariate adjustment for confounders and correction for multiple testing. A pharmacogenetic score, combining these three SNPs, demonstrated a stepwise reduction of risk in the placebo group and a stepwise decrease in treatment benefit of perindopril with an increasing scores (interaction P < 0.0001). A pronounced treatment benefit was observed in a subgroup of 73.5 of the patients [hazard ratio (HR) 0.67; 95 confidence interval (CI) 0.56-0.79], whereas no benefit was apparent in the remaining 26.5 (HR 1.26; 95 CI 0.97-1.67) with a trend towards a harmful effe

Cost effectiveness of perindopril in reducing cardiovascular events in patients with stable coronary artery disease using data from the EUROPA study

BACKGROUND: The EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) trial has recently reported. OBJECTIVE: To assess the cost effectiveness of perindopril in stable coronary heart disease in the UK. METHODS: Clinical and resource use data were taken from the EUROPA trial. Costs included drugs and hospitalisations. Health-related quality of life values were taken from published sources. A cost-effectiveness analysis is presented as a function of the risk of a primary event (non-fatal myocardial infarction, cardiac arrest or cardiovascular death) in order to identify people for whom treatment offers greatest value for money. RESULTS: The median incremental cost of perindopril for each quality-adjusted life year (QALY) gained across the heterogeneous population of EUROPA was estimated as 9700 pounds(interquartile range 6400-14,200 pounds). Overall, 88% of the EUROPA population had an estimated cost per QALY below 20,000 pounds and 97% below 30,000 pounds. For a threshold value of cost effectiveness of 30,000 pounds per QALY gained, treatment of people representing the 25th, 50th (median) and 75th centiles of the cost effectiveness distribution for perindopril has a probability of 0.999, 0.99 and 0.93 of being cost effective, respectively. Cost effectiveness was strongly related to higher risk of a primary event under standard care. CONCLUSIONS: Whether the use of perindopril can be considered cost effective depends on the threshold value of cost effectiveness of healthcare systems. For the large majority of patients included in EUROPA, the incremental cost per QALY gained was lower than the apparent threshold used by the National Institute for Health and Clinical Excellence in the UK