http://repub.eur.nl/res/aut/6745/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/23150/ 2011-03-01T00:00:00Z Aims: To investigate whether genetic variation in the renin-angiotensin- aldosterone system (RAAS) and kallikrein-bradykinin pathways is related to hypertension and blood pressure (BP) response to angiotensin-converting enzyme (ACE) inhibitor therapy in stable coronary artery disease (CAD) patients. Methods and Results: In 8907 stable CAD patients from the EUROPA trial, 52 haplotype-tagging single-nucleotide polymorphisms (SNPs) in 12 candidate genes within the RAAS and kallikrein-bradykinin pathways were investigated for association with hypertension (defined as BP 160/95 mmHg or use of antihypertensives) and BP response to ACE inhibitors, during a 4-week run-in period. All analyses were adjusted for age, sex, body mass index and creatinine clearance and corrected for multiple testing. Results: Hypertension was present in 28.3% of the patients (n = 2526); median BP reduction after perindopril was 10/4 mmHg. Four polymorphisms, located in the ACE (rs4291), angiotensinogen (rs5049) and (pro)renin receptor (rs2968915; rs5981008) genes were significantly associated with hypertension in two vascular disease populations of CAD (EUROPA) and cerebrovascular disease (PROGRESS; n = 3571). A cumulative profile demonstrated a stepwise increase in the prevalence of hypertension, mounting to a 2-3-fold increase (P for trend <0.001). Similar associations on hypertension were observed for angiotensinogen in a healthy population (n = 2197). In addition, genetic polymorphisms were identified that significantly modified the BP reduction by ACE inhibitor therapy; however, the observed BP differences were small and did not remain significant after permutation analysis. Conclusion: This large genetic association study identified genetic determinants of hypertension in three cohorts of patients with vascular disease and healthy individuals. http://repub.eur.nl/res/pub/21072/ 2010-08-01T00:00:00Z 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 effect. In 1051 patients with cerebrovascular disease from the PROGRESS-trial, treated with perindopril or placebo, an interaction effect of similar direction and magnitude, although not statistically significant, was observed. Conclusion The current study is the first to identify genetic determinants of treatment benefit of ACE-inhibitor therapy. We developed a genetic profile which predicts the treatment benefit of ACE-inhibitors and which could be used to optimize therapy. http://repub.eur.nl/res/pub/27597/ 2010-05-01T00:00:00Z Background: The purposes of the study were to determine the effects of addition of perindopril to long-term continuous treatment with calcium-channel blocker (CCB) on cardiac outcomes in the stable coronary artery disease (CAD) population of EUROPA and to explore the presence of synergy between perindopril and CCB in secondary prevention. Methods: We identified participants receiving CCB at every visit during the 4.2-year follow-up and analyzed the effect of addition of perindopril (n = 1,022 perindopril/CCB vs n = 1,100 placebo/CCB). Results: Addition of perindopril to CCB significantly reduced total mortality by 46% (P < .01 vs placebo) and primary end point (a composite of cardiovascular mortality, nonfatal myocardial infarction, and resuscitated cardiac arrest) by 35% (P < .05 vs placebo). There were 41%, 54%, and 28% reductions in cardiovascular mortality, hospitalization for heart failure, and myocardial infarction, respectively. Comparison of hazard ratios suggests the presence of a clinical synergy between perindopril and CCB, with a greater effect than addition of individual effects. Conclusion: Addition of perindopril to CCB in stable CAD patients had a significant supplementary impact on cardiac outcomes and mortality. http://repub.eur.nl/res/pub/24648/ 2009-06-01T00:00:00Z AimsAngiotensin-converting enzyme (ACE) inhibitors have been shown to reduce cardiovascular risk in different groups of patients. Whether these effects can be generalized to the broad group of patients with vascular disease is unknown. Therefore, we undertook a combined analysis using individual data from ADVANCE, EUROPA, and PROGRESS to determine the consistency of the treatment effect of perindopril-based regimen in patients with vascular disease or at high risk of vascular disease.Methods and resultsWe studied all-cause mortality and major cardiovascular outcomes during a follow-up of about 4 years in the 29 463 patients randomly assigned a perindopril-based treatment regimen or placebo. The perindopril-based regimens were associated with a significant reduction in all-cause mortality [hazard ratio (HR) 0.89; 95 confidence interval (CI) 0.82-0.96; P = 0.006], cardiovascular mortality (HR 0.85; 95 CI 0.76-0.95; P = 0.004), non-fatal myocardial infarction (HR 0.80; 95 CI 0.71-0.90; P < 0.001), stroke (HR 0.82; 95 CI 0.74-0.92; P = 0.002), and heart failure (HR 0.84; 95 CI 0.72-0.96; P = 0.015). Results were consistent in subgroups with different clinical characteristics, concomitant medication use, and across all strata of baseline blood pressure.ConclusionThis study provides strong evidence for a consistent cardiovascular protection with an ACE-inhibitor treatment regimen (perindopril-indapamide) by improving survival and reducing the risk of major cardiovascular events across a broad spectrum of patients with vascular disease. http://repub.eur.nl/res/pub/24211/ 2009-04-01T00:00:00Z Aims: We determined whether blood pressure (BP) lowering by perindopril was related to its benefit in the EUROPA study. Methods and results: Twelve thousand two hundred eighteen patients with documented coronary artery disease received perindopril 8 mg once daily or matching placebo after a 4-week run-in period in which all patients received perindopril. Patients were excluded if systolic (S) BP was >180 or <100 mmHg. Mean age was 60 years (range 26-89). 27% had a history of hypertension. After 4.2 years of follow-up, the primary endpoint (cardiovascular death, nonfatal myocardial infarction, or resuscitated cardiac arrest) was observed in 603 (9.9%) placebo versus 488 (8.0%) perindopril patients [20% relative risk reduction (RRR), CI 9-29%, P∈=∈0.003]. There was no interaction between baseline SBP levels (using JNC-7 cutoff values) and treatment effect. If anything, the greatest RRR of the primary endpoint (32%) occurred in patients with the lowest SBP (<120 mmHg) in whom perindopril did not reduce SBP. Also, RRR during blinded treatment was comparable, irrespective of whether BP decreased or not or of the extent of BP reduction during perindopril treatment. Conclusion: The treatment benefit in EUROPA cannot be fully explained by baseline BP or BP reduction with perindopril. Other mechanisms including direct anti-atherosclerotic effects of ACE inhibition may play a role. http://repub.eur.nl/res/pub/24212/ 2009-04-01T00:00:00Z Background: Angiotensin-converting enzyme (ACE) inhibitors reduce clinical symptoms and improve outcome in patients with hypertension, heart failure, and stable coronary artery disease (CAD) and are among the most frequently used drugs in these patient groups. For hypertension, treatment is guided by the level of blood pressure. In the secondary prevention setting, there are no means of guiding therapy. Prior attempts to target ACE-inhibitors to those patients that are most likely to benefit have not been successful, mainly due to the consistency in the treatment effect in clinical subgroups. Still, for prolonged prophylactic treatment with ACE-inhibitors it would be best to target treatment to only those patients most likely to benefit, which would considerably lower the number needed to treat and increase cost-effectiveness. A new approach for such "tailored-therapy" may be to integrate information on the genetic variation between patients. Until now, pharmacogenetic research of the efficacy of ACE-inhibitor therapy in CAD patients is still in a preliminary stage. Methods: The PERindopril GENEtic association study (PERGENE) is a substudy of the EUROPA trial, a randomized double-blind placebo-controlled multicentre clinical trial which demonstrated a beneficial effect of the ACE-inhibitor perindopril in reducing cardiovascular morbidity and mortality in 12.218 patients with stable coronary artery disease (mean follow-up 4.2 years). Blood tubes were received from patients at the beginning of the EUROPA trial and buffy coats were stored at -40°C at the central core laboratory. Candidate genes were selected in the renin-angiotensin-system and bradykinin pathways. Polymorphisms were selected based on haplotype tagging principles using the HapMap genome project, Seattle and other up-to-date genetic database platforms to comprehensively cover all common genetic variation within the genes. Selection also took into consideration the functionality of SNP's, location within the gene (promoter) and existing relevant literature. The main outcome measure of PERGENE is the effect of genetic factors on the treatment benefit with ACE-inhibitors. The size of this pharmacogenetic substudy allows detection with a statistical power of 98% to detect a difference in hazard ratios (treatment effect) of 20% between genotypes with minor allele frequency of 0.20 (two-sided alpha 0.05). Conclusion: The PERGENE study is a large cardiovascular pharmacogenetic study aimed to assess the feasibility of pharmacogenetic profiling of the treatment effect of ACE-inhibitor use with the perspective to individualize treatment in patients with stable coronary artery disease. http://repub.eur.nl/res/pub/25406/ 2009-04-01T00:00:00Z The angiotensin-converting enzyme (ACE) inhibitor perindopril (Coversyl®) is a long-acting lipophilic drug with a high-tissue affinity for the ACE. ACE inhibition by perindopril has two main effects: it inhibits the angiotensin II formation and potentiates bradykinin. Perindopril is one of the ACE inhibitors that has been extensively studied in randomized clinical trials within various patient populations. The clinical efficacy has been demonstrated in patients with hypertension, diabetes mellitus, cerebrovascular disease, stable coronary artery disease (CAD) and heart failure. Perindopril has a positive safety and tolerability profile. Therefore, perindopril, as an ACE inhibitor, has an established place in the major clinical treatment guidelines. This article discusses several studies that have shown that an antihypertensive treatment with perindopril reduces and prevents cardiovascular events in a large range of patients with established vascular disease. The observed cardioprotective benefits of perindopril were independent of blood pressure. The outcome of these and other trials support the concept of specific cardioprotective properties of ACE inhibition by perindopril in addition to the blood pressure-lowering effects, such as anti-atherosclerotic, anti-inflammatory and antithrombotic properties. In addition, the observed consistency of the treatment benefit across subgroups indicates that the absolute benefits conferred by treatment are mainly established by each patient's future risk of vascular complications, rather than their initial blood pressure level or other risk factors. This article describes these issues according to the main studies with perindopril or perindopril-based regimens, concluding that the blood pressure-dependent and -independent cardioprotective effects extend to all patients with vascular disease. This concept supports the provision of ACE inhibitor-based treatment, not on the basis of arbitrary cut-off points for blood pressure but rather on assessment of vascular risk, which is raised in patients with stable CAD, diabetes and stroke. http://repub.eur.nl/res/pub/16110/ 2009-02-01T00:00:00Z Background. - The European trial on Reduction Of cardiac events with perindopril in patients with stable coronary Artery disease (EUROPA) demonstrated the benefits of perindopril with respect to secondary prevention of cardiovascular risk in patients with stable coronary artery disease. Aims. - To describe the clinical effects of perindopril in a subpopulation of patients from EUROPA with a history of myocardial infarction and/or revascularization. Patients and methods. - Of the 12,218 patients in the EUROPA study, 10,962 had a history of myocardial infarction and/or revascularization. In this EUROPA subpopulation, 7910 patients had a history of myocardial infarction and 6709 had a history of revascularization. Patients were randomized to treatment with perindopril 8 mg/day or placebo. The primary endpoint was a composite of cardiovascular mortality, myocardial infarction and resuscitated cardiac arrest. Results. - After a mean follow-up of 4.2 years, treatment with perindopril 8 mg/day was associated with a 22.40% reduction in the primary endpoint compared with placebo (p < 0.001) in patients with a history of myocardial infarction. Patients with a history of myocardial revascularization showed a 17.3% reduction in the primary endpoint with perindopril versus placebo (p < 0.05). In the combined population of patients with a history of myocardial infarction and/or revascularization, treatment with perindopril produced a 22.4% reduction in the primary endpoint compared with placebo (p < 0.001). Conclusions. - This study confirms the benefits of a high dose of angiotensin-converting enzyme inhibitor for the secondary prevention of cardiovascular risk among patients with a history of myocardial infarction and/or revascularization. http://repub.eur.nl/res/pub/29532/ 2008-07-01T00:00:00Z PURPOSE OF REVIEW: Several trials demonstrated that angiotensin-converting enzyme inhibitors reduce the incidence of cardiovascular events during long-term follow-up in high-risk and low-risk patients. Clinical treatment guidelines propose that angiotensin-converting enzyme inhibitors should be considered in the routine secondary prevention in the broad group of coronary artery disease patients. This review discusses several approaches to guide angiotensin- converting enzyme-inhibition therapy to more specific groups of patients that are most likely to benefit. RECENT FINDINGS: The beneficial effect of angiotensin-converting enzyme inhibition has been shown to be consistent across subgroups in stable coronary artery disease. Still, large interindividual variability in blood pressure response is well documented. It should also be realized that the absolute treatment effects are modest. The efficiency and cost-effectiveness of this prolonged prophylactic treatment would be significantly enhanced if those patients can be distinguished who benefit most. Recently, it was suggested that markers of an activated renin-angiotensin- aldosterone system might be used to guide angiotensin-converting enzyme-inhibition therapy. SUMMARY: At the start of treatment, clinical characteristics are not sufficient to distinguish between patients who will and will not benefit from angiotensin-converting enzyme inhibitors. Although pharmacogenetic research in coronary artery disease is still in a premature stage, it may be expected to provide a useful tool in optimizing and individualizing the management of angiotensin-converting enzyme-inhibitor therapy in coronary artery disease patients. http://repub.eur.nl/res/pub/14542/ 2008-01-01T00:00:00Z The PERTINENT study measured biomarkers of atherosclerosis and thrombosis in a stable coronary artery disease population from EUROPA receiving ACE inhibition with perindopril 8 mg/day or placebo. Biomarkers of inflammation, C-reactive protein (CRP), fibrinogen, and tumor necrosis factor-alpha (TNF-α), and a biomarker of thrombosis, d-dimer, were measured at baseline and 1 year. CRP was recorded in 1157 patients; fibrinogen, TNF-α, and d-dimer in 291 patients. There was no significant effect of treatment on CRP or fibrinogen. In contrast, there were significant reductions in TNF-α (27.60-25.20 pg/mL; P < 0.05) and d-dimer (0.24-0.18 μg/mL; P < 0.05) with perindopril over 1 year. Survival analysis of the prognostic significance of baseline CRP failed to detect a significant role for the prediction of cardiovascular events over 4 years (lower versus higher tertile: 1.54; 95% confidence interval 0.88-2.68; P = 0.16). In conclusion, in the PERTINENT trial, we observed significant effects of ACE inhibition on biomarkers of the atherothrombotic complications (d-dimer) and the proinflammatory cytokine TNF-α, but not on biomarkers of inflammation associated with atherosclerosis (CRP and fibrinogen). http://repub.eur.nl/res/pub/36160/ 2007-11-27T00:00:00Z 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 ≥75 and in 631 of 6,295 patients (10.0%) with eGFR <75. Treatment benefits of perindopril were apparent in both patient groups either with eGFR ≥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. http://repub.eur.nl/res/pub/36760/ 2007-11-01T00:00:00Z 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. http://repub.eur.nl/res/pub/36858/ 2007-11-01T00:00:00Z The European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) investigated the effect of angiotensin-converting enzyme inhibition on the prevention of cardiac events in patients with stable coronary artery disease (CAD) without apparent heart failure. Perindopril 8 mg/day significantly reduced a composite outcome of cardiovascular death, nonfatal myocardial infarction or resuscitated cardiac arrest by 20% compared with placebo, in addition to standard preventive therapies. This review describes the substudies and subpopulation analyses carried out within the EUROPA population, concluding that the benefits of perindopril extend to all stable CAD patients, even revascularized patients or those with preserved left ventricular function. Data on the pathophysiological mechanisms underlying CAD indicate direct vascular protection with perindopril. This helps explain why perindopril is beneficial in preventing cardiac events in stable CAD patients. http://repub.eur.nl/res/pub/36776/ 2007-09-01T00:00:00Z 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 (interquartile range £6400-£14 200). Overall, 88% of the EUROPA population had an estimated cost per QALY below £20 000 and 97% below £30 000. For a threshold value of cost effectiveness of £30 000 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. http://repub.eur.nl/res/pub/36429/ 2007-08-01T00:00:00Z Background: ACE inhibition results in secondary prevention of coronary artery disease (CAD) through different mechanisms including improvement of endothelial dysfunction. The Perindopril-Function of the Endothelium in Coronary artery disease Trial (PERFECT) evaluated whether long-term administration of perindopril improves endothelial dysfunction. Methods: PERFECT is a 3-year double blind randomised placebo controlled trial to determine the effect of perindopril 8 mg once daily on brachial artery endothelial function in patients with stable CAD without clinical heart failure. Endothelial function in response to ischaemia was assessed using ultrasound. Primary endpoint was difference in flow-mediated vasodilatation (FMD) assessed at 36 months. Results: In 20 centers, 333 patients randomly received perindopril or matching placebo. Ischemia-induced FMD was 2.7% (SD 2.6). In the perindopril group FMD went from 2.6% at baseline to 3.3% at 36 months and in the placebo group from 2.8 to 3.0%. Change in FMD after 36 month treatment was 0.55% (95% confidence interval -0.36, 1.47; p=0.23) higher in perindopril than in placebo group. The rate of change in FMD per 6 months was 0.14% (SE 0.05, p=0.02) in perindopril and 0.02% (SE 0.05, p=0.74) in placebo group (0.12% difference in rate of change p=0.07). Conclusion: Perindopril resulted in a modest, albeit not statistically significant, improvement in FMD. http://repub.eur.nl/res/pub/35311/ 2007-07-15T00:00:00Z The multicenter EUROPA trial of 12,218 patients showed that perindopril decreased adverse clinical events in patients with established coronary heart disease. The PERSPECTIVE study, a substudy of the EUROPA trial, evaluated the effect of perindopril on coronary plaque progression as assessed by quantitative coronary angiography and intravascular ultrasound (IVUS). In total 244 patients (mean age 57 years, 81% men) were included. Evaluable paired quantitative coronary angiograms were obtained from 96 patients randomized to perindopril and from 98 patients to placebo. Concomitant treatment at baseline consisted of aspirin (90%), lipid-lowering agents (70%), and β blockers (60%). The primary and secondary end point was the difference of minimum and mean lumen diameters (quantitative coronary angiography) or mean plaque cross-sectional area (IVUS) measured at baseline and 3-year follow-up between the perindopril and placebo groups. After a median follow-up of 3.0 years (range 1.9 to 4.1), no differences in change in quantitative coronary angiographic or IVUS measurements were detected between the perindopril and placebo groups (minimum and mean luminal diameters -0.07 ± 0.4 vs -0.02 ± 0.4 mm, p = 0.34; mean luminal diameter -0.05 ± 0.2 vs -0.05 ± 0.3 mm, p = 0.89; mean plaque cross-sectional area -0.18 ± 1.2 vs -0.02 ± 1.2 mm2, p = 0.48). In conclusion, we found no progression in coronary artery disease by quantitative coronary angiography and IVUS with long-term administration of perindopril or placebo, possibly because most patients were on concomitant treatment with a statin. http://repub.eur.nl/res/pub/35504/ 2007-04-01T00:00:00Z 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. http://repub.eur.nl/res/pub/35656/ 2007-01-01T00:00:00Z Objectives: EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease [EUROPA] demonstrates reduction in cardiovascular mortality and myocardial infarction for a possible vascular and antiatherosclerotic effect of angiotensin-converting enzyme (ACE) inhibition with perindopril. Our objective was to study the effect of perindopril on endothelial function and to verify its link to risk and occurrence of cardiovascular events. Methods: Blood from 1200 EUROPA patients was withdrawn at baseline and after 1 year of treatment with either perindopril or placebo to measure von Willebrand factor and from 45 healthy subjects and 87 EUROPA patients to study endothelial function at the cellular level by cultivating in vitro human umbilical vein endothelial cells. In this setting, we determined protein expression/activity of endothelial nitric oxide synthase and the rate of apoptosis. Plasma levels of angiotensin II, bradykinin, tumor necrosis factor α, and nitrite/nitrate were also measured. Results: The occurrence of cardiovascular events was related to von Willebrand factor at baseline (P = 0.013) that also significantly decreased after 1 year's treatment (P < 0.001). Perindopril upregulated 19% and 27% protein expression/activity of endothelial nitric oxide synthase (P < 0.05) as well as reduced the rate of apoptosis by 31% (P < 0.05). There was also a significant reduction in levels of angiotensin II, increase in bradykinin, reduction in tumor necrosis factor α, and increase in nitrite/nitrate (P < 0.05 for all). Conclusions: Abnormal endothelial function occurs in patients with coronary artery disease, and this can be counteracted by angiotensin-converting enzyme inhibition with perindopril. These effects could contribute, at least in part, to explaining the results of the main EUROPA Study. http://repub.eur.nl/res/pub/36836/ 2007-01-01T00:00:00Z Background: Patients with coronary artery disease (CAD) and abnormal glucose regulation (AGR) are at high risk for subsequent cardiovascular events, underlining the importance of accurate glucometabolic assessment in clinical practice. Objective: To investigate different methods to identify glucose disturbances among patients with acute and stable coronary heart disease. Methods: Consecutive patients referred to cardiologists were prospectively enrolled at 110 centres in 25 countries (n = 4961). Fasting plasma glucose (FPG) and glycaemia 2 h after a 75-g glucose load were requested in patients without known glucose abnormalities (n = 3362). Glucose metabolism was classified according to the World Health Organization and American Diabetes Association (ADA; 1997, 2004) criteria as normal, impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or diabetes. Results: Data on FPG and 2-n post-load glycaemia were available for 1867 patients, of whom 870 (47%) had normal glucose regulation, 87 (5%) had IFG, 591 (32%) had IGT and 319 (17%) had diabetes. If classification had been based on the ADA criterion from 1997, the proportion of misclassified (underdiagnosed) patients would have been 39%. The ADA 2004 criterion would have overdiagnosed 8% and underdiagnosed 33% of the patients, resulting in a total misclassification rate of 41%. For ethical concerns and practical reasons, oral glucose tolerance test (OGTT) was not conducted in 1495 of eligible patients. These patients were more often women, had higher age and waist circumference, and were therefore more likely to have AGR than those who were included. A model based on easily available clinical and laboratory variables, including FPG, high-density lipoprotein cholesterol, age and the logarithm of glycated haemoglobin A1c, misclassified 44% of the patients, of whom 18% were overdiagnosed and 26% were underdiagnosed. Conclusion: An OGTT is still the most appropriate method for the clinical assessment of glucometabolic status in patients with coronary heart disease. http://repub.eur.nl/res/pub/13795/ 2005-07-01T00:00:00Z 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. http://repub.eur.nl/res/pub/5735/ 2004-11-01T00:00:00Z AIM: The objective behind the Euro Heart Survey on diabetes and the heart was to study the prevalence of abnormal glucose regulation in adult patients with coronary artery disease (CAD). METHODS AND RESULTS: The survey engaged 110 centres in 25 countries recruiting 4196 patients referred to a cardiologist due to CAD out of whom 2107 were admitted on an acute basis and 2854 had an elective consultation. Patient data were collected via a web-based case record form. An oral glucose tolerance test (OGTT) was used for the characterisation of the glucose metabolism. Thirty-one per cent of the patients had diabetes. An OGTT was performed on the 1920 patients without known diabetes, of whom 923 had acute and 997 had a stable manifestation of CAD, respectively. In patients with acute CAD, 36% had impaired glucose regulation and 22% newly detected diabetes. In the stable group these proportions were 37% and 14%. CONCLUSION: This survey demonstrates that normal glucose regulation is less common than abnormal glucose regulation in patients with CAD. OGTT easily discloses the glucometabolic state and should be a routine procedure. The knowledge of glucometabolic state among these patients should influence their future management because it has great potential to improve the outcome.