Maarten L. Simoons

SeminarAcute myocardial infarction

Acute myocardial infarction is a common disease with serious consequences in mortality, morbidity, and cost to the society. Coronary atherosclerosis plays a pivotal part as the underlying substrate in many patients. In addition, a new definition of myocardial infarction has recently been introduced that has major implications from the epidemiological, societal, and patient points of view. The advent of coronary-care units and the results of randomised clinical trials on reperfusion therapy, lytic or percutaneous coronary intervention, and chronic medical treatment with various pharmacological agents have substantially changed the therapeutic approach, decreased in-hospital mortality, and improved the long-term outlook in survivors of the acute phase. New treatments will continue to emerge, but the greatest challenge will be to effectively implement preventive actions in all high-risk individuals and to expand delivery of acute treatment in a timely fashion for all eligible patients.

Oral glucose tolerance test is needed for appropriate classification of glucose regulation in patients with coronary artery disease: a report from the Euro Heart Survey on Diabetes and the Heart

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 (nu200a=u200a4961). Fasting plasma glucose (FPG) and glycaemia 2 h after a 75-g glucose load were requested in patients without known glucose abnormalities (nu200a=u200a3362). 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-h 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.

Noninvasive assessment of speed and stability of infarct-related artery reperfusion: Results of the GUSTO ST segment monitoring study

OBJECTIVESnThe ST segment monitoring substudy of the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) trial compared the speed and stability of ST segment recovery among four thrombolytic strategies for acute myocardial infarction.nnnBACKGROUNDnRapid resolution of ST segment elevation has been suggested as a noninvasive marker of infarct-related artery patency. We expected that patients treated with accelerated recombinant tissue-type plasminogen activator (rt-PA) would show a quicker recovery than that of other patients but that those treated with streptokinase would show greater stability of recovery.nnnMETHODSnST segment monitoring was initiated in 1,067 patients within 30 min of the start of thrombolysis and continued for > 18 h with the use of a three-channel continuous vectorcardiographic monitor, a 12-lead continuous electrocardiographic (ECG) monitor or a three-channel (V2, V5, aVF) Holter ambulatory ECG monitor.nnnRESULTSnTime to 50% recovery could be assessed in 618 patients and was similar in the four treatment groups: median 45 min with streptokinase/subcutaneous heparin, 45 min with streptokinse/intravenous heparin, 42 min with accelerated rt-PA and 47 min with combination therapy (p = 0.7). No significant difference among the thrombolytic regimens was shown with the three monitors used. Time to initiation of ST segment analysis was directly related to time to 50% recovery (p = 0.0001) and was its best predictor in a multiple regression model. ST segment elevation recurred equally in each treatment group (approximately 36%, p = 0.9) but was significantly more common in patients with a patent infarct-related artery (p = 0.033) or a low ejection fraction (p = 0.001).nnnCONCLUSIONSnThe greater 90-min patency seen with accelerated rt-PA in the angiographic substudy did not correlate with a shorter time to 50% ST segment recovery, possibly because of technical limitations and study design. The similar rates of recurrent ischemia (as assessed by ST elevation) among the regimens support the similar infarction and reocclusion rates seen in the main trial and angiographic substudy.

Chronic stable coronary artery disease: drugs vs. revascularization

Coronary artery disease remains the leading cause of mortality in most industrialized countries, although age-standardized mortality related to coronary artery disease (CAD) has decreased by more than 40% during the last two decades. Coronary atherosclerosis may cause angina pectoris, myocardial infarction, heart failure, arrhythmia, and sudden death. Medical management of atherosclerosis and its manifestation aims at retardation of progression of plaque formation, prevention of plaque rupture, and subsequent events and treatment of symptoms, when these occur as well as treatment of the sequelae of the disease. Revascularization by either percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG) is performed as treatment of flow-limiting coronary stenosis to reduce myocardial ischaemia. In high-risk patients with acute coronary syndromes (ACS), a routine invasive strategy with revascularization in most patients provides the best outcome with a significant reduction in death and myocardial infarction compared with an initial conservative strategy. Conversely, the benefit of revascularization among patients with chronic stable CAD has been called into question. This review will provide information that revascularization exerts favourable effects on symptoms, quality of life, exercise capacity, and survival, particularly in those with extensive CAD and documented moderate-to-severe ischaemia. Accordingly, CABG and PCI should be considered a valuable adjunct rather than an alternative to medical therapy.

Management of patients with heart failure in clinical practice: differences between men and women.

Objectives: This study evaluated gender differences in clinical characteristics, treatment and outcome among patients with heart failure, and to what extent these differences are due to age and differences in left ventricular (LV) function. Although gender differences are observed among heart failure patients, few studies have been adequately powered to investigate these differences. Methods: A total of 8914 (out of 10u2009701) patients (47% women) from the Euro Heart Survey on Heart Failure with confirmed diagnosis of heart failure were included in the analyses. Results: Women were older (74.7 vs 68.3 years, p<0.001), and less often had evidence of coronary artery disease (56% vs 66%, age-adjusted odds ratio (OR) 0.62; 95% CI 0.57 to 0.68). Women were more likely to have hypertension, diabetes, or valvular heart disease. Fewer women had an investigation of LV function (59% vs 74%, age-adjusted OR 0.67; 95% CI 0.61 to 0.74), and, among those investigated, fewer had moderate/severe left ventricular systolic dysfunction (44% vs 71%, age-adjusted OR 0.35; 95% CI 0.32 to 0.39). Drugs with a documented impact on survival, that is ACE-inhibitors and β-blockers, were given less often to women, even in the adjusted analysis (OR 0.72; 95% CI 0.61 to 0.86 and OR 0.76; 95% CI 0.65 to 0.89, respectively). 12-week mortality was similar for men and women. Conclusions: Fewer women had an assessment of LV function, but, when investigated, women had better ventricular function. Women were less often treated with evidence-based drugs, even after adjustment for age and important clinical characteristics. Clinicians need to be aware of deficiencies in the treatment of women with heart failure and measures should be taken to rectify them.

The consistency of the treatment effect of an ACE-inhibitor based treatment regimen in patients with vascular disease or high risk of vascular disease: a combined analysis of individual data of ADVANCE, EUROPA, and PROGRESS trials

AIMSnAngiotensin-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.nnnMETHODS AND RESULTSnWe 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.nnnCONCLUSIONnThis 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.

The incidence and clinical predictors of ACE-inhibitor induced dry cough by perindopril in 27,492 patients with vascular disease.

OBJECTIVESnOur objective was to investigate the actual incidence and clinical determinants of cough leading to discontinuation of ACE-inhibitors. Cough is the most frequent reason to stop ACE-inhibitor treatment.nnnMETHODSnWe studied 27,492 ACE-inhibitor naïve patients randomized to the ACE-inhibitor perindopril or placebo using individual data of 3 clinical trials. Multivariate logistic regression analysis was used to study the incidence of cough in relation to baseline clinical characteristics including racial background.nnnRESULTSnIn 27,492 patients with cardiovascular disease, 1076 patients discontinued ACE-inhibitor perindopril due to cough (3.9%), 703 patients during run-in period of 4 weeks and 373 patients during a mean four years of follow-up. Significant determinants of cough were female gender (OR 1.92 95% CI 1.68-2.18), age above 65 years (OR 1.53 95% CI 1.35-1.73), and concomitant use of lipid-lowering agents (OR 1.37; 95% CI 1.18-1.59). A simple clinical risk score composed of these 3 predictors of cough mounted to an odds ratio of 4.4 (95% CI 3.1-5.4) in the subjects with highest score (i.e. all determinants present). Racial background was not related to a differential incidence of cough in patients of Caucasian or Asian descendent (OR 1.11 95% CI 0.92-1.39).nnnCONCLUSIONnThis large combined analysis of randomized clinical trials in 27,492 patients showed an overall lower incidence of cough leading to discontinuation of ACE-inhibitors (3.9%) as compared to literature. Clinical determinants of such cough are older age, female gender and concomitant use of lipid-lowering agents. In contrast, racial differences were not related to the incidence of cough.

Prediction of 30-day mortality in older patients with a first acute myocardial infarction.

Objectives: This study sought predictors of mortality in patients aged ≥75 years with a first ST-segment elevation myocardial infarction (STEMI) and evaluated the validity of the GUSTO-I and TIMI risk models. Methods: Clinical variables, treatment and mortality data from 433 consecutive patients were collected. Univariable and multivariable logistic regression analyses were applied to identify baseline factors associated with 30-day mortality. Subsequently a model predicting 30-day mortality was created and compared with the performance of the GUSTO-I and TIMI models. Results: After adjustment, a higher Killip class was the most important predictor (OR 16.1; 95% CI 5.7–45.6). Elevated heart rate, longer time delay to admission, hyperglycemia and older age were also associated with increased risk. Patients with hypercholesterolemia had a significantly lower risk (OR 0.46; 95% CI 0.24–0.86). Discrimination (c-statistic 0.79, 95% CI 0.75–0.84) and calibration (Hosmer-Lemeshow 6, p = 0.5) of our model were good. The GUSTO-I and TIMI risk scores produced adequate discrimination within our dataset (c-statistic 0.76, 95% CI 0.71–0.81, and c-statistic 0.77, 95% CI 0.72–0.82, respectively), but calibration was not satisfactory (HL 21.8, p = 0.005 for GUSTO-I, and HL 20.6, p = 0.008 for TIMI). Conclusions: Short-term mortality in elderly patients with a first STEMI depends most importantly on initial clinical and hemodynamic status. The GUSTO-I and TIMI models are insufficiently adequate for providing an exact estimate of 30-day mortality risk.

Genetic variation and gender determine bradykinin type 1 receptor responses in human tissue: Implications for the ACE-inhibitor-induced effects in patients with coronary artery disease

The efficacy of the ACE (angiotensin-converting enzyme) inhibitor perindopril in coronary artery disease [EUROPA (European trial on reduction of cardiac events with perindopril in stable coronary artery disease) study] is associated with the rs12050217 A/G single nucleotide polymorphism in the B1 receptor (bradykinin type 1 receptor) gene. To investigate the underlying mechanism, we examined the effect of this polymorphism on B1-receptor-mediated coronary artery dilation and peripheral blood mononuclear cell activation. Vasorelaxant responses of human coronary microarteries from subjects without coronary disease to des-Arg(9)-bradykinin and to bradykinin were studied in organ bath experiments. Des-Arg9-bradykinin responses were endothelium-dependent and exclusively mediated by B1 receptors, whereas responses to bradykinin were induced through B2 receptors (bradykinin type 2 receptors). The presence of the G allele reduced the response to 3 × 10(-8) mol/l des-Arg(9)-bradykinin by 29% [AA (n=13) compared with AG/GG (n=8); P<0.03], and tended to lower concentration-related responses (P=0.065) to this agonist, whereas the responses to bradykinin were unaffected by the rs12050217 genotype. In freshly obtained human mononuclear cells 1 μmol/l des-Arg(9)-bradykinin increased expression of the pro-inflammatory factors CXCL5 (CXC chemokine ligand 5) and IL6 (interleukin-6). These responses were not affected by genotype and exclusively occurred in blood cells from women, correlating (in the case of CXCL5) with their plasma 17β-oestradiol levels (r(2)=0.32, P=0.02; n=17). IL-1β (interleukin-1β) increased CXCL5 and IL6 expression in both genders, and this response was not associated with 17β-oestradiol levels. The gender difference in responses to B1 receptor stimulation in blood mononuclear cells implies possible gender differences in the response to ACE inhibitor therapy, which needs to be studied more comprehensively. The observed decrease in coronary vasodilator response might contribute to the impaired treatment response to perindopril of G allele carriers found in the EUROPA study.

Trends in clinical trials of non-ST-segment elevation acute coronary syndromes over 15 years

BACKGROUNDnData are limited on whether clinical trials have randomized higher-risk patients over time and how trends in risk profiles and evidence-based pharmacotherapies have influenced trial outcomes. We quantified changes in baseline risk, treatment, and outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) randomized in 9 phase 3 clinical trials of antithrombotic therapy over 15 years.nnnMETHODSnWe studied 58,771 patients in GUSTO IIb, PURSUIT, PARAGON-A, PARAGON-B, PRISM, PRISM-PLUS, GUSTO IV-ACS, SYNERGY, and EARLY ACS. Patient-level data were mapped to 3 pre-specified 5-year randomization periods. Temporal trends in GRACE score-predicted mortality were compared with trends in observed mortality.nnnRESULTSnOver time, in-hospital and discharge use of thienopyridines (p=0.001), statins (p<0.0001), and angiotensin-converting enzyme inhibitors (p<0.0001) increased, and hospital length-of-stay decreased (p=0.024). Blood transfusion use increased (8.3% [1994-98], 10.7% [1999-2003], 13% [2004-08], p=0.0002) despite stable rates of severe bleeding (0.9% [1994-98], 1.4% [1999-2003] and 1.1% [2004-08], p=0.127) and coronary artery bypass grafting (12.4% [1994-98], 13.7% [1999-2003] 13.1% [2004-08], p=0.880). Although predicted 6-month mortality increased (6.9% [1994-98], 9.0% [1999-2003], 7.9% [2004-08], p=0.017), observed 6-month mortality decreased (6.7% [1994-98], 5.8% [1999-2003], 5.1% [2004-08], p=0.025). Thirty-day myocardial infarction rates remained stable (9.2% [1994-98], 9.3% [1999-2003], 10% [2004-08], p=0.539).nnnCONCLUSIONSnDespite enrolling higher-risk patients into these NSTE ACS trials, with better treatment, observed mortality declined over the past 15 years. The appropriateness of increased blood transfusion despite unchanged bleeding rates deserves further study.