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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2010.02.022 Byline: Kai M. Eggers (a), Paul W. Armstrong (b), Robert M. Califf (c), Maarten L. Simoons (d), Per Venge (e), Lars Wallentin (a)(f), Stefan K. James (a)(f) Abstract: ST2 is a member of the interleukin-1 receptor family that is up-regulated in conditions associated with increased myocardial strain. ST2 has been shown to be independently predictive of adverse outcome in heart failure and ST-segment elevation myocardial infarction, but its prognostic value in non-ST-elevation acute coronary syndrome (NSTE-ACS) has not been established. Author Affiliation: (a) Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden (b) Department of Medicine, Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada (c) Duke Translational Medicine Institute, Department of Medicine, Duke University School of Medicine, Durham, NC (d) Thoraxcenter, Department of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands (e) Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden (f) Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden Article History: Received 8 November 2009; Accepted 23 February 2010

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2009.12.042 Byline: Michel E. Bertrand (a), Roberto Ferrari (b), Wilhelm J. Remme (c), Maarten L. Simoons (d), Jaab W. Deckers (d), K.M. Fox (e) Abstract: 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. Author Affiliation: (a) Lille Heart Institute, Lille, France (b) Department of Cardiology, University of Ferrara, and Fondazione Salvatore Maugeri, IRCCS, Ferrara, Italy (c) Sticares Cardiovascular Research Institute, Rhoon, The Netherlands (d) Thorax-Center Erasmus Medical Centre, Rotterdam, The Netherlands (e) Cardiology Department, Royal Brompton Hospital, Sydney Street, London, United Kingdom Article History: Received 23 April 2009; Accepted 31 December 2009

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2007.01.032 Byline: Kim M. Fox (a), Michel E. Bertrand (b), Willem J. Remme (c), Roberto Ferrari (d), Maarten L. Simoons (e), Jaap W. Deckers (e) Abstract: 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). Author Affiliation: (a) Cardiology Department, Royal Brompton Hospital, Sydney Street, London, UK (b) Cardiology Hospital, Lille, France (c) Sticares Cardiovascular Research Institute, Rotterdam-Rhoon, The Netherlands (d) Hospital Santa-Anna, Ferrara, Italy (e) ThoraxCenter Erasmus Medical Centre, Rotterdam, The Netherlands Article History: Received 18 July 2006; Accepted 16 January 2007

Byline: Ben A. van Hout, Lee Bowman, David J. Zelinger, Maarten L. Simoons Abstract: Cost-effectiveness analyses are routinely performed to determine whether the additional cost of a novel therapy is balanced by additional effectiveness. The definitions of costs and effects involve a variety of assumptions, both in general economic terms and with regard to the specific medical setting under consideration. Similarly, differing criteria for acceptability of cost-effectiveness estimates can be used to generate different conclusions regarding cost-effectiveness. The issues and problems inherent in economic evaluation are discussed by an analysis of findings with the platelet glycoprotein IIb/IIIa inhibitor abciximab in the EPIC (Evaluation of 7E3 for the Prevention of Ischemic Complications) study in high-risk patients undergoing percutaneous transluminal coronary angioplasty. (Am Heart J 1998;135:S98-S106.) Author Affiliation: Rotterdam, The Netherlands; Indianapolis, Ind.; and Malvern, Pa Article Note: (footnote) [star] From aErasmus University Rotterdam; bEli Lilly and Company, Indianapolis; cCentocor, Inc., Malvern, [star][star] Reprint requests: Ben A. van Hout, PhD, IMTA/Room L4-070, Erasmus University Rotterdam, Postbus 1738, 3000 DR, Rotterdam, The Netherlands., a 4/0/88302

Byline: Robert M. Califf, Maarten L. Simoons Abstract: Am Heart J 1998;135:S33-S4. Author Affiliation: Durham, N.C., and Rotterdam, The Netherlands Article Note: (footnote) [star] From Duke University Medical Center and Erasmus University Rotterdam., [star][star] 4/0/88300

Background: β-Blockers relieve angina/ischemia in stable coronary artery disease (CAD), and angiotensin-converting enzyme inhibitors prevent CAD outcomes. In EUROPA, the angiotensin-converting enzyme inhibitor perindopril reduced cardiovascular outcomes in low-risk stable CAD patients over 4.2 years. This post hoc analysis examined whether the addition of perindopril to β-blocker in EUROPA had additional benefits on outcomes compared with standard therapy including β-blocker.Methods: EUROPA was a multicenter, double-blind, placebo-controlled, randomized trial in patients with documented stable CAD. Randomized EUROPA patients who received β-blocker at baseline were identified, and the effect on cardiovascular outcomes of adding perindopril or placebo was analyzed. Endpoints were the same as those in EUROPA.Results: At baseline, 62% (n = 7534 [3789 on perindopril and 3745 on placebo]) received β-blocker. Treatment with perindopril/β-blocker reduced the relative risk of the primary end point (cardiovascular death, nonfatal myocardial infarction, and resuscitated cardiac arrest) by 24% compared with placebo/β-blocker (HR, 0.76; 95% CI, 0.64-0.91; P = .002). Addition of perindopril also reduced fatal or nonfatal myocardial infarction by 28% (HR, 0.72; 95% CI, 0.59-0.88; P = .001) and hospitalization for heart failure by 45% (HR, 0.55; 95% CI, 0.33-0.93; P = .025). Serious adverse drug reactions were rare in both groups, and cardiovascular death and hospitalizations occurred less often with perindopril/β-blocker.Conclusions: The addition of perindopril to β-blocker in stable CAD patients was safe and resulted in reductions in cardiovascular outcomes and mortality compared with standard therapy including β-blocker. [ABSTRACT FROM AUTHOR]

Abstract: Cardiogenic shock (CS) may result from ischemic heart disease, cardiomyopathy, valvular heart disease, inflammation, myocardial contusion, and cardiac surgery. CS is the leading cause of in-hospital death in patients with acute myocardial infarction. Although early revascularization strategies have resulted in a better prognosis, in-hospital mortality from CS remains exceptionally high. Notably, long-term annual mortality is similar in survivors of CS relative to patients with myocardial infarction without shock. This underlines the importance of aggressive support of the failing heart in the acute phase of CS. Because CS reflects a state of hypoperfusion induced by heart failure, management of CS should aim at improving cardiac function as well as at optimization of tissue perfusion. This review evaluates the current treatment of CS. In addition, novel approaches to monitor and modulate peripheral circulation at the bedside are highlighted. It is expected that these techniques will improve our understanding of the pathogenesis of CS and will offer new opportunities to guide therapy in CS patients to improve long-term prognosis. [Copyright &y& Elsevier]

Objective: Complications after cardiac surgery may involve multiple organ failure, which carries a high mortality. Development of multiple organ failure may be related to impaired microcirculatory perfusion as a result of systemic inflammation. Microcirculatory blood flow alterations have been associated with impaired outcome. We investigated whether these alterations occurred before, during, and after coronary artery bypass grafting. Methods: We observed 25 consecutive patients who underwent elective coronary artery bypass grafting with cardiopulmonary bypass. The sublingual microcirculation was investigated using side-stream dark-field imaging. Side-stream dark-field imaging was performed before (baseline), during, and after surgery. Microvascular blood flow was estimated with a semiquantitative microvascular flow index in small, medium, and large microvessels. Changes in microvascular flow were tested with Wilcoxon signed rank test. Results: Median microvascular flow index of medium blood vessels decreased after starting cardiopulmonary bypass relative to that after anesthetic induction (2.6, interquartile range 1.6–3.0, vs 3.0, interquartile range 2.8–3.0, P = .02). There was a trend toward decreased microvascular flow index of small and large vessels relative to baseline (P = .08 and P = .05, respectively). Decreases in microvascular flow index occurred irrespective of changes in systemic blood pressure. After each patient''s return to the intensive care unit, microvascular flow index increased and normalized in all microvessels. Conclusion: For the first time, sublingual microvascular blood flow alterations have been observed during cardiopulmonary bypass–assisted coronary artery bypass grafting. [Copyright &y& Elsevier]

Abstract: Aim: The aim of the study was to simultaneously test the EASI lead system and two other derived ECG methods against the standard 12-lead ECG during percutaneous coronary intervention (PCI). Methods: During 44 percutaneous coronary interventions, a simultaneously recorded 12-lead and EASI ECG were marked at the start of the PCI (baseline) and at known ischemia caused by balloon inflation (peak). ST deviations were measured 60 ms after the J point at baseline and peak in all leads and were summated (SUMST) to assess overall changes. For regional changes, the lead with the highest ST deviation (PEAKST) was marked. For each patient, derived 12-lead ECGs were computed from the EASI leads and a lead subset using patient-specific coefficients (PS) and coefficients based on a patient population (GEN). Absolute differences were computed between each derived and routine ECG for SUMST and PEAKST. Results: SUMST was at baseline 567 μV (range: 150-1707) and increased at peak to 871 μV (range: 350-2101). SUMST difference at peak was for EASI: 163 μV (CI: 90-236, P <.001), GEN: 46 μV (CI: 2-91, P = .40), and PS: 16 μV (CI: 3-30, P = .15). PEAKST difference at peak was for EASI: 49 μV (CI: 19-220, P = .02), GEN: 48 μV (CI: -43-154, P = .26), and PS: 20 μV (CI: -51-32, P = .65). Conclusion: Simultaneous direct comparison of three derived ECG methods shows overall and regional differences in accuracy across PS, GEN, and EASI. Median SUMST and PEAKST differences for PS are lower than for GEN and EASI, and show a more accurate reconstruction. [Copyright &y& Elsevier]

Objective: The aim of the study was to assess the long-term results of a selective policy toward pulmonary valve replacement in adult patients with repaired tetralogy of Fallot and severe pulmonary regurgitation. Methods: Sixty-seven patients with tetralogy of Fallot were followed up from 15 ± 3 years until 27 ± 3 years after surgery. Results: Twenty-two patients had mild-to-moderate pulmonary regurgitation. No significant changes occurred in the follow-up period. Of 45 patients with severe pulmonary regurgitation and severe right ventricular dilatation, 28 (62%) remained free of symptoms and did not undergo pulmonary valve replacement. No changes in right ventricular size or exercise capacity were found. In 3 (11%) of 28 patients, QRS duration increased to more than 180 ms. Seventeen patients had symptoms and underwent pulmonary valve replacement: 9 (54%) of 17 patients improved clinically and echocardiographically, and QRS duration shortened postoperatively. Right ventricular dimensions did not regress despite pulmonary valve replacement in 8 patients. Conclusion: Refraining from pulmonary valve replacement in asymptomatic patients led to no measurable deterioration in 25 (89%) of 28 patients. Referring symptomatic patients for pulmonary valve replacement led to an improvement in 9 (53%) of 17 patients. In 11 (24%) of 45, a selective approach led to questionable or unsatisfactory results. [Copyright &y& Elsevier]

Background: Although relationships between chronic Chlamydia pneumoniae (Cpn) infection and the risk of coronary events in stable coronary artery disease patients have been reported, a similar link in acute coronary syndrome (ACS) patients has not been consistently observed. Methods: In a nested case-control substudy of the Global Utilization of Strategies to Open Occluded Arteries IV Acute Coronary Syndromes trial, 295 cases (30-day death/myocardial infarction [MI]) were matched by age, sex, baseline creatine kinase–myocardial kinase, and smoking status with 295 control subjects. To test the hypothesis on 1-year mortality, another subset (n = 276) was drawn from the 590-patient cohort; 138 patients who died at 1 year plus the matching controls who survived at 1 year. We measured Cpn IgG and IgA antibody titers in baseline serum with microimmunofluorescence. Conditional logistic regression was used to quantify the prognostic relevance seropositivity (IgG ≥1:32; IgA ≥1:16) and elevated titer levels. Results: The prevalence of Cpn IgG and IgA was similar between cases and controls (30-day death/MI: IgG, 80% vs 85%, P = .126; IgA, 45% vs 37%, P = .079), and were not statistically significant predictors of 30-day death/MI after baseline adjustment. Likewise, the 1-year death cohort had comparable proportions of Cpn IgG and IgA among cases and controls (86% vs 91% [P = .265] and 49% vs 43% [P = .334], respectively), and did not add prognostic value. Conclusions: These findings are in concert with study results suggesting that chronic Cpn infection is not associated with 30-day death/MI or 1-year mortality in non-ST elevation ACS. [Copyright &y& Elsevier]

Objectives: In this dose-finding study, we sought to compare fondaparinux with enoxaparin in patients with acute coronary syndromes (ACS).Background: Fondaparinux is a synthetic pentasaccharide that selectively inhibits activated clotting factor X. It has been demonstrated as effective in preventing thromboembolic complications in orthopedic surgery.Methods: Four doses fondaparinux (2.5, 4, 8, or 12 mg once daily) and enoxaparin (1 mg/kg twice daily) were compared, both given for three to seven days, in patients with ACS without persistent ST-segment elevation.Results: The rates of the combined primary end point of death, myocardial infarction, or recurrent ischemia after nine days were 27.9%, 35.9%, 34.7%, 30.3%, and 35.7% in patients allocated to fondaparinux doses of 2.5, 4, 8, and 12 mg and enoxaparin, respectively (p = NS). In the per-protocol analysis (929 patients who received adequate study drug and had adequate ST-segment monitoring), these figures were 30.0%, 43.5%, 41.0%, 34.8%, and 40.2%. Again, no dose response was observed. The lowest event rates were observed in the 2.5-mg fondaparinux group, which had significantly lower rates than the enoxaparin group as well as for 4 and 8 mg fondaparinux in the per-protocol analysis (p < 0.05). Bleeding rates were low and not different among the patient groups. No differences were observed in fondaparinux concentrations in patients with or without death, myocardial infarction, recurrent ischemia, or bleeding events.Conclusions: This dose-finding study revealed no dose response for different fondaparinux doses ranging from 2.5 to 12 mg subcutaneously and suggests that the efficacy and safety of fondaparinux may be similar to that of enoxaparin. Further studies with fondaparinux in ACS might include the lowest dose (2.5 mg) investigated in this study. [Copyright &y& Elsevier]

Inappropriate therapy is a common clinical problem in recipients of implantable cardioverter-defibrillators (ICDs). The present study evaluated whether clinical characteristics could predict inappropriate ICD therapy due to atrial tachyarrhythmias in a series of 260 patients. [Copyright &y& Elsevier]

Of 592 patients in the Global Utilization of Streptokinase and tPA for Occluded Arteries-I trial who had a stroke during initial hospitalization, the risk for intracranial hemorrhage was significantly greater in those with recent facial or head trauma (odds ratio 13.0, 95% confidence interval 3.4 to 85.5); dementia was additionally associated with an increased risk for intracranial hemorrhage (odds ratio 3.4, 95% confidence interval 1.2 to 10.2). Because facial or head trauma may greatly influence treatment decisions, this risk factor should be incorporated into models designed to estimate the risks and benefits of fibrinolytic therapy. [Copyright &y& Elsevier]

Background Angiotensin-converting-enzyme inhibition reduces the risk of cardiovascular events at a group level. Presumably, the absolute effect of treatment varies between individuals. We sought to develop multivariable prediction scores to estimate individual treatment effect of perindopril in patients with stable coronary artery disease (sCAD). Methods In EUROPA trial participants, we estimated the individual patient 5-year absolute risk reduction (ARR) of major adverse cardiovascular events(MACE) by perindopril. Predictions were based on a new Coxproportional-hazards model with clinical characteristics and an external risk score in combination with the observed relative risk reduction. Second, a genetic profile modifying the relative efficacy of perindopril was added. The individual patient ARR was defined as the difference in MACE risk with and without treatment. The group level impact of selectively treating patients with the largest predicted treatment effect was evaluated using net benefit analysis. Results The risk score combining clinical and genetic characteristics estimated the 5-year absolute treatment effect to be absent or adverse in 27% of patients. On the other hand, the risk score estimated a small 5-year ARR of ⩽ 2% (NNT5 ⩾ 50) in 20% of patients, a modest ARR of 2-4% (NNT5 25-50) in 26%, and a large ARR of ⩾ 4% (NNT5 ⩽ 25) in 28%. The external risk score yielded similar predictions. Selective prediction-based treatment resulted in higher net benefit compared to treat everyone at any treatment threshold. Conclusion A prediction score combining clinical characteristics and genetic information can quantify the ARR of MACE by perindopril for individual patients with sCAD and may be used to guide treatment decisions. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Pentraxin 3 (PTX3) is the prototype of the long pentraxin family. PTX3 is involved in inflammatory processes affecting the cardiovascular system, and PTX3 levels have been shown to be elevated and independently prognostic in ST-elevation myocardial infarction. Data on PTX3 levels in non-ST-elevation acute coronary syndrome (NSTE-ACS), in contrast, are limited. The aim of the present analysis was to investigate the implications of PTX3 levels in a fairly large sample of NSTE-ACS patients and in comparison to levels of C-reactive protein (CRP). Design and methods: We measured levels of PTX3 and CRP in both 82 healthy controls and 401 NSTE-ACS patients from the GUSTO IV study, and studied the associations of these biomarkers to clinical data and 1-year mortality. Results: NSTE-ACS patients had significantly higher median PTX3 levels compared to healthy controls (3.8 vs. 1.9μg/L; p<0.001). PTX3 levels in patients with NSTE-ACS were independently related to female sex and cardiac troponin T levels, but not to age or cardiovascular risk factors. PTX3 levels were higher in patients who died within 1year but did not emerge as an independent predictor of 1-year mortality (adjusted OR 1.2 [95% CI 0.6–2.3]). This was in contrast to CRP (adjusted OR 1.5 [95% CI 1.1–2.3]). Neither PTX3 nor CRP yielded significant discriminative value regarding mortality prediction. Conclusions: PTX3 levels are elevated in NSTE-ACS. However, the prognostic information provided by PTX3 levels is limited and inferior compared to CRP. Our data, thus, do not support the measurement of PTX3 in patients with NSTE-ACS. [Copyright &y& Elsevier]

Abstract: Background: Data 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 15years. Methods: We 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. Results: Over 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). Conclusions: Despite enrolling higher-risk patients into these NSTE ACS trials, with better treatment, observed mortality declined over the past 15years. The appropriateness of increased blood transfusion despite unchanged bleeding rates deserves further study. [Copyright &y& Elsevier]