Showing papers by "Eugene Braunwald published in 2011"

Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine

Abstract: "Braunwald's Heart Disease" remains your indispensable source for definitive, state-of-the-art answers on every aspect of contemporary cardiology. Edited by Drs. Robert O. Bonow, Douglas L. Mann, Douglas P. Zipes, and Peter Libby, this dynamic, multimedia reference helps you apply the most recent knowledge in molecular biology and genetics, imaging, pharmacology, interventional cardiology, electrophysiology, and much more. Weekly updates online, personally selected by Dr. Braunwald, continuously keep you current on the most important new developments affecting your practice. Enhanced premium online content includes new dynamic cardiac imaging videos, heart sound recordings, and podcasts. With sweeping updates throughout, and contributions from a 'who's who' of global cardiology, Braunwald's is the cornerstone of effective practice.

Diuretic Strategies in Patients with Acute Decompensated Heart Failure

Abstract: Among patients with acute decompensated heart failure, there were no significant differences in patients’ global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00577135.)

Risk of Incident Diabetes With Intensive-Dose Compared With Moderate-Dose Statin Therapy A Meta-analysis

Abstract: Context A recent meta-analysis demonstrated that statin therapy is associated with excess risk of developing diabetes mellitus. Objective To investigate whether intensive-dose statin therapy is associated with increased risk of new-onset diabetes compared with moderate-dose statin therapy. Data Sources We identified relevant trials in a literature search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (January 1, 1996, through March 31, 2011). Unpublished data were obtained from investigators. Study Selection We included randomized controlled end-point trials that compared intensive-dose statin therapy with moderate-dose statin therapy and included more than 1000 participants who were followed up for more than 1 year. Data Extraction Tabular data provided for each trial described baseline characteristics and numbers of participants developing diabetes and experiencing major cardiovascular events (cardiovascular death, nonfatal myocardial infarction or stroke, coronary revascularization). We calculated trial-specific odds ratios (ORs) for new-onset diabetes and major cardiovascular events and combined these using random-effects model meta-analysis. Between-study heterogeneity was assessed using the I 2 statistic. Results In 5 statin trials with 32 752 participants without diabetes at baseline, 2749 developed diabetes (1449 assigned intensive-dose therapy, 1300 assigned moderate-dose therapy, representing 2.0 additional cases in the intensive-dose group per 1000 patient-years) and 6684 experienced cardiovascular events (3134 and 3550, respectively, representing 6.5 fewer cases in the intensive-dose group per 1000 patient-years) over a weighted mean (SD) follow-up of 4.9 (1.9) years. Odds ratios were 1.12 (95% confidence interval [CI], 1.04-1.22; I 2 = 0%) for new-onset diabetes and 0.84 (95% CI, 0.75-0.94; I 2 = 74%) for cardiovascular events for participants receiving intensive therapy compared with moderate-dose therapy. As compared with moderate-dose statin therapy, the number needed to harm per year for intensive-dose statin therapy was 498 for new-onset diabetes while the number needed to treat per year for intensive-dose statin therapy was 155 for cardiovascular events. Conclusion In a pooled analysis of data from 5 statin trials, intensive-dose statin therapy was associated with an increased risk of new-onset diabetes compared with moderate-dose statin therapy.

New horizons in cardioprotection: recommendations from the 2010 National Heart, Lung, and Blood Institute Workshop.

Abstract: Coronary heart disease is the largest major killer of American men and women and accounted for 1 of every 6 deaths in the United States in 2007.1 The annual incidence of myocardial infarction in the United States is estimated to be 935 000, with 610 000 new cases and 325 000 recurrent attacks. Survivors have a much higher chance of suffering from congestive heart failure, arrhythmias, and sudden cardiac death. Prognosis after an acute myocardial ischemic injury is primarily dependent on the amount of myocardium that undergoes irreversible injury.2–4 Large transmural infarcts yield a higher probability of cardiogenic shock, arrhythmias, adverse remodeling, and development of late chronic heart failure. Although it has been known since the early 1970s that the size of a myocardial infarction can be modified by various therapeutic interventions,5 early coronary artery reperfusion by fibrinolysis or percutaneous coronary intervention, including balloon angioplasty with or without stenting, remains the only established intervention capable of consistently reducing infarct size in humans. Although reperfusion has led to significant advances in patient care and reduction in hospital mortality, delays in seeking medical attention and inherent limitations in initiating fibrinolysis or percutaneous coronary intervention dictate that additional substantive improvements in morbidity and mortality can be achieved only with the development of new adjunctive therapies coupled with reperfusion. In addition, reperfusion therapy itself may induce reperfusion injury, a phenomenon that may encompass stunned myocardium, no-reflow phenomenon, and lethal myocardial cell death. If this injury could be prevented or minimized by administration of adjunctive therapy, then the net benefit of reperfusion could be enhanced. The problem of acute ischemic injury and myocardial infarction is not limited to patients with acute coronary artery syndrome. It remains a major problem in cardiac surgery as well. It is well documented that the incidence of myocardial necrosis after surgery, as determined by creatine kinase MB enzyme release and troponin levels, ranges somewhere between 40% and 60%, and, depending on its clinical definition, the incidence of myocardial infarction after coronary artery bypass graft surgery may be as high as 19%. The intermediate and long-term implications are considerable. In a recent retrospective analysis of 18 908 patients who underwent coronary artery bypass graft surgery and in whom long-term follow-up was available, it was shown that myocardial enzyme elevation within the first 24 hours of surgery was associated with increasing mortality over the course of months to years. This study confirms earlier reports that even small enzyme elevations after surgery are associated with worse long-term outcomes.4

Predictors of Bleeding and Time Dependence of Association of Bleeding With Mortality Insights From the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel—Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38)

Abstract: Background—The balance between benefit (ischemia protection) and risk (bleeding) is a key consideration in choosing the intensity of antiplatelet therapy for patients with acute coronary syndromes. The goals of this analysis were to identify baseline characteristics that independently predict bleeding and to determine how bleeding events impact the subsequent mortality in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel—Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38). Methods and Results—Multivariable Cox regression analyses adjusted for treatment, baseline, and procedural variables were used to determine the predictors for serious (TIMI major or minor) bleeding. To analyze the hazard ratio and time dependency of bleeding on mortality, we used iterative day-to-day landmark analyses after the bleed. From the 13 420 patients with acute coronary syndromes included in this analysis, 534 (4.0%) experienced a serious bleeding event. Variables wit...

Risk of Incident Diabetes With Intensive-Dose Compared With Moderate-Dose Statin Therapy

Abstract: David Preiss, MRCP Sreenivasa Rao Kondapally Seshasai, MD Paul Welsh, PhD Sabina A. Murphy, MPH Jennifer E. Ho, MD David D. Waters, MD David A. DeMicco, DPharm Philip Barter, MD, PhD Christopher P. Cannon, MD Marc S. Sabatine, MD, MPH Eugene Braunwald, MD John J. P. Kastelein, MD, PhD James A. de Lemos, MD Michael A. Blazing, MD Terje R. Pedersen, MD, PhD Matti J. Tikkanen, MD, PhD Naveed Sattar, MD, PhD Kausik K. Ray, MD

Growth Differentiation Factor-15 and Risk of Recurrent Events in Patients Stabilized After Acute Coronary Syndrome: Observations From PROVE IT-TIMI 22

Abstract: Objective— To investigate growth differentiation factor (GDF)-15 at hospital discharge for assessment of the risk of death, recurrent myocardial infarction (MI), and congestive heart failure, and to determination of whether these risks can be modified by statins. Methods and Results— GDF-15 is a transforming growth factor-β–related cytokine induced in response to tissue injury. GDF-15 concentration is associated with all-cause mortality in patients with acute coronary syndrome (ACS). We measured GDF-15 in 3501 patients after ACS, treated with moderate or intensive statin therapy in PROVE IT-TIMI 22. By using established cutoff points, GDF-15 ( 1800 ng/L) was associated with 2-year risk of death or MI (5.7%, 8.1%, and 15.1%, respectively; P P P P P P P P P =0.24 for the interaction). Conclusion— GDF-15 is associated with recurrent events after ACS, independent of clinical predictors, B-type natriuretic peptide, and high-sensitivity C-reactive protein. This finding supports GDF-15 as a prognostic marker in ACS and investigation of other therapies that modify this risk.

Assessment of multiple cardiac biomarkers in non-ST-segment elevation acute coronary syndromes: observations from the MERLIN-TIMI 36 Trial

Abstract: Aims The aim of this study is to simultaneously evaluate the incremental prognostic value of multiple cardiac biomarkers reflecting different underlying pathophysiological processes in a well-characterized population of patients with non-ST-segment acute coronary syndrome (NSTE-ACS). Methods and results We measured cardiac troponin I (cTnI), N-terminal pro B-type natriuretic peptide (NT-proBNP), C-reactive protein, and myeloperodixase (MPO) among 4352 patients with NSTE-ACS in the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischaemia in Non-ST Elevation Acute Coronary-Thrombolysis In Myocardial Infarction 36) trial and followed them for a mean of 343 days. When added individually to a multivariable model adjusted for clinical characteristics, the risk of cardiovascular (CV) death rose in a stepwise fashion with increasing quartiles of each biomarker, and when using their pre-defined cut-points [HR(adj) 2.71 (P Conclusion In this study of over 4300 patients presenting with NSTEACS, we found that both cTnI and NT-proBNP offer prognostic information beyond that achieved with clinical risk variables for CV death, MI, and HF. Myeloperoxidase and hs-C-reactive protein, while independently associated with some adverse CV outcomes, did not provide substantial incremental prognostic information when evaluated together with cTnI and NT-proBNP.

The evolving epidemiology of acute coronary syndromes.

Abstract: The clinical entities that comprise acute coronary syndromes (ACS)-ST-segment elevation myocardial infarction (STEMI), non-STEMI, and unstable angina-have been recognized as widespread causes of death and disability for more than a century. Seminal research in the past 50 years has led to important scientific and medical advances in our understanding of ACS. Rapid modernization of the developing world has led to a pandemic of coronary artery disease and its manifestation as ACS, with profound implications for personal, societal, and global health. Epidemiological studies have provided insight into the changing demographics of ACS, and highlighted the importance of modifiable risk factors and adherence to guideline-recommended therapy.

Novel oral anticoagulants: focus on stroke prevention and treatment of venous thrombo-embolism

Abstract: Anticoagulation for the long-term treatment and prevention of thrombo-embolic diseases as well as for stroke prevention in atrial fibrillation (AF) has been accomplished by vitamin K antagonists for the last half century. Although effective under optimal conditions, the imminent risk of a recurrent event vs. the risk of bleeding due to the narrow therapeutic window, numerous food- and drug interactions, and the need for regular monitoring complicate the long-term use of these drugs and render treatment with these agents complicated. As a result, novel anticoagulants which selectively block key factors in the coagulation cascade are being developed. The efficacy and safety of the direct thrombin inhibitor dabigatran etexilate, as well as of the selective factor Xa inhibitors rivaroxaban and apixaban, have been demonstrated in Phase III trials for stroke prevention in AF and the treatment and secondary prophylaxis of venous thrombo-embolism. This review summarizes the results from recently published pivotal clinical trials and discusses the opportunities as well as uncertainties in the clinical applications of these novel agents.

Efficacy and Safety of Intensive Antiplatelet Therapy With Prasugrel from TRITON-TIMI 38 in a Core Clinical Cohort Defined by Worldwide Regulatory Agencies

Abstract: TRITON-TIMI 38 showed that in patients with acute coronary syndrome undergoing percutaneous coronary intervention prasugrel decreased ischemic events compared to standard clopidogrel, but with more bleeding. The United States Food and Drug Administration and the European Medicines Agency approved prasugrel but provided contraindications in patients with previous stroke or transient ischemic attack and recommended limited use or reduced dose in patients ≥75 years old and weighing 60 kg had substantial decreases in ischemic events with prasugrel compared to clopidogrel. Although relative bleeding excess exists in this population, absolute rates and differences in bleeding were attenuated. In conclusion, these data indicate that use of prasugrel in a core clinical cohort that has been defined by regulatory action will maximize the benefit of prasugrel and limit the risk of adverse outcomes.

A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes

Abstract: ACUTE HEART FAILURE SYNDROMES (AHFS) HAVE BEEN defined as new-onset or recurrence of worsening signs and symptoms of HF necessitating urgent or emergency management. More than 1 million hospital admissions occur annually for AHFS both in the United States and in Europe. Initial management of AHFS has changed little over the last decades. Although patients with AHFS experience symptomatic improvement during hospitalization, the postdischarge rehospitalization rate and mortality within 60 to 90 days remain as high as 30% and 15%, respectively. An algorithm is needed for evaluation of AHFS at presentation, given the heterogeneity of this patient population. The ultimate clinical value of any conceptual framework depends on its capacity to improve use of diagnostic and therapeutic modes and to guide design of clinical trials. Three phases of AHFS have been suggested: (1) urgent treatment and stabilization (most often occurring in the emergency department); (2) in-hospital management; and (3) the postdischarge “vulnerable” period. In this Commentary, we focus on assessment and management of AHFS during phase 1.

Intrinsic platelet reactivity before P2Y12 blockade contributes to residual platelet reactivity despite high-level P2Y12 blockade by prasugrel or high-dose clopidogrel. Results from PRINCIPLE-TIMI 44.

Abstract: It was the objective of this study to determine whether the intrinsic platelet response to adenosine diphosphate (ADP) before thienopyridine exposure contributes to residual platelet reactivity to ADP despite high level P2Y12 blockade by prasugrel (60 mg loading dose [LD]), 10 mg daily maintenance dose [MD]) or high-dose clopidogrel (600 mg LD, 150 mg daily MD). High residual platelet function during clopidogrel therapy is associated with poor clinical outcomes. It remains unknown whether the relationship between platelet reactivity prior to treatment with clopidogrel (300 mg LD, 75 mg daily MD) and residual on-treatment platelet reactivity is maintained after more potent P2Y12 inhibition. PRINCIPLE-TIMI 44 was a randomised, double-blind, two-phase crossover study of prasugrel compared with high-dose clopidogrel in 201 patients undergoing cardiac catheterisation for planned percutaneous coronary intervention. ADP-stimulated platelet-monocyte aggregates, platelet surface P-selectin and platelet aggregation were measured pre-treatment, during LD (6 h and 18-24 h) and MD (15 d). Correlations of pre-treatment to on-treatment values were determined by Spearman rank order. Prasugrel resulted in greater platelet inhibition than high-dose clopidogrel for each measure. However, for both drugs, pre-treatment reactivity to ADP predicted 6 h, 18-24 h and 15 day reactivity to ADP (correlations 0.24-0.62 for platelet-monocyte aggregates and P-selectin). In conclusion, a patient's intrinsic platelet response to ADP before exposure to thienopyridines contributes to residual platelet reactivity to ADP despite high level P2Y12 blockade with high-dose clopidogrel or even higher level P2Y12 blockade with prasugrel. Patients who are hyper-responsive to ADP pre-treatment are more likely to be hyper-responsive to ADP on-treatment, which may be relevant to therapeutic strategies.

Upstream Use of Small-Molecule Glycoprotein IIb/IIIa Inhibitors in Patients With Non–ST-Segment Elevation Acute Coronary Syndromes A Systematic Overview of Randomized Clinical Trials

Abstract: Background—The use of upstream small-molecule glycoprotein (GP) IIb/IIIa inhibitors in non–ST-segment elevation acute coronary syndromes (NSTE ACS) has been studied in multiple randomized clinical trials. We systematically reviewed the effect of upstream GP IIb/IIIa inhibitor use in NSTE ACS as reported in published clinical trials. Methods and Results—Randomized clinical trials of upstream small-molecule GP IIb/IIIa inhibitors in NSTE ACS were identified through a PubMed and EMBASE search and were included if they contained 30-day outcome data. Odds ratios were generated from the published data and pooled by means of random effects modeling. The primary outcome measures were 30-day death and 30-day death or myocardial infarction. Primary safety measures were major bleeding and transfusion during the index hospitalization. Twelve clinical trials were included, evaluating tirofiban, eptifibatide, and lamifiban. Of these, 7 evaluated upstream GP IIb/IIIa inhibitors versus placebo (n=24 031) and 5 evaluated ...

Upstream clopidogrel use and the efficacy and safety of early eptifibatide treatment in patients with acute coronary syndrome: an analysis from the Early Glycoprotein IIb/IIIa Inhibition in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial.

Abstract: Background-In the Early Glycoprotein IIb/IIIa Inhibition in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial, routine preangiography eptifibatide use was not superior to delayed provisional use but led to more bleeding. This analysis examines efficacy and safety of early eptifibatide in the setting of concurrent upstream clopidogrel use. Methods and Results-In EARLY-ACS, clopidogrel use and timing were determined by treating physicians, but randomization to early eptifibatide versus placebo was stratified by the intent to use upstream clopidogrel. Among 9166 non-ST-elevation acute coronary syndrome patients who underwent coronary angiography, intent to use upstream clopidogrel was declared in 6895 (75%), and 7068 (77%) received upstream clopidogrel. After multivariable adjustment, intended upstream clopidogrel use did not differentially influence the effect of early eptifibatide on the primary end point of 96-hour death/myocardial infarction/recurrent ischemia requiring urgent revascularization/thrombotic bailout (interaction P = 0.988). Early eptifibatide use reduced 30-day death/myocardial infarction among patients with intended upstream clopidogrel (adjusted odds ratio 0.85; 95% confidence interval 0.73 to 0.99) but not among those without intended upstream clopidogrel use (adjusted odds ratio 1.02; 95% confidence interval 0.80 to 1.30). However, the clopidogrel by randomized treatment interaction term was not significant (P = 0.23). Thrombolysis in Myocardial Infarction major bleeding risk was increased with early eptifibatide in the setting of upstream clopidogrel use. Results were similar using actual clopidogrel treatment strata. Conclusions-Routine early eptifibatide use, compared with delayed provisional use, may be associated with lower 30-day ischemic risk in non-ST-elevation acute coronary syndrome patients also treated with clopidogrel before angiography. The benefit-risk ratio of intensive platelet inhibition with combined early use of antiplatelet agents needs further evaluation in prospective randomized trials.

Hospitalizations for heart failure in the United States--a sign of hope.

Abstract: HEART FAILURE (HF) IS THE MOST COMMON CAUSE OF hospitalization in patients older than 65 years in the United States. In the early 1990s, data from clinical trials and registries demonstrated that in patients hospitalized with HF, mortality and rehospitalization rates could be as high as 15% and 30%, respectively, at 60 to 90 days after discharge. During this period, major efforts were directed toward reducing the length of stay in patients hospitalized with HF. Performance measures were developed and later adopted by the Centers for Medicare & Medicaid Services (CMS) with the intent to improve postdischarge outcomes. Although these measures were implemented across the country, the rehospitalization rate for patients with HF did not appear to decrease. Recently, because of changes in CMS reimbursement patterns, the focus has shifted toward 30-day postdischarge readmission rates as a measure of care. In this issue of JAMA, Chen et al reviewed administrative data of more than 55 million Medicare fee-for-service beneficiaries,withameanageof79years,whowerehospitalizedwith a discharge diagnosis of HF. Black patients represented 11% of the total studypopulation.Theoverall ratesof risk-adjusted hospitalizationforHFdeclined30%over thestudyperiodfrom 2845 per 100 000 person-years in 1998 to 2007 per 100 000 person-years in2008.Theauthorsattribute thisdecline inhospitalizations to reductions in the incidence of coronary artery disease, improved control of blood pressure, increased use of evidence-based therapies, and possibly changes in admission thresholds. In contrast to this significant reduction in hospitalizations forHF,1-year risk-adjustedall-causemortality rate declined minimally but remained high at approximately 30%. This report is a substantial contribution to existing HF epidemiological literature because it is the first to document an improvementinhospitalizationrates inHFintheUnitedStates. These improvementsappear tobemoreevident inrecentyears during which major progress has been made in promoting evidence-basedtherapies forcoronaryarterydisease.However, thissubstantialdecline inhospitalizationrateswassignificantly less in black men than in white men. Another important observation was that the decreases in hospitalization rates across states were not uniform. The authors also noted that comorbidities such as hypertension and renal dysfunction increased over time. Approximately 40% of these patients had diabetes and 30% had chronic obstructive pulmonary disease. The general reduction in admission rates may reflect improvements in overall management of HF risk factors, as suggested by Chen et al, but the persistently high 1-year mortality rates suggest that postdischarge practices for patients with HF have not been as effective. Although the admission rates for HF have decreased based on Medicare data reported by Chen et al, the available data suggest that rehospitalization rates after an index admission for HF have remained unchanged or have even increased over a similar time frame. It is important to recognize that among patients discharged following hospital admission for HF, a significant number of rehospitalizations are not related to HF. In the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome StudywithTolvaptan) trial conducted inpatientsadmitted for worsening HF with reduced ejection fraction, the total rehospitalizationrateexceeded50%at9.9months,andless thanhalf of rehospitalizations were due to HF. This occurred despite the studypopulationbeing relativelyyoung forHF(meanage, 62years),withfewmajorcomorbidconditions.IntheDIG(Digitalis Investigation Group) ancillary trial that studied outpatients with HF and preserved ejection fraction, the total hospitalization rate exceeded 65% during a mean follow-up of 37 months.Ofthesehospitalizations,only35%wererelatedtoHF. Inbothstudies,totalcardiovascularhospitalizationsrepresented a large proportion of the hospitalizations. Targeting total rehospitalization rather than rehospitalization for HF rates may be especially important given the aging population and their associated cardiac and noncardiac comorbid conditions. Chen et al suggested that the reduction in HF admissions may be related to changes in the threshold for admission in emergency departments. Lee et al reported that patients with HF who were discharged home directly from the emergency department, representing 30% of total HF presentations in their cohort, had a high risk-adjusted early death compared with patients who were admitted. If the reduction in number of hospitalizations noted by Chen et al is

Prognostic utility of neopterin and risk of heart failure hospitalization after an acute coronary syndrome.

Abstract: Aims There is increasing evidence that immune mechanisms are involved in the pathogenesis of heart failure (HF). The relationship between neopterin and the risk of HF has yet to be investigated on a large scale. We assessed the relationship between neopterin, a novel marker of monocyte activation, and risk of hospitalization for HF. Methods and results Among the subjects of Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 trial, 3946 had neopterin levels measured at study entry, on average 7 days after acute coronary syndrome (ACS). We assessed the relationship between neopterin and hospitalization for HF, and for death or HF over 2 years mean follow-up in a post hoc analysis using Cox regression models. Unadjusted hospitalization rates for HF increased across quartiles of neopterin, from 0.66 to 3.97 per 100 person-years. Per 1SD increment in log (neopterin), the adjusted risk of HF increased by 34% [hazard ratio (HR) 1.34, CI 1.10-1.64; P = 0.004]. Even after excluding individuals with a prior history of HF or recurrent ischaemic events, the relationship between neopterin and HF hospitalization remained significant. When added to a multivariable Cox model of HF-risk containing traditional risk factors, C-reactive protein and brain natriuretic protein (BNP), the further addition of neopterin significantly improved the HF-risk prediction model by likelihood ratio test analysis (P = 0.005), C-statistic (increasing from 0.743 to 0.773; P = 0.027), integrated discrimination improvement (IDI) analysis (P = 0.001), but not net reclassification improvement (NRI) analysis (P = 0.406). Similar results were obtained for the endpoint of death or HF. Conclusion Neopterin levels are an independent predictor of HF hospitalization, and improve risk prediction over and above conventional biomarkers.

Myocardial Ischemia and Ventricular Tachycardia on Continuous Electrocardiographic Monitoring and Risk of Cardiovascular Outcomes After Non–ST-Segment Elevation Acute Coronary Syndrome (from the MERLIN-TIMI 36 Trial)

Abstract: Among patients with non–ST-segment elevation acute coronary syndromes, recurrent ischemia and ventricular arrhythmias detected on continuous electrocardiographic monitoring remain common events that are associated with worse outcomes. The relative clinical significance of both events together is not well described. We determined the risk associated with ischemia (≥1 mm ST depression lasting ≥1 minutes) and ventricular tachycardia (VT) (≥4 beats) detected on 7-day continuous electrocardiographic monitoring in 6,355 patients with non–ST-segment elevation acute coronary syndromes from the Metabolic Efficiency with Ranolazine for Less Ischemia in Non–ST-elevation Acute Coronary Syndrome–Thrombolysis In Myocardial Infarction (MERLIN-TIMI) 36 trial. The patients were categorized into 4 groups according to the presence or absence of VT and ischemia. Cardiovascular death, sudden cardiac death (SCD), myocardial infarction, and recurrent ischemia were assessed during a median follow-up of 348 days. A total of 60.0% patients had no VT or ischemia, 20.0% had VT alone, 14.7% had ischemia alone, and 5.3% had both. The patients with either VT or ischemia were at increased risk of cardiovascular outcomes. The combination of ischemia and VT identified a particularly high-risk population for cardiovascular death (10.1% vs 3.0%, p 6,300 patients with non–ST-segment elevation acute coronary syndromes, the presence of myocardial ischemia or VT alone, and particularly in combination, was independently associated with poor cardiovascular outcomes and thus provides incremental improvement in early risk stratification.

Clinical efforts to reduce myocardial infarct size--the next step.

Abstract: Prompt myocardial reperfusion reduces infarct size in patients experiencing coronary occlusion. However, its clinical value is limited because reperfusion also causes ischemic myocardial reperfusion injury (IMRI). Considerable research to reduce IMRI has been conducted. Three interventions appear to be promising: 1) myocardial conditioning, which consists of repetitive occlusions of coronary or other arteries prior to or at the time of myocardial reperfusion; 2) the administration of cyclosporine A; and 3) the administration of adenosine. A plan for the testing of these interventions in patients with acute myocardial infarction is described.

Opposing Effects of β Blockers and Angiotensin-Converting Enzyme Inhibitors on Development of New-Onset Diabetes Mellitus in Patients With Stable Coronary Artery Disease

Abstract: We used data from patients with stable coronary artery disease (CAD) to assess the risk of new-onset diabetes mellitus (NOD) with β blockers and to determine whether angiotensin-converting enzyme (ACE) inhibition would modify this risk. The Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial randomized 8,290 patients with stable CAD to trandolapril or placebo. Presence of NOD was assessed at each study visit over a median follow-up time of 4.8 years. We examined the risk of NOD associated with β-blocker use with Cox regression models adjusting for 25 baseline covariates and tested whether this risk was modified by randomization to the ACE inhibitor. Of 6,910 patients without diabetes mellitus at enrollment (1,179 women and 5,731 men, mean age 64 ± 8 years), 4,147 (60%) were taking β blockers and 733 (8.8%) developed NOD. We observed a significant interaction between β-blocker use and randomization to ACE inhibitor with respect to NOD (p = 0.028). Participants taking β blockers assigned to the placebo group (n = 2,090) were at increased risk for NOD adjusting for baseline covariates (hazard ratio 1.63, 95% confidence interval 1.29 to 2.05, p

Prognostic Utility of Secretory Phospholipase A2 in Patients with Stable Coronary Artery Disease

Abstract: BACKGROUND: Secretory phospholipase A2 (sPLA2) may contribute to atherogenesis. To date, few prospective studies have examined the utility of sPLA2 for risk stratification in coronary artery disease (CAD). METHODS: We measured plasma sPLA2 activity at baseline in 3708 subjects in the PEACE randomized trial of trandolapril vs placebo in stable CAD. Median follow-up was 4.8 years. We used Cox regression to adjust for demographics, clinical risk factors, apolipoprotein B, apolipoprotein A1, and medications. RESULTS: After multivariable adjustment, sPLA2 was associated with an increased risk of cardiovascular death, myocardial infarction, or stroke (adjusted hazard ratio Q4:Q1 1.55, 95% CI 1.13–2.14) and cardiovascular death or heart failure (1.91, 1.20–3.03). In further multivariable assessment, increased activity levels of sPLA2 were associated with the risk of cardiovascular death, myocardial infarction, or stroke (adjusted hazard ratio 1.47, 95% CI 1.06–2.04), independent of lipoprotein-associated phospholipase A2 mass and C-reactive protein, and modestly improved the area under the curve (AUC) beyond established clinical risk factors (AUC 0.668–0.675, P = 0.01). sPLA2, N-terminal pro-B-type natriuretic peptide, and high-sensitivity cardiac troponin T all were independently associated with cardiovascular death or heart failure, and each improved risk discrimination ( P = 0.02, P < 0.001, P < 0.001, respectively). CONCLUSIONS: sPLA2 activity provides independent prognostic information beyond established risk markers in patients with stable CAD. These data are encouraging for studies designed to evaluate the role of sPLA2 as a therapeutic target.

Abstract 9150: Re-Elevation of Troponin Following Percutaneous Coronary Intervention Significantly Predicts 1-Year Mortality in Patients with High-risk Non-ST-Segment Elevation Acute Coronary Syndromes

Abstract: Background: The prognostic value of cardiac troponin (cTn) elevation post PCI is controversial. Moreover, in high-risk NSTE ACS patients presenting with elevated necrosis markers, the ability to us...

Abstract 9309: Benefit of Prasugrel in ST-Elevation Myocardial Infarction According to Timing of Percutaneous Coronary Intervention: Insight from the TRITON-TIMI 38 Study

Abstract: Background: Prasugrel is approved as an alternative to clopidogrel in STEMI. Treatment strategies and outcomes for primary PCI ( 12 hours from ons...

HMG CoA Reduction in Patients with Average Cholesterol Concentrations

Abstract: Featured Article: Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–9.4 In 1984, a National Heart, Lung and Blood Institute trial demonstrated that reducing LDL cholesterol (LDL-C)5 with a combination of diet and large doses of the cholesterol-binding resin cholestyramine reduced coronary events (1) and slowed the progression of coronary artery obstruction (2) in men with increased cholesterol concentrations. Resins were not well tolerated, however, and patient compliance was poor. Subsequently, the availability of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HmG CoA) reductase inhibitors changed the approach to cholesterol management, because these drugs were well tolerated and caused marked reductions in total cholesterol (TC) and LDL-C in the majority of individuals. Two important clinical-outcome trials were launched promptly for patients with hypercholesterolemia. The Scandinavian Simvastatin Survival Study (3) enrolled patients with coronary artery disease and hypercholesterolemia [average TC, 261 mg/dL (6.6 mmol/L); average LDL-C, 188 mg/dL (4.87 mmol/L)], and the West of Scotland Coronary Prevention Study (4) used pravastatin in men without clinical coronary disease [average TC, 272 mg/dL (7.0 mmol/L); average LDL-C, 192 mg/dL (5.0 mmol/L)]. On the basis of the earlier findings (1, 2), we assumed that these trials would show clinical benefit; however, patients with the …

Abstract 11255: PON1 Q192R (rs662) Genetic Variant and Response to Clopidogrel and Prasugrel

Abstract: Background: Clopidogrel and prasugrel are pro-drugs requiring biotransformation into active metabolites. Multiple studies have validated the relationship between loss-of-function alleles in the CYP...