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INSIDE THIS ISSUE

Inside This Issue

	State-of-the-Art Paper and Commentary

Top State-of-the-Art Paper and... Clinical Research Pre-Clinical Research Year in Cardiology Series

Sanjay Kaul, George A. Diamond

Kaul and Diamond review the strengths and limitations of randomized controlled trials to guide clinical decision making. The difference between statistical significance and clinical significance is reviewed. The potential to obscure with composite end points is highlighted. Finally, many trials publish subgroup analyses without the use of statistically appropriate adjustment for interactions and multiple comparisons. These potential faults are discussed in this review and are highlighted with examples from recent clinical trials. The accompanying figures will help the clinician to visualize these mathematical concepts.

Commentary.   Randomized Trials, Statistics, and Clinical Inference
428

Gregg W. Stone, Stuart J. Pocock

In a commentary accompanying the state-of-the-art paper, Stone and Pocock agree with many of the recommendations for interpreting the results of randomized clinical trials (RCTs), although they take issue with the specific examples given. The authors lament that RCTs are not infrequently poorly designed, implemented with inadequate quality control, and/or subject to inappropriate interpretation or generalization. Many common and egregious misrepresentations from RCTs are due to the fallacies that arise from underpowered studies, particularly in regard to composite outcomes, secondary end points, and subgroup analyses. The authors conclude with the hope that the paper by Kaul and Diamond and this commentary will spur improved design of future RCTs and thoughtful, critical appraisal by caregivers, editors, and regulatory bodies.

	Clinical Research

Top State-of-the-Art Paper and... Clinical Research Pre-Clinical Research Year in Cardiology Series

 
Clinical Trials.   Randomized Trial of CABG Versus PCI in Diabetic Patients

432

Akhil Kapur, Roger J. Hall, Iqbal S. Malik, Ayesha C. Qureshi, Jeremy Butts, Mark de Belder, Andreas Baumbach, Gianni Angelini, Adam de Belder, Keith G. Oldroyd, Marcus Flather, Michael Roughton, Petros Nihoyannopoulos, Jens Peder Bagger, Kenneth Morgan, Kevin J. Beatt

The CARDia (Coronary Artery Revascularization in Diabetes) trial investigated the safety and efficacy of percutaneous coronary intervention (PCI) with stents compared with coronary artery bypass grafting (CABG) in patients with diabetes and multivessel disease. The primary outcome was a composite of death, myocardial infarction (MI), or stroke, and over 500 diabetic patients were randomized to PCI or CABG with a noninferiority design. At 1 year, the composite rate of death, MI, and stroke was 10.5% in the CABG group versus 13.0% in the PCI group (p = 0.39). All-cause mortality was the same at 3.2%, and the secondary composite of major adverse coronary and cerebral events, including repeat revascularization, favored CABG at 11% versus 19%. The 1-year results of the CARDia trial do not demonstrate that PCI is noninferior to CABG for the combined end point of death, MI, and stroke, although longer follow-up is pending.

Heart Failure.   NT-proBNP Can Identify Asymptomatic Subjects at Risk of Developing HF

441

Christopher R. deFilippi, Robert H. Christenson, John S. Gottdiener, Willem J. Kop, Stephen L. Seliger

deFilippi and colleagues sought to determine if measurement of N-terminal pro–B-type natriuretic peptide (NT-proBNP) would provide prognostic information in elderly patients with no history of heart failure (HF). NT-proBNP was measured at baseline and 2 to 3 years later in nearly 3,000 older adults. Those with NT-proBNP levels in the highest quintile (>268 pg/ml) were 3 times more likely to develop HF or to die from a cardiovascular (CV) cause than those in the lowest quintile (<47 pg/ml). Serial testing revealed that subjects with initially low NT-proBNP who developed a >25% increase to >190 pg/ml were 2 times more likely to develop HF or suffer a CV death compared with those with sustained low levels. These results suggest that NT-proBNP levels independently predict heart failure and CV death in older adults, and serial examinations provide further prognostic information.

Editorial Comment: Matthew G. Daly, Christopher M. Frampton, Richard W. Troughton, p. 451

Vascular Disease.   Hemodialysis Linked to Impaired Vascular Function Through Release of Free Hemoglobin
454

Christian Meyer, Christian Heiss, Christine Drexhage, Eva S. Kehmeier, Jan Balzer, Anja Mühlfeld, Marc W. Merx, Thomas Lauer, Harald Kühl, Jürgen Floege, Malte Kelm, Tienush Rassaf

Meyer and colleagues investigated the mechanisms that underlie endothelial dysfunction in patients undergoing hemodialysis. Hemodialysis significantly impaired endothelial function measured with flow-mediated dilation (FMD) of the brachial artery. This was accompanied by an increase in cell-free plasma hemoglobin; the hemoglobin absorbs free nitric oxide (NO) such that its bioavailability was reduced by more than 70%. Oxidation of the released hemoglobin prevented the consumption of NO, and there was an inverse correlation between free hemoglobin and the change in FMD. These results link hemodialysis to impaired vascular function and suggest that interventions that reduce red blood cell hemolysis or oxidize the plasma hemoglobin may reduce the risk of cardiovascular events in patients undergoing hemodialysis.

Editorial Comment: Chenell L. Donadee, Mark T. Gladwin, p. 460

Cardiomyopathy.   Autoantibodies Against G-Protein–Coupled Receptors May Lead to Chagas' Cardiomyopathy and Megacolon
463

Gerd Wallukat, Silvia Gilka Muñoz Saravia, Annekathrin Haberland, Sabine Bartel, Raul Araujo, Gregorio Valda, Diana Duchen, Ivan Diaz Ramirez, Adrian Constantin Borges, Ingolf Schimke

Chagas' disease affects 15 million people, mostly in Latin America. Despite being lifelong parasite carriers, two-thirds of the patients remain clinically asymptomatic while one-third eventually develop either a cardiomyopathy or megacolon. Wallukat and colleagues studied the expression of autoantibodies (AAB) against G-protein–coupled receptors in patients who developed Chagas' cardiomyopathy and/or megacolon and also in asymptomatic subjects with Chagas' disease. Nearly all Chagas' patients with symptoms had high levels of AAB with specific patterns seen in those with either cardiomyopathy and/or megacolon. Similar patterns were seen in some asymptomatic subjects with a frequency that mirrors epidemiological data on the likelihood of chronic carriers developing symptoms. Measurement of AAB might be a useful tool for risk assessment in asymptomatic subjects with Chagas' disease.

	Pre-Clinical Research

Top State-of-the-Art Paper and... Clinical Research Pre-Clinical Research Year in Cardiology Series

 
Pre-Clinical Research.   CTGF and Rac1 May Predispose to Developing AF

469

Oliver Adam, Daniel Lavall, Katharina Theobald, Mathias Hohl, Markus Grube, Sabine Ameling, Mark A. Sussman, Stephan Rosenkranz, Heyo K. Kroemer, Hans-Joachim Schäfers, Michael Böhm, Ulrich Laufs

Adam and colleagues used a series of experiments to study atrial structural remodeling that contributes to the pathogenesis of atrial fibrillation (AF). The studies began by performing transcriptional profiling of left atrial (LA) myocardium from patients with AF and sinus rhythm (SR), which showed a marked up-regulation of connective tissue growth factor (CTGF) expression in those with AF. This was associated with increased fibrosis, nicotinamide adenine dinucleotide phosphate-oxidase, Rac1, and RhoA activity, and increased angiotensin II levels. In vitro studies of rat cardiac myocytes and fibroblasts showed that inhibitors of Rac1, including simvastatin, prevented the up-regulation of CTGF. Finally, in mice predisposed to developing AF, inhibition of Rac1 by oral statin treatment prevented up-regulation of these pathways and reduced the incidence of AF. These data identify CTGF as an important mediator of atrial structural remodeling that predisposes to developing AF.

Editorial Comment: James K. Liao, p. 481

	Year in Cardiology Series

Top State-of-the-Art Paper and... Clinical Research Pre-Clinical Research Year in Cardiology Series

 
Year in Cardiology Series.   Year in Cardiac Imaging
483

Raymond J. Gibbons, Philip A. Araoz, Eric E. Williamson

This review by Gibbons and colleagues highlights the most important literature regarding single-photon emission computed tomography (CT) myocardial perfusion imaging, cardiac positron emission tomography, cardiac CT, and cardiac magnetic resonance imaging from approximately July 2008 to June 2009. Almost 100 papers are highlighted with summaries of the key findings and commentary to place them in context with other literature. The authors hope that this review will encourage the reader to examine some of these papers in more detail and, ultimately, to more carefully apply the correct imaging modality to each clinical problem.

Related Articles

Trial and Error: How to Avoid Commonly Encountered Limitations of Published Clinical Trials

Sanjay Kaul and George A. Diamond
J. Am. Coll. Cardiol. 2010 55: 415-427. [Abstract] [Full Text] [PDF]

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