HEARTJNL225904 1286..1292

Recent advances in cardiovascular magnetic resonance (CMR) now allow the accurate and reproducible measurement of many aspects of cardiac and vascular structure and function, with prognostic data emerging for several key imaging biomarkers. These biomarkers are increasingly used in the evaluation of new drugs, devices and lifestyle modifications for the prevention and treatment of cardiovascular disease. This review outlines a conceptual framework for the application of imaging biomarkers to clinical trials, highlights several important CMR techniques which are in use in randomised studies, and reviews certain aspects of trial design, conduct and interpretation in relation to the use of CMR. INTRODUCTION The randomised controlled trial (RCT) is the gold standard approach to the evaluation of a new proposed therapy for cardiovascular disease. 2 The growth in the number and scale of RCTs is in part a consequence of the growth in candidate drug targets, driven by new technologies for drug discovery and screening and by a need to test established therapies in new groups of patients. Cardiovascular magnetic resonance (CMR) offers a range of powerful imaging and spectroscopic techniques which can be used to identify suitable participants for entry into trials, to ensure baseline comparability of treatment arms and to generate markers of disease presence, severity or activity for use as outcome measures in clinical trials. Many of these CMR-derived markers have been validated, and increasingly have been shown to be closely linked to important clinical endpoints. These developments have led to a rapid increase in their use in clinical trials, a trend which is likely to continue. The versatility of CMR arises from the wide range of sequences available, but only a limited number can reasonably be applied to one individual during a CMR study lasting perhaps 60 min. Each technique differs in terms of its accuracy, precision, reproducibility, sensitivity, link with clinical endpoints and ease of use in terms of both acquisition and analysis. Trialists must therefore understand these characteristics for each outcome measure selected. The development and evaluation of a potential new therapy is a complex process which varies substantially in terms of time, costs and difficulty, depending on the target condition and the therapy proposed. CMR may have a role in several of the four phases of drug or device development: to identify suitable participants for enrolment and to confirm baseline distribution of key prognostic factors in different treatment arms at any phase of treatment evaluation; to establish efficacy in phase II and III studies, where it may be used to inform a large-scale RCT of ‘hard’ clinical outcomes; to extend the application of a proven therapy to other groups of patients. Reconciling the expanding pool of candidate therapies and indications for treatment with the desire to have the best possible evidence for efficacy, safety and clinical effectiveness represents a significant challenge. One approach is to accept only hard clinical outcome-driven studies, accepting that the resources required to do this mean that only a small number of particularly promising therapies will be evaluated. In this model, CMR may have an important role in identifying the most promising therapies for further evaluation. A second approach is to broaden the scope of therapies but to evaluate them in restricted patient groups, commonly highrisk groups (who are most likely to experience clinical events). Here, CMR may have a role in confirming efficacy in wider patient groups. A third approach has been to measure a circulating biomarker which is linked to disease severity and to assume that, if the biomarker moves in a direction thought to be advantageous, this will correspond to a consequent reduction in clinically meaningful endpoints. While such studies may be useful in demonstrating efficacy, recent high-profile studies highlight the risks inherent in assuming that a single circulating biomarker can adequately capture all of the relevant consequences of manipulating a complex biological system. For example, in the ILLUMINATE study the CETP inhibitor torcetrapib was shown to worsen clinical outcome despite a theoretically favourable direction of movement of circulating biomarkers. CMR and other imaging modalities may have an intermediate role between early studies showing potential benefit in single biomarkers and large-scale RCTs using clinical outcomes. It is of interest that two imaging studies of torcetrapib (RADIANCE 1 and ILLUSTRATE) did not demonstrate plaque regression. The advantage of imaging surrogate endpoints over circulating surrogate biomarkers is that they capture the downstream activation or common final pathway of disease progression, whereas circulating biomarkers may interrogate a single pathway which may be only one of many relevant pathways. Imaging surrogate endpoint studies can have an important (though not exclusive) role in the evaluation of potential therapies taking place after animal and human dose-ranging studies (phase IeII) but before (and generally as a supplement to or screening process for) large-scale randomised trials. In such cases, it may be that Department of Cardiovascular Medicine, Oxford Centre for Clinical Magnetic Resonance Research, John Radcliffe Hospital, University of Oxford, Headington, Oxford, UK Imperial Clinical Trials Unit, School of Public Health, Imperial College London, London, UK Department of Epidemiology and Biostatistics, MRC-HPA Centre for Environment and Health, School of Public Health, Imperial College London, London, UK Centre for Advanced Cardiovascular Imaging, William Harvey Research Institute, Barts