Author + information
- Colin Berry, MBChB, PhD∗ (, )
- Kenneth Mangion, MD and
- David Corcoran, BMedSci(Hons), MBChB
- British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow
- West of Scotland Heart and Lung Centre, Golden Jubilee National Hospital, Glasgow, Scotland, United Kingdom
- ↵∗Address for correspondence:
Prof. Colin Berry, BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, 126 University Place, University of Glasgow, Glasgow G12 8TA United Kingdom.
Management guided by invasive coronary angiography (ICA) is the reference pathway for identifying and treating obstructive epicardial coronary artery disease (CAD). In patients with flow-limiting CAD, revascularization improves symptoms and in certain high-risk subgroups may confer a survival advantage (1). ICA provides anatomical information and the physiological significance of a stenosis can be determined using adjunctive diagnostic tests, such as fractional flow reserve (FFR) and nonhyperemic pressure–derived indexes (1).
Myocardial ischemia reflects the metabolic insult of flow-limiting CAD and the extent of ischemia (2) and worsening of ischemic burden (3) correlates with prognosis. Revascularization reduces ischemia compared with medical therapy only (2,3), but whether relief of ischemia by revascularization improves prognosis is not well established (2–4). This knowledge gap is currently being investigated in the ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) trial (NCT01471522). Furthermore, invasive management with percutaneous coronary intervention is not beneficial when performed in patients without angina or objective evidence of ischemia (or flow-limiting CAD) (5).
The National Institute for Health and Care Excellence clinical guideline (CG-95) recommends use of coronary computed tomography angiography (CTA) for patients with recent onset chest pain and no prior history of CAD (6). However, information on ischemia will be lacking in patients who are referred for ICA following coronary CTA. Coronary artery imaging by coronary CTA does not reduce the referral rate for ICA. Therefore, the coronary CTA strategy increases the number of coronary angiogram procedures (first a noninvasive coronary CTA then an ICA), leading to repeated exposures to ionizing radiation for individual patients. Multiple current trials are testing hypotheses for different strategies that are intended to disrupt and optimize the standard care management of patients with symptoms and known or suspected ischemic heart disease (IHD).
In the MR-INFORM (MR Perfusion Imaging to Guide Management of Patients With Stable Coronary Artery Disease) trial (NCT01236807), Nagel et al. (7) hypothesized that an initial management strategy based on myocardial perfusion cardiac magnetic resonance (CMR) would be noninferior to a strategy guided by ICA ± FFR in terms of major adverse cardiac events. They performed a multicenter, prospective, clinical-effectiveness trial by randomizing 918 patients with typical angina and ≥2 CAD risk factors into a noninvasive (MR-INFORM trial group) or an invasive (FFR-INFORM [Fractional Flow Reserve-INFORM - MR Perfusion Imaging to Guide Management of Patients With Stable Coronary Artery Disease] trial group) group. Evidence of myocardial ischemia by CMR (perfusion defect ≥2 of 32 segments) or FFR (<0.8) warranted proceeding to revascularization. The composite primary endpoint was death, myocardial infarction (MI), or target vessel revascularization within 1 year. Ischemia occurred in 40% of the MR-INFORM trial group (n = 184; CMR criteria) and 46% of the FFR-INFORMED trial group (n = 213; FFR criteria) and fewer patients in the CMR group underwent index revascularization. A clinical case from the trial is summarized in Figure 1. The proportions of patients free from angina were not different at 12 months (44% vs. 49%; p = 0.21) and the MR-INFORM trial strategy was noninferior for the primary outcome. The MR-INFORM trial is a landmark trial because it serves evidence that noninvasive imaging with stress perfusion CMR has potential to serve as an alternative reference strategy to anatomical imaging with ICA for guiding the management of patients with known or suspected IHD.
Global clinical practice will not change in light of 1 trial and more research is warranted. In this regard, the MAGnet (Magnetic Resonance Adenosine Perfusion Imaging as Gatekeeper of Invasive Coronary Intervention) trial in this issue of iJACC is timely (8). Buckert et al. (8) randomized 200 symptomatic CAD patients in a single center to standard diagnostic ICA or adenosine stress CMR. The primary endpoint was the composite of cardiac death and nonfatal MI. Quality of life was assessed by the Seattle Angina Questionnaire at baseline and during follow-up. Compliance with the randomized strategy was high (97%) and complete follow-up information was available in ∼95% of the population. At 3 years, 13 primary outcome events had occurred (cardiac death: 2 cases, nonfatal MI: 11 cases). Four (4.1%) events occurred in the invasive group and 9 (9.4%) events occurred in the CMR group. This numerical difference was not statistically significant (p = 0.25). Noninferiority of the noninvasive strategy for cardiac death and nonfatal MI was not confirmed (p = 0.88). Revascularization was reduced initially in the CMR group, but by 3 years there were no between-group differences in revascularization or quality of life.
The MAGnet trial has limitations including the lack of concealment of treatment group allocation, lack of a sham procedure, limited sample size, low event rate, lack of power for the primary analysis, and the single-center setting. By chance, there were imbalances in the proportion of patients with diabetes and prior history of IHD, both higher in the CMR group. Detailed information on medical therapy was lacking, which is particularly relevant because the effectiveness of the noninvasive strategy is dependent on effective medical management. The late catch-up of coronary revascularization procedures may reflect CAD progression, symptoms due to persistent or new ischemia, lack of effective medical therapy, or the bias of patients and the attending clinicians in this unblinded trial.
The MAGnet trial has notable strengths. CMR does not expose patients to ionizing radiation and the CMR strategy reduced ICA within the first 12 months following randomization. The noninvasive strategy is highly disruptive to standard care, yet compliance with the protocol was high. The follow-up period was 3 times longer than in the MR-INFORM trial.
In conclusion, the MR-INFORM and MAGnet trials lend support to adoption of noninvasive myocardial imaging as an alternative reference strategy in patients with risk factors for IHD. The clinical utility of this strategy will improve with advances in technology (9) and adherence with pharmacological and lifestyle interventions. FFR computed tomography, which uniquely integrates coronary anatomy and physiology, also holds promise for becoming a tractable option. For now, ICA is the standard of care for decision making, but watch this space.
↵∗ Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Prof. Berry is supported by a British Heart Foundation Centre of Research Excellence award (RE/13/5/30177). The University of Glasgow holds research and consultancy agreements with Abbott Vascular, AstraZeneca, Coroventis, Corstem, GlaxoSmithKline, HeartFlow, Menarini, Neosoft, Novartis, Philips, and Siemens Healthcare. These companies had no involvement in this manuscript. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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