Is Stress CMR Ready for Prime Time?

Introduction: What Do We Mean by Stress CMR?

Significant advancements have been made in the development and validation of stress cardiovascular magnetic resonance (CMR) imaging, so an assessment of its routine clinical utility is warranted. One of the earliest capabilities of CMR imaging was the acquisition of cine images, which are high spatial and temporal resolution gated images acquired without contrast at standard short and long axis slice locations for the assessment of left ventricular (LV) volumes, function, and wall motion. Using CMR cine imaging to assess wall motion during the identical pharmacological protocol as dobutamine stress echocardiography (DSE), dobutamine stress magnetic resonance (MR) has been shown to be safe,1 have a higher diagnostic accuracy than DSE,2 and predict prognosis.3,4 Because of the similarity of dobutamine stress MR to DSE, there is little "ready for prime time" to debate about dobutamine stress MR. Current limitations to utilization stem primarily from the longer scan times and physician monitoring imposed by graded dobutamine and atropine administration within the MR scanner.

Contemporary use of the term stress MR typically refers to stress perfusion CMR, a study that includes imaging the first pass of a gadolinium-based contrast agent bolus injection during pharmacologic vasodilation. In addition to stress and rest perfusion imaging for ischemia assessment, the basic stress perfusion CMR study also includes cine imaging for chamber volumes and function and late gadolinium enhanced imaging for scar and viability (Figure 1). This comprehensive myocardial assessment can be obtained for a wide range of body habitus, without ionizing radiation. And because of the short infusion time of adenosine and regadenoson, it can be completed in under 30 minutes.5 Stress perfusion CMR has advanced considerably and is now ready for prime time.

Figure 1

Figure 1
(A, B) Three-chamber and short-axis slice positions imaged by stress perfusion CMR demonstrate severe anterior and anteroseptal hypoperfusion. (C, D) Rest perfusion images demonstrate complete reversibility of the defect. (E, F) Cine images demonstrate mild anteroseptal wall motion abnormality. (G, H) Late gadolinium-enhanced images demonstrate minimal subendocardial myocardial infarction (MI).

Safety and Contraindications

Currently, stress perfusion CMR requires pharmacologic vasodilation, but treadmill exercise perfusion CMR is on the horizon.6 Overall, pharmacologic stress perfusion CMR is safe and has a similar incidence of adverse reactions compared with other pharmacologic stress tests. In the multinational, multicenter European Cardiovascular Magnetic Resonance (EuroCMR) registry, 8,018 patients underwent adenosine stress and 2,219 patients underwent dobutamine stress, for a total of 10,228 stress MR patients. Severe and mild complications were observed in 0.07% and 7.3% of patients, respectively. Severe complications included anaphylactic shock (n = 1) in the setting of adenosine administration, ventricular tachyarrhythmias with dobutamine infusion (n = 3), heart failure (HF) (n = 2), and unstable angina (n = 1). Mild complications included dyspnea, chest discomfort, and ectopy attributed to the pharmacologic agent and mild allergic reactions from gadolinium-based contrast agents.7

Overall, gadolinium-based contrast agents have an excellent safety profile. In the 2015 EuroCMR registry update, 0.12% patients (n = 45 of 37,788) experienced acute gadolinium-based contrast agent-related adverse reactions, with only 2 experiencing a severe anaphylactic reaction.8 The often-cited risk of nephrogenic systemic fibrosis with gadolinium-based contrast agent is rare and confined to patients with acute renal failure or severe chronic renal disease (estimated glomerular filtration rate < 30 mL/min/1.73m2). In fact, a recent report notes that fewer than 1,000 confirmed cases have been reported despite over 200 million administered doses of gadolinium to date, and no cases of nephrogenic systemic fibrosis have been reported in patients without significant renal disease.9

The presence of a cardiovascular implantable electronic devices (CIEDs) such as pacemakers and implantable cardioverter-defibrillators have conventionally been considered absolute contraindications to MR imaging. However, increasing evidence from retrospective studies and prospective registries suggest that with proper protocols in place, patients with non-conditional devices can safely undergo MR imaging.10 Current Heart Rhythm Society guidelines give a Class IIa indication for the use of MR in patients with non-conditional CIEDs if there are no fractured, epicardial, or abandoned leads.10 Additionally, the recent availability of MR-conditional devices improves the compatibility of CIEDs with MR procedures. Several trials of patients with CIEDs randomized to undergo MR imaging versus no MR imaging have demonstrated safety (freedom from MR-related complications) and non-inferiority in efficacy endpoints (no changes in pacing thresholds, R wave amplitude, and lead function parameters).11-13 However, regarding CMR, the impact of devices on image quality should also be considered.

Validation and Diagnostic Accuracy

Validation studies in animal models comparing CMR perfusion to gold-standard microspheres have demonstrated accurate detection of flow limiting stenosis.14 Given its high spatial resolution, stress perfusion CMR can also identify transmural differences in myocardial perfusion,15 enabling detection of subendocardial ischemia in patients with Syndrome X (i.e., microvascular dysfunction).16

Meta-analyses of studies comparing stress perfusion CMR with coronary angiography or fractional flow reserve (FFR) as a reference standard have reported high pooled sensitivity (89-91%) and specificity (76-81%) with overall performance measured by diagnostic odds ratio significantly higher than single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) and similar to positron-emission tomography (PET).17-20 Although meta-analyses may be limited by heterogeneity between studies, these results suggest that the diagnostic performance of stress perfusion CMR is at least as good as nuclear perfusion modalities.

Three prospective trials have compared the diagnostic accuracy of stress perfusion CMR and SPECT performed in the same patients with angiographic correlation.21-23 The two largest to date are MR-IMPACT II (Magnetic Resonance Imaging for Myocardial Perfusion Assessment in Coronary Artery Disease Trial) and CE-MARC (Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease). In the multicenter, multinational MR-IMPACT II trial, 533 patients underwent stress perfusion CMR and SPECT, with coronary angiography as the gold standard comparator study. CMR sensitivity was superior (0.67 vs. 0.59), but specificity was inferior (0.61 vs. 0.72) to SPECT in the detection of coronary artery disease (CAD).22 The CE-MARC trial, with 752 patients, found stress perfusion CMR to be superior to SPECT in detecting significant CAD, with statistically significantly higher sensitivity (86.5 vs. 66.5%) and negative predictive value (90.5 vs. 79.1%) and similar specificity (83.4 vs. 82.6%) and positive predictive value (77.2 vs. 71.4%).23

Prognosis

Stress perfusion CMR provides prognostic information for the risk of developing major adverse cardiovascular events (MACE), including cardiovascular death, acute coronary syndrome, or urgent revascularization. A meta-analysis of stress perfusion CMR studies in 11,636 patients with a mean follow-up of 32 months showed that annual event rates of cardiovascular death and MI was 0.8% in patients with a negative stress perfusion CMR, compared with 4.9% in those with a positive stress perfusion CMR study. The presence of late gadolinium enhancement conferred a worse prognosis as well.24,25 The 5-year follow-up study of CE-MARC also showed a hazard ratio (HR) of 2.77 (95% confidence interval, 1.85-4.16) for MACE with an abnormal stress perfusion CMR, which remained a significant independent predictor after multivariate adjustment.26 These findings have been recapitulated in several other studies, including in patients with diabetes, where a stress perfusion CMR showing inducible ischemia was an independent predictor of cardiac death and nonfatal MI (HR = 4.86; p < 0.01).27

Guidelines

Recognition of the clinical utility of CMR is beginning to emerge in the recommendations outlined in current society guidelines. In the 2012 guideline for the diagnosis and management of patients with stable ischemic heart disease, pharmacologic stress CMR received a Class IIa recommendation for patients with an intermediate-to-high pretest probability of ischemic heart disease who are unable to exercise.28 That pharmacologic stress perfusion CMR received a Class IIa indication compared with the Class I indication for both pharmacologic stress SPECT and echocardiography may reflect a delay in guideline adoption with the most contemporary data. In the 2013 report on the appropriate utilization of cardiovascular imaging in HF, stress CMR was rated as appropriate in the evaluation for ischemic etiology and in viability evaluation in patients with HF, similar to stress echocardiography and SPECT.29,30 In the 2013 appropriate use criteria for stable ischemic heart disease, stress CMR was generally rated as appropriate in settings where pharmacologic stress echocardiography and SPECT were appropriate. The panel noted that in comparison to the prior guideline document, ratings for stress CMR were "more often in accord with the ratings for stress radionuclide imaging, stress echocardiography, and exercise treadmill testing," likely reflecting "the growing body of evidence supporting the utility and accuracy of stress CMR."30

Utilization and Limitations

With a growing body of literature supporting its clinical diagnostic and prognostic abilities, why does stress perfusion CMR remain underutilized in clinical practice in comparison with other stress imaging modalities? Factors such as the relative novelty of CMR imaging and an underappreciation of the comprehensive clinical utility of CMR by non-cardiologists certainly play a role, as does the current inability to provide exercise functional capacity information. Moreover, many cardiologists have had limited formal exposure to CMR. Training in the methodology and utilization of CMR has been only recently incorporated into cardiovascular fellowship training program guidelines.31 Thus, the availability of appropriately trained physicians remains a limitation for many centers wishing to offer stress perfusion CMR.

Patients with acute kidney injury, severely impaired renal function (estimated glomerular filtration rate < 30), and patients requiring dialysis generally should not undergo stress perfusion CMR because of the increased risk for developing nephrogenic systemic fibrosis. Non-contrast studies such as dobutamine stress MR or alternative imaging modalities (e.g., echocardiography, SPECT, and PET) should be considered in these patients.

One of the major diagnostic limitations of first pass perfusion of stress CMR is the dark rim artifact, which can potentially lower the diagnostic accuracy for ischemia. The dark rim artifact is a transient dark band along the subendocardial border of the LV thought to be secondary to limited spatial resolution, motion artifact, and susceptibility artifact of the immediate gadolinium bolus, causing distortion of the local magnetic field.32 Although it can be accounted for in a visual analysis of perfusion defects, this artifact can potentially compound error in quantitative and semi-quantitative assessments of perfusion and transmural perfusion comparisons. Stress perfusion CMR acquisition is generally limited to three short-axis slices of the LV (base, mid, apex), although newer acquisition techniques are allowing faster imaging and more complete slice coverage.

Conclusions regarding stress CMR for risk stratification are derived from relatively small studies compared with other noninvasive imaging modalities such as SPECT MPI33 and are thus limited by length of follow-up and total aggregate patient population sample size.

Future Directions

Advancements in stress CMR acquisition techniques will lead to continued improvement in spatial resolution, slice coverage, and acquisition time. Additionally, the ability to quantitatively assess absolute myocardial blood flow in mL/min/g34 using stress CMR may further improve diagnostic accuracy by enhancing detection of balanced ischemia and recognition of multivessel CAD.35

Although diagnostic accuracy and improved risk stratification are essential, the true measure of the efficacy of an imaging study is its ability to improve patient outcomes. Randomized, comparative effectiveness studies are rare even for more established techniques such as echocardiography and SPECT. That noted, stress CMR has been included in recently reported and ongoing comparative effectiveness studies of ischemia imaging. The CE-MARC 2 (Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease 2) study randomized 1,202 symptomatic patients with suspected CAD to one of three strategies: stress CMR-guided, SPECT-guided, and National Institute for Health and Care Excellence (NICE) guidelines-directed care.36 Overall, MACE were similar in the three groups, and CMR resulted in a lower rate of uneccesary angiography compared with NICE guideline-directed care and a rate similar to SPECT. The recently completed MR-INFORM (MR Perfusion Imaging to Guide Management of Patients With Stable Coronary Artery Disease) study randomized 918 patients with symptomatic, stable ischemic heart disease to stress CMR-guided versus invasive angiography with FFR-guided treatment to compare the occurrence of death, MI, and repeat revascularization.37 Results from MR-INFORM and the ongoing ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) study are anticipated to further eludicate the value of stress CMR in the management of patients with CAD. Preliminary results from MR-INFORM were recently presented at the American College of Cardiology Annual Scientific Sessions in Spring 2017 and suggested that the use of stress CMR may reduce the number of unnecessary coornary angiograms without compromising patient outcomes.38

Summary and Recommendations

Stress perfusion CMR is safe, has a diagnostic accuracy at least as good as other stress imaging modalities, and predicts prognosis. Comparative effectiveness studies are emerging supporting the use of CMR in the evaluation of patients with known or suspected CAD. Thus, with the breadth and robustness of the diagnostic and prognostic information that it provides, stress CMR is ready for prime time today and is the stress imaging modality to watch in the future.

References

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Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Implantable Devices, SCD/Ventricular Arrhythmias, Acute Heart Failure, Echocardiography/Ultrasound, Magnetic Resonance Imaging, Nuclear Imaging

Keywords: Dobutamine, Echocardiography, Stress, Gadolinium, Exercise Test, Nephrogenic Fibrosing Dermopathy, Anaphylaxis, Glomerular Filtration Rate, Atropine, Adenosine, Defibrillators, Implantable, Retrospective Studies, Cicatrix, Vasodilation, Prospective Studies, Purines, Pyrazoles, Magnetic Resonance Imaging, Myocardium, Magnetic Resonance Spectroscopy, Angina, Unstable, Perfusion Imaging, Myocardial Infarction, Heart Failure, Diagnostic Imaging


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