SUPPLEMENTAL MATERIAL FOR
RISKS AND BENEFITS OF CARDIAC IMAGING
An Analysis of Risks Related to Imaging for Coronary Artery Disease
Juhani Knuuti MD, PhD*, Frank Bengel, MD, PhD#, Jeroen J. Bax, MD, PhD †, Philipp A. Kaufmann,
MD, PhD ‡, Dominique Le Guludec, MD, PhD§, Pasquale Perrone Filardi, MD, PhD¶, Claudio
Marcassa, MD**, Nina Ajmone Marsan, MD, PhD†, Stephan Achenbach, MD, PhD##, Anastasia
Kitsiou, MD, PhD††, Albert Flotats, MD, FEBNM ‡‡, Eric Eeckhout, MD, PhD§§, Heikki Minn, MD,
Prof.¶¶, Birger Hesse, MD, MSci***
Imaging procedures
Cardiac magnetic resonance imaging (CMRI)
CMRI relies on three different types of low-frequency electromagnetic waves: a static magnetic
field, radiofrequency (RF) pulses, and gradient magnetic fields. Potential risks associated with MR
may derive from the effects of each component on biological tissues and mainly on ferromagnetic
objects. The latter is a well-known limitation of MR that can be avoided by appropriate patient
selection, i.e. exclusion of patients with metal object in the body.
Strong static magnetic field as such is unlikely to cause significant adverse biological effects,
although sporadic and transient sensations of nausea and dizziness have been reported. RF
energy applied to the body may be responsible for tissue heating1. The dosimetric term used to
define RF energy is the specific absorption rate (SAR). To avoid significant heating, clinical CMRI
scanners are settled to operate within defined SAR ranges.
Most reported cases of CMRI-related injuries were apparently caused by inappropriate information
and procedures. Many devices commonly used in cardiology, such as coronary stents, septal
occluder devices and cardiac valves, are generally safe in CMRI. However, solid data about the
size of the overall risk remain elusive as reporting of CMRI-related accidents is not mandatory in
many countries. In a recent survey conducted in Japan involving 405 medical institutions
performing CMRI, a total of 97 accidents caused by large ferromagnetic materials accidentally
1
brought into the CMRI suite have been recorded with a mean accident rate of 0.7/100,000
examinations 2.
Simi et al3 and recently also Fiechter et al4 have investigated the impact of cardiac MR on
circulating lymphocyte DNA. DNA double-strand breaks in vivo have been used as a marker of
biologic damage and genotoxic effects induced by medical procedures especially studying the
effects of ionizing radiation. The level of DNA double-strand breaks after cardiac MR were at the
same level than those detected after low dose coronary CT angiography, nuclear imaging and
invasive X-ray angiography.
Contrast agents and tracers
Contrast agents for cardiac CT and invasive coronary angiography (iodinated)
The reported incidence of contrast-induced acute kidney injury varies widely across the literature,
depending on the patient population and the baseline risk factors. Some degree of contrast
induced renal failure was reported to occur in 0.8% of 4,622 in general hospital patients5. In a large
retrospective study of over 16,000 hospitalized patients undergoing procedures requiring iodinated
contrast, a total of 183 (1.17%) subjects developed contrast-induced kidney injury6
The incidence of contrast-induced nephrotoxicity is found to be higher in patients with impaired
renal function before contrast application7. The risk is assumed to be small for GFR values >
60ml/min/1.73m², moderate for GFR between 30 and 60 ml/min/1.73m², and high for values below
30 ml/min/1.73m² 8. Further predisposing factors include diabetes, dehydration, cardiovascular
disease and hypertension, myeloma and advanced age. However, in most patients the increase in
serum creatinine values is temporary and clinically significant kidney failure was found in 0.48% of
patients without previous kidney disease9.
Patients taking metformin have an increased risk of lactic acidosis, a potentially life-threatening
condition, when they are exposed to iodinated contrast agents. Metformin should therefore be
interrupted for 48 hours after contrast exposure10. In recent two studies the whole existence of
clinically significant contrast induced kidney failure was questioned11, 12.
Contrast agents for echocardiography
In 2007 serious AEs occurring within 30 minutes after contrast administration were reported.
However, subsequent retrospective analysis of large databases13-17 showed no increased
incidence of adverse events (AEs) in patients who received echo contrast. In particular, in a recent
meta-analysis18 including more than 200,000 patients the incidence of all-cause mortality was
0.34% (726 of 211,162 patients) in patients receiving echo contrast (n=45,970) compared to 0.9%
2
in patients undergoing echocardiography without contrast (n=5,078,666). The incidence of
myocardial infarction was also similar in the contrast and the non-contrast groups (0.15% or 86 of
57,264 patients and 0.2% or 92 of 44,503 patients, respectively). These results suggest that these
major AEs may not be related to the use of ultrasound contrast agents. The most serious
complication secondary to ultrasound contrast administration is considered to be the occurrence of
allergic/anaphylactoid reactions, which has been reported in 1-3/10,000 patients17-19. In addition,
the occurrence of minor AEs, such as headache, back pain, urticaria, and local hypersensitivity,
was observed in 4-7%, particularly in patients with severe cardiovascular disease. Similar results
were also obtained in the only prospective multicenter study which enrolled 1,053 patients
undergoing contrast echocardiography with a perflutren-based agent, reporting an incidence of
3.5% of minor adverse events, while no deaths or serious AEs were observed20.
Contrast agents for CMRI
Renal biopsy from patients with gadolinium-associated nephropathy suggests that gadolinium
induces global sclerosis, tubular atrophy, and interstitial fibrosis, thus leading to permanent renal
impairment21.
Gadolinium-based contrast agents are also associated with the development of nephrogenic
systemic fibrosis (NSF), which is characterized by thickening and hardening of the skin,
predominantly involving the extremities. In some patients the disorder may also involve muscles,
the diaphragm, and parenchymal organs. In a large single center analysis of 94,917 patients, the
risk of histologically proven NSF was 0.012%22 and in haemodialysis patients 1.0%. It was never
seen in patients with normal renal function. More recently, the incidence of NSF was 8.4% in
patients with acute renal failure23 and 18% in high-risk patients with a GFR <15 mL/ min/1.73 m2.24
Use of low doses and avoidance of repeated doses and screening of all patients for renal
dysfunction are recommended before CMRI.
Limitations of the study
The current analysis was based on the data available in the literature which is incomplete.
Although some of the figures applied in our analysis can be debated, we are convinced that the
risk levels would not change strikingly from the current analysis. The selected approach was based
on estimations of upper limits of the risk of imaging tests so that the risk would not be
underestimated.
Due to this approach the composite risk figures may not represent the purest truth since many of
the risk components are uncertain and may be overestimated. For the same reason the risks
among the different tests should be used cautiously. The risk of radiation is based on linear
3
extrapolation from risks known from atomic bomb survivors. Typically the risks of components are
so small that hard evidence is very difficult to establish. The risk of contrast agents is mostly
caused by contrast induced nephrotoxicity. This effect can be clearly reduced when kidney function
is carefully monitored before the administration of contrast agents. Recently also the whole
concept of contrast induced nephropathy has been questioned11, 12. With gadolinium based
contrast agents the risk of acute nephrotoxicity has not been as well proven as with the iodine
based contrast agents and the used amounts are smaller. Based on literature evidence, we
assumed in our analysis the same risk estimations as for iodine based contrast agents, but it may
be smaller in patients with normal kidney function. In addition, the recent evidence that CMRI may
also cause DNA damage3, 4 was not taken into account since no clinical data is available. Last, but
not least our knowledge about the varying benefit of different imaging tests in different patient
groups is far from unequivocal, but that basic question was not the purpose of this analysis. It is
indisputable that patients with CAD cannot be treated without imaging.
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