As no standardized definition of residual platelet reactivity (RPR) exists, we defined RPR as the upper tertile of platelet aggregation.

Multiple linear regression analysis was used to identify determinants of immature platelet levels.

Two-sided P- values < 0.05 were considered statistically significant.

Figures and statistics were performed using STATA Ò version 10.0 (StataCorp, College Station, TX, USA) and GRAPHPAD PRISM 5 (GraphPad Software, San Diego, CA, USA).


Clinical characteristics of the study population are shown in Table 1.

We included a population of stable CAD patients with a relatively high-risk profile.

Thus, only patients without any cardiovascular events or revascularization procedures within the previous year were included, and there was a high prevalence of type 2 diabetics (48%), previous percutaneous coronary intervention (92%), myocardial infarction (66%), coronary artery bypass grafting (23%) and stroke (10%).

Pill counting and face-to-face interviews did not reveal any non-compliant patients, and optimal compliance was confirmed by serum thromboxane B 2 levels < 7.2 ng mL )1 in all patients [21].


As shown in Table 2, no significant correlations were observed between platelet aggregation and the IPF, whereas absolute IPC correlated with platelet aggregometry measured by MEA (r = 0.31-0.35, all P-values < 0.0001), but not with Verify- Now Ò results (r = 0.12, P = 0.104).

IPC (but not IPF) correlated with the platelet activation marker sP-selectin (r = 0.19, P = 0.014, Fig. 1).


Whole blood platelet aggregometry results obtained using MEA significantly correlated with platelet count (r = 0.45- 0.68, all P-values < 0.0001), whereas only a trend was seen with the VerifyNow Ò Aspirin test (r = 0.14, P = 0.066).

Similarly, the VerifyNow Ò analyzes were not affected by MPV (r = 0.02, P = 0.755), whereas results obtained using MEA correlated with MPV (r = 0.17-0.23, P-values < 0.05), except when aggregometry was induced by ADP (r = 0.01, P = 0.906).


As expected, there was a negative correlation between platelet count and MPV (r = )0.30, P < 0.0001) and between platelet count and IPF (r = )0.32, P < 0.0001).

Platelet count also correlated with PDW (r = )0.30, P < 0.0001), P-LCR ()0.29, P < 0.001) and IPC (r = 0.13, P = 0.08, Fig. 1).

Significant positive correlations were seen between PDW and MPV, IPF and IPC (r = 0.64-0.95, P-values < 0.0001) as well as between P-LCR and MPV, IPF and IPC (r = 0.63- 0.99, P-values < 0.0001).


As shown in Table 3, platelet characteristics differed between patients with and without residual platelet reactivity defined as the upper tertile of platelet aggregation.

Most strikingly, platelet counts (MEA: P < 0.0001, VerifyNow Ò : P = 0.055)


Despite treatment with the same dose of aspirin, CAD patients with diabetes mellitus type 2 had significantly higher levels of serum thromboxane B 2 (1.03 [0.5;2.2] vs. 0.58 [0.35;0.92] ng mL )1 , P < 0.0001) and higher levels of residual AA- induced platelet aggregation (159 [91;232] vs. 121 [68;180] aggregation units · min, P = 0.009).

Furthermore, sP-selectin (77.8 ± 25 vs. 66.3 ± 28 ng mL )1 , P = 0.005) and throm- bopoietin levels (36 [19;56] vs. 24 [12;35], P < 0.001) were significantly higher in diabetics.


Independent determinants of platelet turnover were investi- gated using multivariate regression analyzes including platelet count, age, gender, body mass index, previous myocardial infarction, diabetes, smoking and thrombopoietin levels.

Ana- lyzes were performed to identify determinants of the relative (IPF) and absolute (IPC) number of immature platelets.

The IPF was affected by platelet count (P < 0.001), whereas this


The present study provides novel insight into the relation between platelet turnover and platelet aggregation in aspirin- treated patients with CAD.

Previous studies have primarily evaluated the relative fraction of immature platelets, but our study showed that the absolute number of immature platelets (i) has a stronger correlation with platelet aggregation, (ii) is not significantly affected by the total platelet count, (iii) signifi- cantly correlates with the platelet activation marker sP-selectin and (iv) is stronger associated with the presence of residual platelet reactivity.

Furthermore, we showed that commonly used platelet function tests seem to differ in their dependence on platelet count.

Contrary to MEA, the VerifyNow Ò Aspirin test is not significantly affected by variations in platelet count and other platelet parameters.

Importantly, this is the largest study employing measurements of thrombopoietin and imma- ture platelets to investigate platelet production and turnover in a population of aspirin-treated stable CAD patients.

In a multivariate regression analysis, smoking, diabetes and throm- bopoietin levels were identified as significant determinants of platelet turnover.


No previous studies have evaluated platelet turnover in stable CAD patients on chronic, low-dose aspirin.

We specifically aimed to investigate this population in order to strengthen the external validity of our results.

We have demonstrated that aspirin-treated CAD patients with a high platelet turnover have a reduced antiplatelet effect of aspirin.

Our findings are consistent with recent reports of reduced antiplatelet efficacy in individuals with high levels of immature, reticulated platelets.

This has been demonstrated in healthy volunteers after a single-dose administration of aspirin [5] and in CAD patients on dual antiplatelet therapy with aspirin and clopi- dogrel [6,7].


There are several possible explanations for these findings.

First, the response to antiplatelet therapy is probaly affected by the ability of newly formed RNA-containing platelets to produce glycoprotein IIb/IIIa, COX-2 and alpha-granule proteins, such as fibrinogen and von Willebrand factor [5,14,15].

The fact that newly formed platelets express more COX-2 is likely to be particularly important, as COX-2 is not blocked by low-dose aspirin, thus resulting in an increased thromboxane production [5,15].

Additionally, an increased platelet turnover may be important per se, as platelets unaffected by aspirin are introduced into the blood stream possibly causing the overall platelet inhibition to be insufficient, especially during the last hours of the dosing interval.

Owing to the irreversible inhibition of the platelet COX-1 enzyme, once- daily dosing of low-dose aspirin is sufficient in patients with a normal platelet turnover, whereas this may not be the case in individuals with an increased platelet turnover [4].


A high frequency of residual platelet reactivity according to MEA was found in patients with high platelet counts, large MPV and high levels of immature platelets.

Furthermore, residual platelet reactivity was associated with higher levels of sP-selectin and serum thromboxane B 2 , suggesting a lower aspirin-induced COX-inhibition in these patients.

These find- ings are in accordance with previous studies showing that complete inhibition of COX is necessary to achieve sufficient inhibition of platelet aggregation [4,22].


When residual platelet reactivity was defined according to the VerifyNow Ò Aspirin test, no significant association was observed with platelet parameters, indicating that this assay is less dependent on platelet parameters compared with MEA.

These results extend our recent findings of a very high reproducibility of the VerifyNow Ò assay compared with MEA and other platelet function tests [23].

Moreover, a very recent study on 20 healthy volunteers reported that results


Large platelets are known to be more reactive than small platelets [8-10].

In this population of aspirin-treated patients with CAD, MEA induced by collagen or AA significantly correlated with MPV, whereas test results obtained with the VerifyNow Ò Aspirin assay were not affected by MPV.

The finding of a significantly higher MPV in patients with residual platelet reactivity according to AA-induced MEA might be explained by an increased hemostatic potential of large platelets.

These results are consistent with findings of a lower inhibitory effect of aspirin on large compared with small platelets [25].

Furthermore, even after indexing for surface area, large platelets have been shown to contain more dense granules and express more fibrinogen, von Willebrand factor and sP-selectin in response to AA compared with small platelets [25].

An increased MPV has been reported in patients with myocardial infarction and as a risk factor of recurrent myocardial infarction in patients with CAD [26,27].


In our population of CAD patients, highly significant correlations between platelet distribution width, platelet large cell ratio and platelet parameters were observed.

Although PDW and P-LCR have been reported to be elevated in patients with acute coronary syndromes [28], further studies are needed to investigate the clinical importance of these platelet volume indices.

The present study was not designed to identify determinants of platelet count, but a significant negative correlation was seen between MPV and platelet count, thus supporting the well-known phenomenon of a relatively stable platelet mass (platelet count · MPV).


Cardiovascular disease is a major cause of death in diabetics [29], who may have an insufficient cardiovascular protection from aspirin [30].

We observed a higher residual platelet reactivity in aspirin-treated type 2 diabetics with CAD com- pared with CAD patients without diabetes, thus confirming previous findings by DiChiara et al. [ 31].

The present study suggests that this may be explained by increased platelet activation as indicated by significantly higher levels of sP- selectin and less effective inhibition of COX-1 as indicated by significantly higher levels of serum thromboxane B 2 .

Further- more, platelet turnover might be accelerated in diabetics [32], and this may result in an increased number of non-aspirinated platelets, especially during the last part of the 24-h dosing interval.


Using multivariate regression analysis, we identified type 2 diabetes, smoking and thrombopoietin levels as three indepen- dent determinants of platelet turnover, thus extending our findings in patients with acute coronary syndromes [16].

The accelerated platelet turnover in diabetics is in accordance with a previous study showing that CAD patients with diabetes have increased megakaryocyte ploidy, levels of inflammatory mark- ers and MPV [33].


In a population of stable CAD patients with a large proportion of diabetics, we carefully optimized compliance, dose and timing between aspirin ingestion and blood sampling.

How- ever, when interpreting the results, some limitations should be considered.

Off-aspirin measurements were considered uneth- ical in this population and were not performed.

Although statistically significant, many of the correlations observed were relatively weak.

Platelet turnover was evaluated by measure- ments of platelet parameters and thrombopoietin levels, but might have been even better explored by including measure- ments of, for example, interleukin-6.


The present study supports the hypothesis that an increased platelet turnover may render aspirin less effective in patients with CAD.

Accordingly, inter-individual differences in imma- ture platelet levels may partly explain previous findings of a variable response to antiplatelet therapy.

In particular, these data suggest that the reduced cardiovascular protection from aspirin observed in diabetics might be at least partly explained by an increased platelet turnover.

Furthermore, we have shown that commonly used platelet function tests differ in their dependence on platelet parameters such as platelet count.

We conclude that the antiplatelet effect of aspirin is reduced in CAD patients with an increased platelet turnover.

Once-daily dosing of aspirin might not be sufficient to adequately inhibit platelet aggregation in patients with an increased platelet turnover.


We read with great interest the recent report by Grove et al. [ 1] related to the effect of platelet turnover on platelet aggregation in patients with stable coronary artery disease (CAD).

In their study [1], the authors investigated the relationship between platelet aggregation, platelet activation and platelet turnover in a population of subjects with stable CAD and demonstrated that aspirin-treated patients with stable coronary artery disease who have a high platelet turnover also have a reduced antiplatelet effect of aspirin [1].


In fact, platelets are quite heterogenous blood elements, diverging in terms of size, density and reactivity [2].

Platelet size has been shown to be related to platelet reactivity [3] and along with this finding, there is evidence that mean platelet volume (MPV) is an important biological variable, and immature platelets have larger MPV with higher thrombotic potential [4].

In the recent study [1], a high frequency of residual platelet reactivity was reported in patients with high platelet counts, large MPV and high levels of immature platelets.


In a study by Yilmaz et al. [ 5], the authors evaluated patients undergoing an exercise stress test and found that patients with a strongly positive exercise test, in whom presence of coronary artery disease was demonstrated by coronary angiography, had a significant increase in MPV values after exercise.

Platelet reactivity, as indicated by MPV values, which increases after exercise in patients with significant coronary artery disease, may be associated with fresh release of platelets from bone marrow, the spleen and other reservoirs representing immature platelets.

Although the report by Grove et al. [ 1] showed a trend towards increased levels of immature platelets in patients with CAD and type 2 diabetes, the effect of exercise on MPV values in patients with occlusive CAD [5] should not be neglected.


We appreciate the letter by Refiker et al. [ 1] in response to our recent article [2].

The main finding of our study was a reduced antiplatelet effect of aspirin among patients with coronary artery disease and an increased platelet turnover.

Thrombopoiesis and the rate of platelet turnover are reflected by the amount of platelets newly released from the bone marrow.

An accelerated platelet turnover causes faster renewal of unacetylated cyclooxygenase-1 and an increased number and fraction of immature, reticulated platelets with an increased hemostatic potential [2,3].

Quantification of this platelet subpopulation can be used as a proxy for platelet turnover [4].


In our study, whole blood aggregometry was performed, and immature platelets were identified by automated flow cytometry with fluorescent RNA-staining dyes.

Using the same methods, we have recently shown that patients with previous stent thrombosis have a reduced antiplatelet effect of aspirin, which might be explained by increased platelet turnover and the fact that the fraction of immature platelets is increased in acute coronary syndromes, especially in the acute phase of ST-segment elevation myocardial infarction [5,6].


Refiker et al. [ 1] stress the importance of increased platelet volume, which has been shown to coexist with increased platelet aggregability [7].

As the identification of immature platelets is partly based on cell size (forward light scatter), we believe that many previous findings on platelet volume reflect the importance of large, immature platelets, as also indicated by the relatively strong correlation between mean platelet volume and the immature platelet count (r = 0.65, P < 0.0001) in our study [2].


The authors suggest that, in patients with coronary ischemia, platelet volume increases after exercise and that this may be associated with the release of immature platelets from the bone marrow, spleen and other reservoirs [1].

Although this mechanism cannot be completely ruled out, we believe that our findings are valid and not affected as suggested.


First, any platelet reservoir outside the bone marrow is unlikely to contain significant amounts of immature platelets, which are partly identified on the basis of their RNA content (fluorescence intensity) that degrades within approximately 24 h once platelets are released into the circulation [4].

Furthermore, only stable patients without any cardiovascular events or revascularization procedures within the previous year were included, and blood sampling was performed with patients in the supine position after 30 min of rest.


Previous studies have demonstrated considerable variation in the antiplatelet effect of aspirin [8], and our study provides evidence that the rate of platelet turnover contributes to this variation [2].

Importantly, interindividual differences in the efficacy of antiplatelet drugs have been shown to affect cardiovascular outcomes [8–10].

Therefore, the importance of platelet turnover may have clinical relevance, as also suggested by studies showing a progressive reappearance of platelet aggregation with time after aspirin intake, even within the usual 24-h dosing interval [11,12].

Accordingly, the currently recommended once-daily dosing of aspirin may offer insufficient protection against cardiovascular events in patients with increased platelet turnover.


Inappropriateness of medical imaging has been a trending topic in the last few years [1-4].

The linear growth in the health care expenditures due to costs of imaging exams [5-7] along with new evidence that medical radiation may cause long-term cancer [8, 9] is contributing to the increased inter- est of the medical community and general population.

Stud- ies demonstrate that imaging exams are responsible for a 45 % increase in health expenditures [5].

In addition, it is estimated that up to one-third of all imaging exams are partially or totally inappropriate [3, 10].

As inappropriate- ness of imaging exams is seen as a potential cause of pa- tients' harm, the current ethical and legal forms and rules are being reviewed, as well as the informed consent process, which is one of the most important tools to protect patients and physicians.


Clinical imaging has conferred undoubted benefits on modern medical practice.

But this does not mitigate the fact that even with low ionising exposure every radiological or nuclear medicine examination may lead to a long-term risk The main aim of this article is to discuss the role and impact of the informed consent process in patients undergoing imaging exams containing ionising radiation.

The legal aspects of the informed consent process, risk communication and uncertainties within the consent process are also emphasised in this review.


Physicians must justify their decision to request an imaging exam using ionising radiation, and the decision is based on a trade-off between risks and benefits [11].

The benefits from diagnostic procedures utilising radiation must overcome the risks [12, 13].

The decision must consider the likelihood of immediate benefit as well as future damage to health [14-17].

In order to make a decision, clinicians must be familiar with the given radiation dose and the possible harmful effects of the radiation exposure [12].

Without solid knowledge of the radi- ation risk from imaging exams, physicians are unable to properly ponder the risks compared to potential benefits and may find it difficult to justify the exposure of patients to medical radiation [18-21].

Referral guidelines can partially replace the lack of deep knowledge [22-25].

Limited knowl- edge about radiation and an inadequate use of guidelines indicate a suboptimal justification of referrals [25].


Many studies reveal important shortcomings in physi- cians', as well as in medical students', awareness and knowl- edge about radiation risk [18-21].

Since today's medical students are future medical practitioners, they will be unable to make appropriate informed clinical decisions unless they are taught principles of radiation protection.

A white paper of the European Society of Radiology [26]-in line with the European MED Directive [27]-emphasises that undergrad- uate and graduate students need to acquire a broader and deeper understanding of the hazards of radiation, patients' protection, awareness of which tests deliver a larger absorbed radiation dose, the value of alternative investigations without the use of radiation, etc.

In addition, undergraduate and grad- uate students need to comprehend the principle of informed consent and its impact on clinical imaging and interventional procedures [28].


The doctrine underlines the ideal of using informed consent to improve patient autonomy and physician-patient communication.

Nevertheless, some authors argue that informed consent itself often fails to achieve this goal [29-32].

Other authors describe the difference between the doctrine and the operational ap- plication of informed consent, which is still imperfect and requires improvement [33-36].


Following a representative then simplified perspective, there are basically two manners in which to implement the informed consent (see Table 1), and they are described by two models: the event- and the process-based model.

The event-based model, the one most often used [37-40], can be applied at a given moment and in any diagnostic path.

This procedure must, therefore, cover all the legal elements in that precise circumstance in which the template will be subjected to being signed by the patient [36, 41].

The event-based model impedes the patient from deciding freely and deliber- ately, as the patient remains unaware of possible biological consequences of radiological interventions.

Also, physicians are not fully protected under the event-based model, as-by using this ineffective communication approach-they can carry out unsuccessful clinical acts more frequently, with legal consequences.

Research has shown that effective patient-physician communication can improve health out- comes [42-45].

On the other hand, a lack of physician- patient communication also generates more recurrent medi- cal litigations [46-49].

The event-based model is considered ineffective [37, 41, 50, 51], additionally contributing to inappropriateness, as only written information is provided and this does not necessarily imply that patients are truly informed about the risks and benefits of the examination and potential alternatives [52, 53].


The process-based model, on the contrary, integrates the information process to the patients in an outgoing dialogue with the physicians as part of the diagnostic and treatment routine [36, 41].

Authors suggest that the process-based model shows many advantages compared to the event- based model, such as enhancing the physician-patient inter- action, thus the responsibility from both parts [36, 41].


The arbitrary nature of the medical act is well known in Italian criminal law, which prosecutes illegal medical acts such as the lack of informed consent, providing inadequate or incomplete information, and communicative disclosure between the physician and patient.


After being fully informed by their physicians, patients should carefully read the consent form before agreeing with the medical act [54-57].

If patients are unaware of the radiation risk from imaging exams, they will therefore not perceive the intrinsic danger; consequently, a signature on the consent form will not be legally valid.


Physicians have an ethical and legal responsibility when requesting a patient to sign a consent form agreeing to a risky 648 Insights Imaging (2013) 4:647-653 medical act [58-60].

The possibility of a patient developing cancer as a result of ionising radiation is often omitted by the physician requesting or performing the imaging exam.

This is the result of several malfunctions such as poor interaction and/or communication between the physician and patient, lack of clinical appropriateness and lack of organisational appropriateness.

The latter is a cause of internal disecon- omies within clinical structures, where ionising imaging represents a large segment of clinical practice.

Specifically, these diseconomies include (1) an increased incidence of civil litigation; (2) increased insurance premiums for medical responsibility; (3) a consequent refusal by insurance compa- nies to assume the warranty of the clinical risks; (4) longer waiting lists; (5) more general and unsustainable waste in healthcare expenditures.


The physicians must justify their own prescriptions, from a clinical and legal standpoint, as well as the carrying out the procedure.

The Euratom Law states that an examination involving radiation exposure must be justified in advance before a patient is referred to a radiologist or nuclear medi- cine physician [27].

The justification integrates scientific and clinical elements with a certain type of ionising technology to be used.

Therefore, it is precisely in this correlation between the use of ionisation and the specific patient's dis- ease that the legal right to "real" informed consent is ac- knowledged [58-60].

According to some authors, it is rea- sonable that the provision of risk information within the informed consent process should be mandatory only for procedures with a radiation dose higher than 1 mSv, such as CT, nuclear medicine exams, positron emission tomogra- phy (PET), PET/CT and fluoroscopic procedures [58, 61, 62].


An important problem linked to informed consent is the time factor, whether informed consent expressed immediate- ly before the execution of the radiological procedure is legally valid [59, 60].

In response to this question concerning the timing of informed consent, we should remember that information, dialogue and trust between the physician and patient should exist within a planned and active clinical implementation [61].

Thus, it is imperative an appropriate chronological separation between conveying the information to the patient and the implementation of the procedure utilising radiation [60].

Only in this way, can the communi- cative and legal intent be preserved in order to minimise any psychological coercion connected to the time factor influencing the willingness of the patient to provide informed consent.

The decision-making autonomy of the patient-a fortiori and in this specific type of informed consent-cannot be constrained by the time factor, which even more strongly collides with the specific scientific and clinical significance of the radiological risk, as well as with complex problems related to effective communication [58-60].


Results from a study showed that communication, time to talk and information are probably the most important features that patients desire from their physicians, including from radi- ologists [63].

A study [64] demonstrated, that even in a busy practice driven by time constraints and financial pressure, 80 % of the patients were satisfied and were able to convey their problems to physicians in only 2 min of interaction [64].

Therefore, physicians should not blame their busy schedule to justify poor interaction with their patients or a lack of time to properly explain the risks and benefits of complementary exams to their patients.


Risk communication is a projection of the legal duty of the physician.

This projection should be related to the patients' rights to have input concerning medical acts that could damage their health or expose them to a real middle- or long-term danger of death.

Failure to provide such informa- tion to the patient in the context of informed consent can subsequently (and in court) lead to the investigation and possible conviction of the professional who performed an arbitrary act of ionising imaging.

This occurs when the physician-prior to the exam-does not explain the risks and benefits connected to the diagnostic act to the patient, and the patient cannot exercise an explicit, free and con- scious choice (acceptance or rejection).


Another aspect of informed consent in ionising medical imaging regards the concept of population statistics and risks [29].

Many studies about risk communication have addressed the difficulty of conveying correct information to patients, and they have suggested interesting solutions [65-68], such as the use of visual displays [66, 68].

Visual displays include risk ladders, human and Chernoff faces, line graphs, dots and Xs in which the Xs represent those affected by the hazard, marbles, pie charts and histograms.

Evidence mostly suggests that combining visuals with numerical and written descriptions improves the perceived helpfulness of the information and the accuracy of perceived risk [68].

Another solution is pro- vided by consistent and robust literature showing that people better understand risk information (in terms of gross compar- ison and risk assessment tasks) if risks are presented in terms of frequencies (e.g., 5 out of 100 people) rather than in percentages (5 %) [66, 69].


The role of the physician is arguable in certain situations, such as when the physicians have to share scientifically controversial data with their patients, even if the data are significant, such as the potential cancer risk of low levels of medical radiation [29].

These uncertainties are expressed in terms of scientific reliability from a clinical and legal stand- point, generating many consequences.

We refer in particular to managing these uncertainties in the context of risk com- munication, as an atypical legal duty inherent in informed consent in radiology and nuclear medicine.

Uncertainties in risk can jeopardise the fundamental right to patients' health and should not be omitted by the physicians.

Uncertainties can be determined and clarified via risk communication solutions and by providing a justification and consideration of risks and benefits, essential elements in obtaining in- formed consent for any medical act that may have potential risk [70].


Some authors argue that informed consent cannot account for stochastic risk uncertainties [29].

In this scenario, patients must be fully informed of what is known and what is un- known, but it is not advisable to establish a contract between a patient and the physician that reflects uncertainty [29].

On the contrary, we claim that patients must be fully informed about the potential risks in order to provide their consent, even if the potential risks are based on controversial scien- tific data.


The main dispute relating to discussing radiation risk with patients focusses on the certitude of radiation risk estimates [61] and the linear no-threshold risk model for assessing potential correlation between radiation and cancer.

It is nec- essary to take into account several important factors, as proposed in the following points.


(1) The linear no-threshold risk model is endorsed by all the major radiation regulatory boards, including the International Commission on Radiological Protection [11, 12], the National Academy of Sciences BEIR com- mittee [71], the United Nations Scientific Committee on the Effects of Atomic Radiation [72] and the US Food and Drug Administration [73].

The BEIR VII summary claims that, at lower doses without a thresh- old, the cancer risk progresses in a linear fashion and that even the smallest dose can potentially provoke a slight increase in cancer risk to humans [71].

Low dose is defined by the BEIR VII committee as doses ranging from zero to 100 mSv.


(2) Most published articles that examine medical radiation in a scientific fashion suggest a significant risk [9, 74-76].


The tendency to justify a mild misperception of low risk has no scientific basis and is misleading from a legal stand- point.

This is significant for radiologists or any physician who requests an imaging exam.

We cannot ignore the scien- tifically proven fact that the different types of ionising radi- ation, artificial or natural, produce a cumulative effect of low-level chronic exposure and are related to adverse effects on human cells [4, 13, 22, 23].


Efforts can be made to assess the relative importance of the several epidemiological uncertainties.

There are some approaches to quantifying uncertainties in lifetime attribut- able risk, like for instance that followed by the Monte Carlo method [77].

Nevertheless, the linear no-threshold model is still considered as the most robust model for medical decision-making about radiation exposure and cancer risk.

This model should be used in conjunction with general dose optimisation strategies [27] and increased use of protocols [27] and patient-individualised information [77].


The attention to scientific uncertainty opens a reflection of alternative and non-ionising diagnostic procedures, justified by similarities of diagnostic information and management of clinical cases.

Accordingly, the Euratom Law establishes that a non-ionising technique must be used whenever it will provide information grossly comparable to that provided by an ionising radiation technique [27].


From this viewpoint, the problem focussed on should not be "whether" informed consent should be performed or not, but rather "how" this universal legal institution should deal with the ever-present scientific uncertainties [70].

The real problem is how to communicate risk in a way that is under- standable to the patient.

Informed consent should include risk uncertainties [70].

If this were not so, not only all informed consent forms (even those for issues other than ionising imaging), but also all drug leaflets (in which there is a contract subtended between a consumer and a pharma- ceutical company) would be eliminated.

In fact, all the risks that are normally described within informed consent deal with uncertainties and intrinsically have a stochastic nature.


Information and clinical argumentation within the frame- work of informed consent in radiology and nuclear medicine have significant legal importance.

One aspect is the degree of validity of scientific sources on which effective risk commu- nication about ionising radiation should be based.

There should be particular focus on evidence-based medicine, which should be state of the art in every branch of medical research.

Thus, the legal principles of diligence, prudence and expertise, which every physician must follow when carrying out a medical act, should be extended to the pre- ventive obligation of clinical information and communica- tion in the context of informed consent.


The legal validity of informed consent for ionising imag- ing cannot allow omission of information dictated by scien- tific and clinical uncertainties.

On the contrary, if well- communicated by the physician, uncertainty can pro- actively contribute to the formation of a conscious decision by the patient.


In the eyes of the law, two key aspects must be considered.


(1) The evaluation of the continuous training of radiologists and nuclear medicine physicians in relation to the technical- scientific sources to be used in the context of the overall informed consent process.

These sources should be characterised by scientific rigor and the presence of scien- tific data-with consequent clinical information-that are worthy of note.

Currently, this can be provided accurately by means of evidence-based medicine.


(2) The continuous training of radiologists and nuclear medicine physicians in the techniques and tools of physician-patient communication and risk communica- tion.

Physician must be able to discuss technical knowl- edge with the patient and to deal with patient's feeling of "fear" whenever patients are subjected to risky clin- ical activities such as ionising imaging.

Information and communication by the physician should be calibrated according to the specific pathological condition of the patient.

This justifies both the correctness of the act of ionising imaging and the validity of the resulting con- sensus expressed by the patient.


This perspective, founded on a process-based vision of informed consent and shared decision-making, deserves to be extended under both a clinical and legal profile, even to informed consent characterised by a "contract" matrix, typ- ically conceived and applied within the framework of the Anglo-Saxon legal tradition.


On this basis, the subject of informed consent in ionising medical imaging, although addressed differently in legal profiles in the different worlds of Common Law and Civil Law, appears analogous if we focus on the information and communication process regarding radiation risk when implementing informed consent.

It is a unique methodolog- ical approach, applicable with respect to both the law as applied in the Western world and going beyond state borders.

This reinforces the idea that the concrete implementation of the informed consent process in ionising medical imaging is the only way to:


& Protect the universal patient right to decide on their psycho-physical well-being in the context of "risky" acts of nuclear and radiological medicine.


& Allow physicians to develop greater communication skills and be legally protected, within a framework cur- rently characterised by major doubts, issues and aspects of inappropriateness, both operational and relational.


Certainty regarding this topic must be ascribed to ethical and legal condemnation, in both Common Law and Civil Law jurisdictions, of all those attitudes and behaviours of defensive medicine or characterised by the lack of appropri- ate communication, at the levels of both the structures and the individual doctor-patient relationship.


Following our analysis of the main problems linked to the controversy about scientific uncertainties, we concur with a series of authors that informed consent is still a distinctive process that defends patient health as well as both patient and physician dignity and autonomy in rule-of-law states [18, 61, 70, 78, 79].

By means of an overall strategy and model of Insights Imaging (2013) 4:647-653 651 communication, shared decision-making and balanced legal protection, one will be able to implement the best possible informed consent, founded on a "process-based" vision.

This can contribute significantly to patient autonomy, radiation pro- tection and appropriateness in ionising medical imaging.


The authors of this article [1] have to be congratulated for their clear presentation of stepwise, process-based informed consent, including evidence-based justification, full patient information on benefits and risks, and interactive communication with enough time for the patient before taking the decision on whether to undergo an examination.

Recchia et al. are in line with the clinical consent process [2], and even some radiological articles head in the same direction [3, 4].

The authors will likely get unanimous approval for their approach whenever risky interventions or complex examinations with an elevated dose level are considered.

Non-invasive imaging examinations using low-dose levels, however, are not discussed differently by the authors, although this contrasts to the reality in radiology departments in Europe, the USA [5] and probably most countries.

In other words, the theory is not applied in a large segment of the real world, and this brings up several questions: referring physician [6].

Correct justification and full information of the patient in the latter scenario are the primary responsibility of the referrer whereas the radiologist acts on demand in the first phase and has the main responsibility in giving answers to questions of the patient, in verifying that the patient has understood the information and in documenting the consent.

Whatever the solution, the changes in practice will have a substantial impact on the operational load in an imaging department [6].

This may be the reason for US academic departments to delegate the duty of obtaining informed consent to radiological technologists [5], a solution that probably cannot fully satisfy all needs.

In any case, both the referrer, the radiologist and any medical professional involved need adequate education and training in this task.

The new guidance document of the European Union for training and education in medical radiation protection, as currently developed in the EC MEDRAPET project, will cover this in detail (www.medrapet.eu).

Who is responsible for obtaining informed consent?

Recchia et al. do not specify this point; they seem to rely on a model where the physician—as a general practitioner—has repeated contacts to the patient, allowing for an ongoing interaction and a chronological separation of the different steps.

Most diagnostic radiologists performing radiography, fluoroscopy and CT see their patients just once, for the examination.

To achieve a correct informed consent procedure, they either have to offer an additional previous consultation or to share the task with another medical professional, such as the


Is informed consent identical for all imaging examinations using ionising radiation? In their clear, interactive approach, Recchia et al. do not differentiate between paediatric whole-body PET-CT and two-plane radiography of a broken finger in an elderly patient.

Indeed, the risk of cancer induction may differ by a factor well above 1,000 between these two examples, and it seems logical that our efforts concentrate on those exposure situations with a significant risk.

The widespread lack of qualified professional staff and economic constraints of the healthcare systems, due to the financial crisis, underline this point.

Thus, we might postulate an approach adapted to the cancer risk, i.e. based on organ doses, the age at exposure and gender.

This would mean a careful, stepwise process including the parents in the case of children and an abbreviated procedure in the case of elderly patients.

Furthermore, imaging in emergency situations has to respect the medical urgency, and situations where the patient is not able to give an informed consent require a modified approach, e.g. after loss of consciousness.

Is there a threshold for the need for risk information? Recchia et al. briefly mention authors discussing a minimal effective dose of 1 mSv for detailed risk information [6].

To control the workload in a busy department, this might be an attractive pragmatic option: most radiographic examinations would pass below this threshold, and even modern low-dose CT protocols might fit, whereas most CT, fluoroscopic and interventional examinations would deserve the full process-based steps for getting informed consent.

For higher dose investigations, e.g. those above 10 mSv, Malone et al. suggest a more detailed informed consent procedure and forms specific for the examination [6].

Scientific arguments would even favour a risk-based rather than dose-based threshold, e.g. to allow for different decisions for a baby girl and an adult, according to the BEIR VII data [7].

When patient groups were asked about the information they wanted to receive prior to a medical act with potentially severe side effects, Barnett et al. [ 8] reported a 0.1 % risk to be critical for many; subjective needs for information varied widely and were greater in young than elderly people.

Terry mentions that there is no formally recognised threshold of risk above which we ought to obtain informed consent but that an ethical guideline might be any risk greater than that which we might ordinarily encounter when carrying out normal daily activities [2].

This would correspond roughly to a risk of 1:2,000.


How do we communicate the risk and stochastic uncertainties? In a survey of physicians affiliated with tertiary hospitals, Karsli et al. [ 4] obtained the best support for the following two statements: (1) that X-rays are a known human carcinogen and that there is an epidemiological association between X rays and cancer; (2) that the risk of cancer from radiation exposure from a CT scan is much smaller than the high background risk of cancer in the population.

Recchia et al. [ 1] are right in suggesting a combination of visual displays and descriptions of the risk in order to help the patient understand the magnitude.

It may be easier to perceive the approximate exposure of a specific examination if the dose is expressed by the corresponding number of chest radiographs rather than by the physical dose.

Similarly, patients are more likely to get an idea of the risk when this is expressed as “one patient out of x patients” rather than a percent number.

Regarding stochastic risk uncertainties, Recchia et al. clearly state that “patients must be fully informed of what is known and what is unknown”.

This task is not as easy as they claim and rather time-consuming: while the mean risk to the population by a certain examination can usually be quantified, the individual risk of cancer induction depends on many factors, such as organ dose, sex and age; recent research has even shown that there is an important genetic variation in the sensitivity to ionising radiation.

Thus, even if we fully accept the linear no-threshold (LNT) model, it is not easy for experts and difficult for patients to understand the absolute risk to an individual person with its large statistical uncertainty.

It may be preferable to justify that the benefits to the patient are well above the range of the risk and that the clinical question cannot be answered by an alternative diagnostic procedure.

Arguing with these uncertainties and the difficulty of exactly defining the individual age- and gender-specific risk of an imaging examination, Image Gently and Image Wisely (www.imagegently.org; www.imagewisely.org) do not support a formal informed consent for diagnostic ionising radiation.

The two campaigns for pragmatic radiation protection in the US advocate for providing every patient with educational material and for replacing informed consent by a standardised “radiation consent” form, similar to the form used before the injection of contrast media.

In conclusion, there are no easy answers to these questions that do not provoke debates.

We need to improve informed consent for radiation exposure in imaging.

In times of limited resources, concentrating on critical situations and adapting the process to the magnitude of the risk deserve consideration and might have a stronger impact on the practice of imaging than asking for a rigid full process.


We thank Prof. Vock for his noteworthy and constructive commentary [1].

This gives us the opportunity to briefly provide additional observations to elaborate this topic further.

We agree with Prof. Vock that our theoretical approach [2] may not be applied in a non-invasive and low-dose medical imaging.

Nevertheless, this makes the innovation that we are trying to develop even more challenging.

We are all discussing about something similar to a “paradigm shift”, in the sense described by Kuhn [3]: (a) presenting results “sufficiently unprecedented to attract an enduring group of adherents away from competing modes of scientific activity” and (b) “being sufficiently open-ended to leave all sorts of problems for the redefined group of practitioners to solve.”


Who is responsible for obtaining informed consent?


This question could be completely answered only if contextualised in each legal State taken into consideration, which is clearly beyond the scope of our article.

We agree, however, with Prof. Vock that in the informed consent process in medical imaging there is a range of factual situations in need to be optimised in terms of coordination between the referring and executing physicians.

Risk communication and informed consent do not represent an exclusive competence of the referrer, as ethically, legally and clinically attributable even to the radiologist.

Therefore, it seems unconceivable to rule out a direct communicative duty in informed consent, as well as the possibility of a refusal to perform the examination if deemed inappropriate.

As a result, the education and training of professionals should focus not only on radiation protection but also on risk communication and informed consent [4, 5].


Is informed consent identical for all imaging examinations using ionising radiation?


At a level of abstraction, informed consent should be identical for all imaging examinations using ionising radiation.

From a legal and ethical viewpoint, the patient’s will deserves to be expressed in full, with freedom and real awareness; and it is precisely in this regard that we find, in a nutshell, the essence of informed consent.

Nonetheless, we are in line with Prof. Vock that in front of this mandatory statement it is necessary to develop a consistent fine-tuning of the ideal model, accordingly with the different peculiarities of the real clinical practice.


Is there a threshold for the need of risk information?


At the level of risk acceptability, we have to put together too many variables only to determine the cases in which informed consent is necessary.

We have to contemplate both the variables involved in the personalised risk (dose, age, sex, genetic variables, etc.) and the variables that determine the acceptability by the specific patient.

Moreover, if we consider that an average acceptable risk is 1:2,000, we assume that the patient has an average risk propensity, while we know that there are many variables that affect his willingness to take risks.

Complicating this picture, even healthcare professionals have different levels of risk propensity that inevitably come into play in medical decision-making.

Consequently, in order to decide whether to make an explicit and comprehensive informed consent, to ex ante consider individual acceptability may not be the right way.

In a sense, there would be once again too many filters to the final choice of the patient.

Instead, if the filter is given only by the dose threshold (and perhaps age), the patient can, based on his subjective characteristics, decide freely and consciously if his personalised risk is acceptable and whether or not to undergo the imaging exam, even considering the proposed alternatives [5, 6].


How do we communicate the risk and stochastic uncertainties?


If we deem it too difficult to communicate radiation risk in medical imaging, we should not communicate it at all.

Why would we only communicate the average population risk and omit the personalised risk?

Conversely, if we follow the logic that it is right to provide a patient with the most accurate information possible, then the patient can make the decision he or she believes to be the most acceptable.

We should strive to create conditions so that the needed information could be conveyed also through a personalised risk communication.

In this way, a real integrated process of informed consent would be merely the most natural, proper and routine approach to protect both physician and patient in decision-making.

In this way, we believe that we all—as a scientific community—would be acting to find possible solutions to what looks like a new paradigm.