Abstract The physician who decides to administer a thrombolytic therapy to a patient with acute stroke, has to consider both the results of randomized controlled ...
© Springer-Verlag 2001
Neurol Sci (2001) 22:339–344 SIN DOCUMENT
A. Ciccone • V. Bonito and the Italian Neurological Society’s Study Group for Bioethics and Palliative Care in Neurology
Thrombolysis for acute ischemic stroke: the problem of consent
Received: 7 August 2001 / Accepted in revised form: 16 October 2001
Abstract The physician who decides to administer a thrombolytic therapy to a patient with acute stroke, has to consider both the results of randomized controlled trials, a complex matter itself, and problems related to consent, with its deontological and legal aspects, in the difficult contest of the emergency situations and acute stroke care. Although the analysis of studies on thrombolysis in medical literature has been ample and may be redundant, the latter aspect, i.e. that of how to cope with the problem of consent, has never been treated adequately. The problem of consent is particularly important and delicate in Italy and in most countries of the European Union, where thrombolytic therapy can be used only off label or within experimental studies.
Study Group members: C.A. Defanti (Coordinator), C. Pasetti (Vice-coordinator), V. Bonito (Secretary), G.D. Borasio, A. Caraceni, R. Causarano, F. Chiodo Grandi, A. Ciccone, V. Crespi, A. Fascendini, L. Fera, M. Gasparini, P. Marano, N. Marcello, A. Primavera, M. Rizzo, V. Silani, P. Sola, R. Sterzi
A. Ciccone () Stroke Unit Department of Neurological Sciences Hospital Niguarda Ca’ Granda, Piazza Ospedale Maggiore 3, I-20162 Milan, Italy V. Bonito Department of Neurology Ospedali Riuniti di Bergamo Largo Barozzi 1 I-24100 Bergamo, Italy
This document aims to provide the tools needed to overcome the gap between the generic indication for thrombolytic therapy in acute stroke, coming from clinical studies, and its effective use.
Introduction The use of thrombolytic therapy for acute ischemic stroke is controversial and the opinion of the international scientific community is still anything but unanimous, as is shown by the fact that it has been authorised for some years in Canada and the United States, but has still not been registered in the majority of European countries. If we consider the data available today as a whole [1], the position of those who prefer not to use it because of its uncertain risk-benefit ratio is as acceptable as that of those who think it is indicated for selected patients. It is obvious that the problem of consent only concerns the people who use it in clinical practice or for experimental purposes. The aim of this document is not to discuss the still open question of the indications for its use, but only the problems concerning consent that the treatment raises once the decision has been taken to administer it. The principle that physicians must not undertake any diagnostic or therapeutic activity without the informed consent of their patient is a consolidated part of the Deontological Code of the Italian Order of Physicians. However, in everyday clinical practice, there are some situations in which physicians are authorised to intervene when patients are not in a position to give their consent, such as emergency situations when the patient is unconscious. Under such circumstances, physicians are justified in taking diagnostic and therapeutic action without consent when the intervention cannot be delayed and is indispensable to safeguard the life and health of the patient. In the case of emergencies, physicians must often act in problematic situations ranging from the ideal one in which the patient is lucid, capable of being correctly informed and of giving consent, to one in which the patient is unconscious
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and the physician is authorised to intervene without consent. The situation of a stroke patient for whom thrombolytic therapy is being considered can be one in which informed consent is difficult or even impossible. In this case, the difficulty of operating in an emergency is compounded by problems relating to the complexity of the information to give a patient who has just suffered cerebral damage. We shall first review the different aspects that make consent difficult or impossible, and then consider the possible solutions foreseen in the regulations and their bioethical analysis, distinguishing between the experimental context and that of everyday clinical practice.
The difficulty of consent in emergency situations Under emergency conditions, informing patients with an acute disease about their condition and the therapies available can be extremely difficult not only because of the contingent context of a casualty department (e.g. noise, continuous comings and goings, other urgencies) and the limited time for giving adequate information and ensuring an awareness of the pathology, but also because of the stress of the acute phase and the emotional situation of dependence and anguish [2]. These aspects are even more important if the proposed therapy needs to be administered quickly in order to be effective. A study of the cognitive performances of a cohort of patients with acute myocardial infarction in a casualty department came to the conclusion that about 20% were incapable of fully understanding the information given to them about their state of health and the therapies available, and therefore of providing adequate informed consent to the therapies proposed [3].
Specific difficulties in stroke In the case of stroke, the consent procedure is further complicated by the presence of a cerebral lesion: some are not even aware of being ill because of anosognosia, others are incapable of understanding and communicating because of aphasia, and yet others have consciousness disturbances. Consequently, the problems that commonly emerge in emergency situations are accompanied by those of the cognitive impairment caused by the stroke itself. Furthermore, it must be taken into account that those patients who are at greatest risk of disablement or death, and therefore with a greater likelihood of acute phase cognitive impairment, are often incapable of giving their consent.
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demonstrated the efficacy of thrombolytic therapy. They have been considered as a whole in a systematic review [1], which showed that intravenous (systemic thrombolysis, 15 trials) and intra-arterial (locoregional thrombolysis, two trials) thrombolytic therapy increased the possibility of returning to an autonomous life after a stroke but at the price of an increased risk of death. Although the overall result of this review is a useful means of summarising the trial results, it needs to be considered cautiously because the results themselves are not homogeneous in terms of the excess mortality, i.e. data indicating the risk/benefit ratio of the therapy go in different directions. It is therefore essential to make an analysis that is not limited to the overall result but that considers the characteristics of the individual studies. One of the most favourable scenarios from this perspective is that provided by a study conducted by the National Institute of Neurological Disorders and Stroke (NINDS) [4]. It was on the basis of the results of this trial that the US Food and Drug Administration (FDA) approved the use of the thrombolytic recombinant tissue-plasminogen activator (rt-PA) in stroke, and it is the protocol of this trial (e.g. patient selection criteria, dose and method of administration, concomitant therapies) that is followed when using rt-PA. It is worth going into the details of this trial, which showed that the intravenous administration of rt-PA within three hours of symptom onset allows 50% of the patients (as against 39% of those treated with placebo) to return to a completely autonomous life without any increase in the risk of death three months after the stroke. However, there was a risk of about 6% of developing a possibly fatal cerebral hemorrhage in the days immediately following the treatment. On the basis of the NINDS study, it can be said that, in carefully selected stroke patients, thrombolysis considerably increases the probability of a long-term return to an autonomous life albeit at the price of an immediate risk of worsening the neurological deficit or death as a result of cerebral haemorrhage. Consequently, all of the difficulties in patient communication mentioned previously are compounded by the fact that the information concerning the effect of the thrombolytic (the drug can do good in the long term but involves some immediate risks that may even lead to death) also implies a strictly personal value judgement. The decision to consent requires a complex evaluation that patients may find themselves having to face for the first time at the moment of the stroke.
Problems related to the experimental context
Problems related to thrombolytic therapy A large number of randomised controlled trials, most of which have been published during the last ten years, have
Despite the fact that more than 5000 stroke patients have been involved in trials of thrombolytic drugs, there is still debate as to patient selection, the risk-benefit ratio, the method of administration and the applicability of the therapy in routine clinical practice [1]. New trials are ongoing or
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about to start precisely with the aim of clarifying these issues. The administration of thrombolytic therapy in the context of controlled clinical trial makes the information to be given to patients more complex. Within a few hours of experiencing a stroke, the patients must understand not only the causes of their state of health and the uncertainties concerning the risk-benefit ratio of the treatment, but also why they are being asked to participate in a trial; they must also accept to be randomised (i.e. they must understand that the type of treatment will be decided by chance rather than by themselves or their physicians) and must understand that, since there is no specific alternative therapy to thrombolysis within the first hours of the onset of ischemic stroke, placebo is considered the best possible alternative. Furthermore, the public is little prepared and generally sees participation in a trial not as a contribution to medical progress, but as a therapeutic opportunity. In this light, the concept of randomisation is certainly difficult to accept.
tion to minors, the incompetent and the prohibited. The Deontological Code of the Italian Order of Physicians foresees the use of substitutive consent for patients who have become suddenly incompetent. Nevertheless, an Italian survey of more than 600 stroke patients and their relatives found that 43% of the interviewees expressed a preference for having an informed relative make a decision while 41% preferred that the physician decide [7]. The involvement of close relatives in decisions relating to incompetent patients therefore seems to be widely shared in our country. On the other hand, the same survey showed that 41% of the relatives felt uncertain about making such choices. Consequently, despite the generic willingness to be informed, there is an understandable hesitance about making choices on behalf of others. Like the patient, relatives also find themselves in difficulty because of the problems related to the emergency, the acutemess of the disease, the particular nature of the riskbenefit ratio, and the possible proposal of trial participation.
Theoretical models of consent applied to thrombolysis
The model of avoidable consent
The model of direct consent
Article 35 of the 1998 Deontological Code of the Italian Order of Physicians foresees that, in the case “of urgent and life-threatening” situations in which it is impossible to ask for consent, the physician is authorised to choose “indispensable treatments and care” on behalf of the patient. However, this principle is difficult to apply in the case of a stroke not only because it is not easy to determine whether the patient’s life is at risk within a few hours of the onset of the symptoms, but also because (in addition to the risk of death) it is also necessary to consider the risk of disability, which is a major and frequent consequence of stroke (the most frequent cause of diability in Western countries). In efficacy trials, death or disability is usually considered to be a single composite outcome, and studies have shown that the majority of patients and their relatives see post-stroke diability as an outcome that is equivalent to, if not worse than death [7]. Thrombolytic therapy further complicates the interpretation of the state of need because, as described previously, it is not “life-saving” (it may actually increase the risk of death during the acute phase), but “disability-saving” insofar as it increases the probability of a return to an autonomous life. The previously cited Italian survey [7] described the orientation of a sample of our population in this regard. In answer to the question: “There is now a therapy (thrombolytic therapy) for people experiencing a stroke which, if administered within a few hours of the onset of the symptoms, is capable of reducing subsequent disability but increases the risk of death during the first few days; if you were the patient in question, would you agree to undergo thrombolytic therapy while knowing the risks?”, 59% answered yes, 19% answered no, and 22% could not decide. Although it is obvious that no “majority vote” can replace the choice of each individual, knowing the orientation of our population under
In the case of standard and risk-free procedures, patients normally put their trust in their physicians and accept a series of diagnostic and therapeutic interventions without their explicit consent being necessary. In the case of clinical trials or an unusual and risky procedure, the direct, explicit, aware and informed consent of the patient is fundamental not only because it provides protection in the face of a medical intervention involving a certain amount of risk, but also because it guarantees autonomy and favours active participation in the treatment or trial. However, the particular nature and emergency condition of acute stroke patients, as well as the complexity of the information to be given, make it difficult and sometimes impossible to apply such a model. Direct consent can solve the problem of consent only in the few cases in which it can be obtained.
The model of substitutive consent If a patient is incompetent, physicians generally ask for the consent of a representative (usually a member of the family such as the spouse, a parent, or a child). The role of family members has been criticised because they may not always be capable of interpreting the patient’s interests [5]. In Italy, the consent of a member of the family is a widely used, but is not foreseen in legislative terms. Only in the case of trials involving emergency situations in which it is not possible to obtain the patient’s consent does the law [6] indicate the need to ask the consent of a “legally recognised representative”, although such a figure has only been legally defined in rela-
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such circumstances can aid a physician who, when it is impossible to assess the choice of the patient, is in any case forced to decide. The complex decision as whether or not to administer a thrombolytic is one that physicians must prepare themselves to make.
The model of deferred consent As a result of the adoption of substitutive or avoidable consent, it may happen that a patient who was incapable of giving direct consent to participate in a trial was treated in accordance with the trial protocol and subsequently recovered normal competence. In this case, the patient should be informed as soon as possible in order to obtain “deferred consent”. This also applies if the experimental treatment does not go beyond the acute phase (as in the case of thrombolysis). The data relating to the results of the treatment belong to the patient and cannot be used without his or her consent, even if this is given after the beginning of the trial (randomisation and treatment).
Advance directives Advance directives are well-suited to chronic or subacute, evolving diseases about which a patient has been previously informed of what will probably happen, and has therefore had the time to consider the situation and express his wishes and preferences in relation to likely future diagnostic and therapeutic interventions. Despite the fact that a stroke is by definition a sudden event, it is nevertheless possible to foresee an advance directive concerning the acute phase. Given that stroke is a common and socially important disease, it should be possible to give people the information necessary to allow them to express in advance their views concerning the administration of a thrombolytic agent in a clinical trial or as a standard therapy (once the procedure becomes a part of everyday clinical practice). Even if it is not followed by the formalisation of a directive, an advertising campaign could increase the number of people capable of giving their valid consent, encourage family discussions of the issues involved, and allow relatives to bear witness as to the will of a patient who is no longer able to give consent because of a stroke [7].
Thrombolysis consent in trials and clinical practice
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bility of the consent in some cases [8]. In the PROACT II trial [9], which evaluated locoregional thrombolysis with pro-urokinase, the consent that the patient should have been asked to give on the angiographic table once the occlusion of the middle cerebral artery had been identified was actually requested from a relative in most cases (A. Furlan, Cleveland, personal communication). Furthermore, the frequency of the recourse to substitutive consent is not clear in other published trials. In the Multicentre Acute Stroke Trial – Italy (MAST-I), although the investigators were asked to always inform the patient and relatives, the request for formal consent was optional [10]. We can say a posteriori that the trial made reference to the three main models of direct, substitutive and avoidable consent [11]. The proposal of the American Food and Drug Administration. Worried by the fact that the impossibility of carrying out appropriate trials might deprive many acute situations of any treatment, the FDA [12] has recently proposed a series of rules that allow the recruitment of patients in emergency situations even when it is not possible to obtain their consent or that of substitute decision makers. These proposals were greeted with some reservation [13–15], but there is no doubt that they make an appreciable contribution toward solving the problem. The FDA holds that a patient can be enrolled in a therapeutic trial if: a. The life of the subject is threatened; b. No treatments of proven efficacy are known or they are unsatisfactory; c. It is indispensable to have recourse to clinical research in order to identify the most beneficial treatment. Furthermore, a patient can be enrolled if: a. It is not possible to obtain the informed consent of the patient because his or her clinical condition prevents it or because there is no time to obtain the consent of a proxy and, in any case, it is not possible to identify beforehand the subjects who will be affected in order to obtain their previous consent; b. The trial is in the interests of the patient insofar as the situation of emergeny requires an intervention and the trialrelated risk is reasonable if compared with existing therapies (or the absence of therapies). The FDA adds two other recommendations to these basic conditions: a. Consultations with the community from which the trial patients will be selected will ensure that it is involved in the decision-making of the ethics committee; b. The trial and its aims should be communicated to the public before it begins, as should the results once the trial has been completed.
Clinical trials The problem of obtaining consent for the administration of thrombolysis first had to be faced by clinical trials, and the already mentioned difficulties cause one to doubt the relia-
The Italian law governing consent in situations of emergency. The Italian law [6] incorporates all of the the European Good Clinical Practice (GCP) Guidelines concerning consent for therapeutic research in an emergency,
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thus sanctioning both the hypothesis of substitutive consent (a concept that was previously extraneous to Italian legislation) and the possibility, also foreseen in the Declaration of Helsinki [16], of waiving informed consent for therapeutic trials in situations of emergency if there is a presumable direct advantage for the subject. The proponents of the Ischemic Stroke Trial 3 (IST-3), a multicentre randomised and controlled trial of the efficacy of rt-PA [17] in which Italy has also also recently been involved, made an interesting proposal concerning the model of avoidable consent: a second physician – in the capacity of consultant – should be involved in cases in which it is impossible to obtain consent. This should avoid conflicts of interest when a neurologist is simultaneously responsible for the trial and for the treatment of the patient [18].
Thrombolysis consent in clinical practice In 1996, soon after the conclusion of the NINDS trial [4], the FDA authorised the therapeutic use of rt-PA in the United States for intravenous thrombolytic treatment only during the three hours following the onset of symptoms [19]. In 1999, the use of rt-PA for stroke was also authorised in Canada. However, the majority of European countries have so far not authorised thrombolysis as a stroke therapy, although various European scientific societies have recommended the continuation of clinical trials [20, 21]. In Italy, supported by the data published so far (and by the NINDS trial in particular), the conviction that thrombolysis is efficacious has induced some clinical centres to begin using it in highly selected cases despite the absence of a Ministerial indication. In these cases, which can be seen as examples of the off-label use of rt-PA, the sine qua non juridical condition is obtaining the patient’s informed consent [22]. Given the involvement of various professional figures in this therapeutic procedure, which presupposes particularly intra-hospital pathways (e.g. the need for rapid access to computed tomography (CT) and patient monitoring during and immediately after the therapy), it is desirable that the decision to use thrombolysis is discussed and taken by the casualty department of the hospital rather than being made personally by a single physician. It is also recommended that the hospital’s ethics committee be informed in advance, specifying the rationale for the treatment and, above all, the criteria prompting the indication which, in the case of intravenous therapy, should tendentiously be the same as those used in the NINDS trial. A strategy agreed by the department involved and informing the ethics committee provides a guarantee for both the patient and the healthcare staff, and favours greater homogeneity among the various professional figures involved in the treatment. For more than 15 years, alongside experiences with intravenous thrombolysisis, there have been published
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reports of patients treated with locoregional intra-arterial thrombolysis in centres of interventional neuroradiology [1, 23]. The need to verify the results has prompted investigators to organise clinical trials, two of which have already been concluded with promising outcomes [9, 24]. Intra-arterial thrombolysis is also practised by a number of Italian interventional neuroradiology centres in selected cases, but the selection criteria are all too often not explicit and it is used outside the framework of an experimental protocol. Without prejudice to the principle that, in situations of uncertainty, the most correct way to proceed is to organise a controlled clinical study in order to obtain a dual therapeutic and informative benefit, there are no ethical reasons against individual therapeutic interventions outside the ambit of research protocols after having obtained the patient’s informed consent, provided that these are carried out in centres with a long experience of arterial catheterisation and are based on rigorous and previously specified criteria. Having seen the surprising results of some of these interventions on more than one occasion is encouraging, but this does not dispense with the need to explain clearly the decision-making criteria followed and to account for them publicly. Once again, it is recommendable to agree on a strategy within the involved department and to inform the ethics committee.
Conclusions In situations in which it is difficult or impossible to obtain a stroke patient’s consent for thrombolytic therapy – and these are not infrequent – it is fundamentally important that physicians contact a possible “representative”, not to delegate to others a decision that should be taken by them but to be able to make the decision bearing in mind how the patient evaluates the possible outcomes (the risk of death vs. the recovery of autonomy). If thrombolysis is proposed within the framework of a trial, it is admissible to waive consent provided that it is impossible to use the models of direct or substitutive consent, and the whole waiving procedure is adequately explained. In countries such as Italy, in which thrombolytic therapy for stroke is not authorised, the thrombolytic can be used offlabel only with the consent of the patient. In such cases, it may be useful to agree on a therapeutic protocol inside the department involved and to inform the hospital’s ethics committee in order to prevent conflicts between the different professional figures participating in the treatment. An information campaign concerning the treatment of cerebrovascular diseases and the usefulness of expressing advance directives would increase the number of patients and relatives capable of choosing at the time of the stroke. Finally, it is to be hoped that, also in Italy, procedures allowing everyone to indicate a legal representative for health decisions will soon be defined.
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