Eur J Cardiothorac Surg 2002;21:981-986
© 2002 Elsevier Science NL
Acceptance of gene therapy by the heart surgery patient
Johannes Bonatti*,
Christa Haeusler,
Alexander Klaus,
Monika Fink,
Angelika Hammerer-Lercher,
Günther Laufer
Department of Cardiac Surgery and Institute of Medical Chemistry and Biochemistry, Innsbruck University Hospital, Anichstrasse 35, A-6020 Innsbruck, Austria
Received 15 November 2001;
received in revised form 15 March 2002;
accepted 15 March 2002.
* Corresponding author. Tel.: +43-512-504-3806; fax: +43-512-504-2528
e-mail: johannes.o.bonatti{at}uibk.ac.at
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Abstract
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Objective: The aim of the present study was to evaluate the attitude of cardiac surgery patients towards gene therapeutic approaches to heart disease. Methods: One hundred and fifty patients having undergone coronary artery bypass grafting (n=97), valvular operations (n=40) or combined procedures (n=13) were personally interviewed prior to discharge using a self designed questionnaire. Results: Seventeen percent of the surveyed patients were unable to complete the interview because of total non-understanding of the topic. Of the remaining patients, 33% could basically define the term ‘gene’. After explanation of gene therapy principles 70% believed that gene therapy protocols had already been started clinically. Fifty-two percent would accept enrollment in a clinical trial (85% in cases of otherwise incurable disease). If clinical gene transfer would be carried out 73% of patients would accept adenovirus as a vector, 94 and 80%, respectively, would accept catheter-based intervention or surgery for performance of gene therapy. Fifty-four percent would agree to a prophylactic gene therapy protocol. Conclusions: We conclude that the general attitude of heart surgery patients regarding gene therapy is positive. A considerable number of patients are unable to understand the basic principles of gene therapy. These data can be useful for planning of clinical gene therapy trials and show potential difficulties in obtaining informed consent.
Key Words: Gene therapy • Cardiac surgery • Acceptance • Trials
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1. Introduction
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Gene therapy of cardiovascular disease has recently entered the clinical arena and the heart surgery community is starting to pay increased attention to the topic of gene therapy as a variety of problems of cardiovascular treatment in the future might be tackled by gene transfer approaches. Surgical problems that could potentially be solved by gene therapeutic procedures include myocardial angiogenesis [1], treatment of heart failure [2–4], prevention of coronary artery vein graft disease[5,6], myocardial ischemia-reperfusion injury [7,8] and prevention of acute and chronic heart transplant rejection [9]. A critical view on gene therapy with all its infectious, immunologic, and biosafety issues is absolutely mandatory in order to achieve the public's trust in this form of therapy. Little is known about the patients' hopes and concerns regarding cardiovascular gene therapy. The aim of our present study was therefore to evaluate the principal knowledge of heart surgery patients concerning genes and gene therapy. In addition we sought to receive an impression of the patients' general attitude to gene therapy.
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2. Patients and methods
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One hundred and fifty patients underwent an interview prior to discharge after a heart surgery procedure. A self designed questionnaire (see Appendix A) was used and the interview was carried out personally by physicians (J.B., A.K.) or a medical student (Ch.H.). Questions on the basic knowledge about genes were followed by a brief explanation of gene therapy principles. If a discussion on the term ‘gene’ was impossible or if understanding of an explanation was questionable the interview was discontinued.
The data obtained were entered into a computerized database and calculated using the SPSS for Windows statistical software package. Categorical data are given as percentages, continuous variables are given as median and range. Comparisons were done using the Mann–Whitney U-test.
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3. Results
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Of the 150 patients interviewed 94 were males, and 56 were females, the median age was 68 (38–84) years. Ninety-seven patients (64%) had undergone coronary artery bypass grafting, 40 (27%) and 13 (9%), respectively, had undergone a valve procedure or a combination of valve operation and coronary artery bypass grafting. One hundred and twenty (80%) patients were living in a rural area and 29 (19%) in an urban area (1% unanswered). The percentage of academically educated persons was 8%.
In 26 (17%) of the 150 cardiac surgery patients an interview on cardiovascular gene therapy could not be completed because of non-understanding of the topic. Of the remaining patients (n=124) 41 (33%) could basically define the term gene or describe certain features of genes. A list of explanations what the term ‘gene’ means is given in Table 1. Patients unable to discuss were significantly older than patients who continued the interview (median age 71 vs. 67 years, P=0.036). There were no academically educated people in this group, and all people in this group came from a rural area.
As shown in Fig. 1
the majority of patients thought that gene therapy is at present performed in USA and in Europe. Ninety-seven percent of the 124 patients who completed the interview accepted cell or tissue culture for pre-clinical testing of gene therapy whereas animal experiments were regarded as acceptable in 83%. As demonstrated in Fig. 2
52% of the patients would accept enrollment in a clinical cardiovascular gene therapy trial. Thirteen percent would principally not give their consent to such a trial. Thirty-three percent of patients, however, would enroll in a clinical trial in cases of otherwise incurable heart disease, giving an overall acceptance rate of 85%.
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Fig. 1. Estimation of heart surgery patients on where gene therapy is performed at present. The majority of patients thought that gene therapy is primarily carried out in USA and in Europe (80 patients answering).
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Fig. 2. Acceptance of potential enrollment in a clinical gene therapy trial by heart surgery patients. Fifty-two percent of the 124 patients completing the interview would at present accept enrollment in a clinical trial. The enrollment rate would be 33% if otherwise incurable heart disease was present, giving an overall acceptance rate of 85%.
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Figs. 3 and 4
show how cardiac surgery patients willing to undergo treatment see potential ways of clinical gene transfer. Catheter-based clinical gene transfer received a 94% acceptance rate whereas surgical ways to deliver genes received a 14% lower acceptance rate. Seventy-three percent of the patients would agree to adenovirus as a vector for transfer of therapeutic genes. A prophylactic gene therapy protocol in order to prevent future heart disease would at present be accepted by 54% of the 105 patients who would enroll in a clinical protocol.
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Fig. 3. Acceptance of catheter based gene transfer by heart surgery patients who would enroll in a clinical trial. Ninety-five percent of these patients would accept gene transfer by percutaneous catheter techniques. GTx=GeneTransfer (105 patients who would enroll in a clinical protocol).
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Fig. 4. Acceptance of surgical gene transfer by heart surgery patients who would enroll in a clinical trial. Eighty-four percent of these patients would accept gene transfer by open surgical techniques. GTx=GeneTransfer (105 patients who would enroll in a clinical protocol).
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Table 2 lists the risks of gene therapy as seen by heart surgery patients and Table 3 lists suggestions on how to lower potential risks. The question ‘should gene therapy research be carried out at the local university hospital?’ was answered ‘yes’ in 93% and ‘no’ in 5% (2% unanswered). The question ‘should gene therapy research be funded by the state’ received ‘yes’ in 88% and ‘no’ in 9% (3% unanswered). Patients estimated that it will take 10 (2–200) years until cardiovascular gene therapy is part of clinical routine.
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4. Discussion
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Cardiac surgery is at present entering an exciting phase where transfer of therapeutic genes for intra- and postoperative problem solving seems to become a reality at least in the experimental setting. As with other critically viewed types of therapy like radiation therapy, chemotherapy, or transplantation a clear view on the patients' expectations or concerns is important for the treating team in order to maintain self confidence and motivation for continued research. Patient surveys have been carried out for other types of new treatment strategies; to our knowledge this has not yet been done for gene therapy in the special field of cardiac surgery.
We think that one of the strengths of the present survey is the fact that personal interviews were carried out instead of distributing anonymous questionnaires. Thereby a personal impression of the patients' knowledge on the term ‘gene’ could be obtained. We speculate that by anonymous questioning bias towards an increased response rate by people knowledgeable on the topic would have been a problem.
One-third of the patients in whom the interview could be conducted was able to basically describe the term ‘gene’ or to define certain features or functions of genes. Some patients were aware of the biochemical characteristics of genes, some patients described their functions, and some patients noted that genes could be transferred and manipulated. Basic knowledge on genes was primarily influenced by age, education, and by urban or rural residency of the population surveyed. Overall, we had the impression that with the explanations provided to the patients after their initial attempt to define the term gene an acceptable level of understanding of gene therapy principals was present during further questioning. We think that public education could be one way to improve basic knowledge of patients on genetic engineering technology. It will be, however, an important responsibility of gene therapy investigators to provide adequate personal information to individuals who enroll in clinical trials. Explanations for the patients could probably be well supported by drawings or short films, but we had the impression that narrative and descriptive information is also adequate for understanding the topic.
The patients' estimation that the majority of clinical gene therapy protocols is carried out in USA and in Europe corresponds well with data on the current distribution of such protocols (http://www.wiley.co.uk/wileychi/genmed/clinical).
As expected acceptance of cell or tissue culture experiments for pre-clinical gene therapy testing was greater than acceptance of animal experiments. About one-half of the patients would at present enroll in a clinical trial on cardiovascular gene therapy. Of the patients not accepting enrollment 70% would consent if they were suffering from incurable heart disease. Looking at other critically viewed future forms of therapy Schlitt et al. [10] conducted a survey among heart transplant recipients and heart transplant candidates whether cardiac xenograft transplantation would be accepted. Seventy-seven percent of the patients would principally agree to transplantation of a xenograft, 58% would accept this treatment even if additional medical treatment would be more intense than with human allografts. A similar study carried out in France revealed a 66% acceptance rate of human xenograft if a life-or-death situation was present [11]. Data from both studies seem to be in accordance with our results and even a slightly higher rate of acceptance was noted in our surveyed patient population.
As expected catheter-based gene delivery received a higher acceptance rate than surgery-based gene transfer. Concerning this question we think it was a major advantage that people surveyed had experienced both approaches, placement of a percutaneous angiography catheter and thoracotomy for a heart operation before. Whether the short period between the operation and the survey might have in part caused the lower acceptance rate of an operation can be debated.
Adenovirus as a vector received a high appreciation in our survey. Basically the term ‘adenovirus’ in explanations was described as a ‘virus causing common cold’ and that by infection with the virus genes would be brought into the cardiac tissue. It has to be stated that knowledge on the current problems with adenovirus mediated clinical gene transfer [12,13] was rather low. In addition significant complications were not extensively reported in our referral area during the conduction of this study. One limitation of our survey is that we did not investigate reactions to known adverse effects of gene therapy like toxicity or lacking regulation methods of gene expression. As definite knowledge on serious side effects in the clinical setting is still scanty it was difficult to construct corresponding questions.
We chose to concentrate questions about vectors on adenovirus because of its high infectious and immunologic properties. We had thought that of all viruses used for gene transfer at present adenovirus would be the most commonly known and the easiest one to be understood by the patients.
Concerning potential risks of gene transfer unpredictable and potentially irreversible changes of a functioning biological system were the major concerns of the patients surveyed. Cloning seems to receive a special negative appreciation. As with every new potentially powerful technology misuse and gain of power by those controlling the technology are specially feared situations. When looking at suggested safety measures properly designed studies and controlling institutions were a major desire of the patients surveyed. Patient information and patient isolation as well as special measures like protective clothes or labeling of genetic material were proposed. Before widespread application, otherwise incurable diseases would be the cases to start with for some patients.
A great majority of our patients wished that gene therapy research should be carried out at the local research institutions and that such research should be funded by the public. The population surveyed estimated that it will take 10 years until gene therapy is part of routine clinical cardiovascular treatment. This result may show that trust in this kind of research is present and that the expectations by the patient are high. By comparison Julvez et al. [11] showed that the majority of the French population estimates that xenografts would be part of clinical routine within 10 years. Also in their study research on a critical type of treatment 88% of the population surveyed supported and a generally good level of confidence in medical biotechnology was demonstrated.
From our present survey we conclude that a positive attitude of heart surgery patients towards gene therapy is present and that the patient's level of understanding basic principles of gene therapy is high. Our data may be useful for planning clinical gene therapy trials.
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Appendix
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References
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Abstract
1. Introduction
