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European Journal of Heart Failure 2001 3(2):217-223; doi:10.1016/S1388-9842(00)00151-3
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© 2001 European Society of Cardiology

Perceived benefit after participating in positive or negative / neutral heart failure trials: the patients' perspective

Rita Yuvala, Klari Uziela, Nomi Gordona, Amnon Merdlera, Nader Khadera, Basheer Karkabia, Moshe Y. Flugelmana,b, David A. Halona,b and Basil S. Lewisa,b,*

a Cardiovascular Clinical Trials Unit, Department of Cardiology, Lady Davis Carmel Medical Center Haifa, Israel
b Bruce Rappaport School of Medicine, Technion-IIT Haifa, Israel

* Corresponding author. Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center, 7 Michal Street, Haifa 34362, Israel. Tel.: +972-4-825-0457; fax: +972-4-834-3755. E-mail address: lewis{at}tx.technion.ac.il (B.S. Lewis).


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 Appendix A. Patient...
 References
 
Background: Clinical trials, the gold standard for the evaluation of new therapeutic strategies, may prove a drug to be beneficial, harmful or neutral according to its effect on the end-point(s) under study.

Aims: To study the reaction and perspective of the patients participating in a clinical heart failure trial, particularly in relation to whether the trial subsequently proved to be positive, negative or neutral.

Methods: Anonymous self-completed questionnaire was sent to 78 and returned by 70 consecutive patients 1–6 months after participating in six clinical heart failure trials. The trial was neutral or negative regarding the primary end-point in four (47 patients) of the six studies (MACH-1 trial of mibefradil, REACH trial of bosentan, CASCO trial of calcium sensitizer, ecadotril trial of neutral endopeptidase inhibitor) and positive in two (23 patients) (ICARUS Israel carvedilol study, exercise study of candesartan cilexetil).

Results: Most patients reported subjective global clinical benefit (78% for positive, 74% for negative or neutral trial, NS) after participating in a clinical trial. After adjustment for age, sex, level of education, previous research, perceived comprehension, and treatment allocation (active drug/placebo) in a stepwise regression model, perceived global improvement was greater in older patients (P = 0.02), after participation in a positive trial (P = 0.05) and in females (P = 0.07). The major reason given by the patient for perceived clinical improvement was better follow-up, some believed it was due to change in medication, particularly those who had participated in a positive trial.

Conclusions: More than 70% of patients participating in clinical trials of new drugs for heart failure reported perceived global improvement. Clinical improvement was greater in, but not limited to, patients who participated in positive trials. These salutary findings support the continued recruitment of patients to clinical heart failure trials.

Key Words: Clinical trials • Placebo effect • Patient perception • Patient benefit

Received May 19, 2000; Revised September 11, 2000; Accepted November 30, 2000


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 Appendix A. Patient...
 References
 
Randomized clinical trials have established that drug therapy may improve hemodynamics and symptomatology in heart failure patients, and may [1–9] or may not [10,11] confer survival benefit. Clinical trials are currently evaluating the role of newer drugs in the management of heart failure, including new angiotensin II receptor blockers and selective antagonists of aldosterone and endothelin, and remain the gold standard for evaluating the effect of new treatment strategies on long-term outcome.

The reaction and perspective of the patients participating in a trial, particularly one which subsequently proves to be negative or neutral, has not been studied. The present study was designed to examine perceived benefit of patients participating in clinical heart failure trials, to examine the determinants of perceived benefit and to compare the findings after participation in a positive trial with one subsequently shown to have a negative or neutral result.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 Appendix A. Patient...
 References
 
2.1. Patient population
The study population included 70 consecutive patients who responded to an anonymous patient questionnaire after participating in six heart failure trials: 34 in the Mortality Assessment in Congestive Heart failure-1 (MACH-1) study of the T-channel calcium blocker mibefradil [12], 10 in the Israel carvedilol study (ICARUS), 4 in the REACH-1 study of the endothelin EA/EB receptor antagonist bosentan [13], six in the CASCO study of MCI-154, a calcium sensitizer, three in a dose-finding study of the atriopeptidase inhibitor ecadotril and 13 in a trial of the angiotensin receptor antagonist candesartan cilexetil. The trials examined different primary and secondary end-points (Table 1). The duration of follow-up ranged from 3–36 months.


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  		Table 1 Summary of heart failure trials

 
2.2. Study methods
All clinical trials were performed according to current ethical standards as outlined in the guidelines of good clinical practice (GCP) under the rules and regulations of the Declaration of Helsinki, with proper documentation and administration, approval of the study protocol by the Institution Review Board, and approval by the Israel Ministry of Health and Director of the Medical Center. Randomization was carried out using the standard procedure laid down for each trial-sequential treatment packs, telephone to central randomization center or by incremental dosage in the open label carvedilol study. At entry into the trial, all patients were given an oral and written explanation of the study and ample time for discussion prior to signing the informed consent document. The trials were monitored closely and their conduct open to independent audit.

Within 3 months of completion of the trial, an anonymous questionnaire was mailed or given to 78 consecutive patients. To ensure patient confidentiality and to promote co-operation and frankness, questionnaires were completed outside the hospital environment, without assistance of the medical team and mailed in pre-addressed return envelopes. Fully or partially completed questionnaires were received from 70 of 78 (90%) patients, and form the basis of this report.

2.3. Patient questionnaire
The patient questionnaire (Appendix A) was modified from a questionnaire developed to assess patient response in the circumstances of acute myocardial infarction [14]. The questionnaire included 26 items relating to four different aspects and stages of the trial: (1) patient background, including previous treatment and research (questions 1–4); (2) informed consent procedures and perceived patient comprehension of the trial (questions 5–12); (3) subjective feelings and reactions of the patient, including a global patient assessment of perceived clinical improvement, and reaction of family and family physician to the study (questions 13–23); and (4) patient inconvenience during the trial and patient attitude to participating in possible future clinical research (questions 24–26). The functional class of the patient was noted on the form at the time of sending (not done for first 6 patients). An independent party coded the questionnaires and entered trial and treatment allocation into the database while maintaining patient anonymity for the trials unit and research team. Replies were analyzed using standard statistical tests of frequency distribution, correlation, association and univariate and multiple stepwise regression.


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 Appendix A. Patient...
 References
 
3.1. Background patient data
The patients were aged 64±9 years, 62 males, eight females. Patient selection depended on the inclusion criteria for each clinical trial, thus 26 (41%) were in New York Heart Association Functional Class 2, 35 (55%) in class 3 and three (5%) in Class 4 (remainder unknown). Sixty-seven patients (96%) reported receiving chronic medication before entry into the trial; 55/69 (80%) had been followed by physicians of the same health care facility for ≥6 months prior to enrollment into the trial. Fifteen (21%) patients reported participating in a research trial previously. Half the patients (35 patients, 50%) had less than 12 years of schooling, 26 (37%) were high school graduates and nine (13%) had received a university education.

3.2. Perceptions regarding explanation and comprehension of the study
All patients signed an informed consent form on recruitment to the study. Although all patients received an oral and written explanation as part of the process of informed consent, less than half (26/63, 41%) recalled both the oral and written explanation, 32 (51%) recalled only the oral explanation, 2 (3%) only the written description of the project, 3 (5%) no recollection. The duration of the explanation was estimated by 17/68 (25%) patients to have lasted more than 15 min, 41 (60%) believed that the explanation had taken 5–15 min, 10 (15%) less than 5 min and 2 (3%) did not recall any explanation.

Perceived full comprehension of the study (understood most/all) was reported by 18 (27%) of the patients, while 38 (56%) claimed partial comprehension and 12 (18%) little or no understanding at all of the trial. Comprehension of the study was related to the recollected duration of explanation (P=0.003) (Table 2), but not to the personnel explaining the study or to the level of education. Comprehension was not different in the subset who had participated in previous research project(s). Perceived comprehension was reported to be greater in patients who participated in positive trials ({chi}2=6.52, P=0.03) and this remained significant (P=0.01) after correction for recollected duration of explanation, education, personnel in a multivariate model.


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  		Table 2 Perceived global improvement in patients participating in positive and negative/neutral clinical trials

 
3.3. Perception of benefit during the study
Fifty-three (76%) patients (78% in positive, 74% in negative/neutral trials) reported subjective global improvement after participating in a trial. In 12 (23%) improvement was classified as minor, in 29 (55%) moderate and in 12 (23%) marked. The degree of perceived improvement tended to be greater in patients who had participated in positive studies, with only 1/23 patients reporting improvement as ‘minor/little’ (Table 2). After adjustment for age, sex, level of education, previous research, perceived comprehension, and treatment allocation to active drug or placebo, perceived improvement was greater in older patients (P=0.02), after participation in a positive trial (P=0.05) and in females (P=0.07) (Table 3). Although improvement appeared to be somewhat greater in patients receiving active drug in a positive trial and in patients receiving placebo in a negative trial (Table 4), the small numbers did not permit statistical comparison.


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  		Table 3 Determinants of perceived improvement (patient global assessment) (multiple stepwise regression)

 


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  		Table 4 Perceived improvement (patient global assessment) by treatment allocation

 
3.4. Reasons for perceived improvement
Perceived clinical improvement, when present, was ascribed by most patients (64%) to better clinical follow-up during the study. Six patients (12%) believed that participation in the trial had given them better motivation in daily living, while 13 (25%) related improvement to a change(s) in medication (one no reply). A slightly larger number of patients in a positive trial (33% vs. 21%) ascribed improvement to change in medication rather than the follow-up, probably reflecting that some patients could relate improvement to a given point in time, that when they were given the new medication. The remainder related improvement again to follow-up or motivation.

3.5. Patient attitudes to placebo therapy
The possibility of receiving placebo therapy was of no concern to 41 (59%) of the patients participating in these clinical trials. In 20 instances (29%), patients reported some concern regarding the use of placebo, only 9 (13%) reported a major concern but nonetheless had knowingly agreed to participate in the trial. Concern regarding placebo therapy was more frequent in patients who received active drug vs. placebo (P=0.03), this due to the response of patients participating in negative/neutral (P=0.02), but not positive (NS) trials (Table 5).


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  		Table 5 Concern regarding placebo therapy

 
3.6. Attitude to results of trial and to possible future studies
Most (97%) patients expressed an interest in the results of the trial, and 88% indicated willingness to participate in future trials. There was a positive correlation between a supportive family and interest in future trial(s) (P=0.04). Interest in future studies was high irrespective of trial outcome (96% for positive vs. 86% for negative trials, NS) or drug allocation (83% active drug vs. 93% placebo, NS). Multivariate analysis showed that male sex (P=0.03), family support (P=0.02) and participation in a previous research project(s) (P=0.04) were related to expressed willingness to participate in future trials, but not age, level of education, treatment allocation or trial outcome.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
Appendix A. Patient...
 References
 
4.1. Perceived patient benefit in clinical heart failure trials
The main finding of this study was that more than 70% of patients reported some degree of perceived global benefit irrespective of whether the trial proved to be positive or was subsequently shown to be negative or neutral. Importantly, the patient was altogether unaware of the outcome of the trial or his treatment allocation at the time of completing the questionnaire. Although the placebo effect in a trial, although not always understood, is well known [15–18], the high degree of perceived subjective benefit in the present study was striking, particularly in patients with stable heart failure, supposedly receiving optimal standard therapy before entry into the trial. Older patients reported a greater degree of perceived clinical benefit, possibly reflecting awareness of a greater difference in attention (medical and psychosocial) which they received after recruitment to a trial as opposed to a regular practice setting. These salutary findings justify the continued recruitment of patients to clinical heart failure trials, where a large number of patients will be inevitably randomized to placebo therapy and considering that many trials turn out to be neutral or negative.

4.2. Patient comprehension in clinical trials
The present study included patients participating in elective clinical trials, performed on an outpatient basis, and there was ample opportunity for discussion and thought before agreeing to participate in the trial [19]. Nonetheless, more than 50% of patients recalled only the oral explanation of the study, and most thought that this had taken less than 15 min. Almost 20% of patients responded that they had little or no comprehension of the study. On the other hand the fact that some 80% of patients believed they had partial (or full) understanding of the trial was encouraging. In a Swedish gynecologic study [20], one of 43 consenting patients was unaware that she had been in a trial, seven were not aware of the meaning of participating in the project (including undergoing research laparoscopy) and 17 stated that they had no information about the possibility of withdrawing from the study, findings which clearly did not meet the guidelines of the Declaration of Helsinki. Their data may have been less reliable, since the questionnaire was administered approximately 18 months after the trial.

The level of perceived comprehension was lower in patients participating in neutral or negative clinical trials. Unrealized expectations of clinical benefit during the trial (compared to positive trial patients) may have been interpreted by the patient that he had not understood the discussion at the time of consent and recruitment. The recollected duration of explanation was also reportedly shorter in these patients.

4.3. Patient attitudes to participating in clinical trials
The fact that almost 90% of patients expressed an interest in the results of the study and most a stated willingness to participate in future trials supports the finding that patients experienced true benefit by participating in a trial, irrespective of outcome or treatment allocation. These data auger well for patient recruitment to clinical trials. Recruitment may be facilitated further by attention to detail and an attempt to lessen sources of patient inconvenience and dislike in trials. The ease of access to a medical center should be a major consideration when recruiting patients to a clinical trial [21] [22], especially if the protocol dictates frequent patient visits. Attention to organizational detail may include assistance with transportation and minimization of visits where allowed by the protocol. We have also learnt that shortening the duration of each visit would be appreciated, and that updating the patients’ physician and family worthwhile [22].

4.4. Potential limitations of the study
The study reported subjective patient recollection and perceptions and not the actual events at the time of recruitment and consent procedures. This was indeed the aim of the study and objective data would not be relevant. Although inherent bias may exist in that patients responding to the questionnaire probably had more extreme views (both positive and negative), the high response rate minimized the effect of any such bias. While this was a single center experience and differences between centers may occur [23], the findings are probably representative of trials in many countries, given that explanations, treatment and follow-up are adapted for language, practice patterns and local medico-legal requirements.

The number of patients in the study is relatively small and the statistical comparisons should be judged accordingly. Although patients from several different studies are grouped in each subset, preliminary analysis of individual trials in each subset showed consistent findings across the range of trials included each time.

4.5. Clinical implications of the study
The study showed that patients recruited to clinical trials appreciated the closer follow-up inherent to a clinical research project and were almost all interested in participating in future research trials. The positive subjective patient experience reported in the majority of cases, even after trials which turned out to be neutral or negative, provided strong support for the continued conduct of clinical trials in heart failure patients.


   Appendix A. Patient questionnaire
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 Appendix A. Patient...
References
 

Duration of clinical follow-up in department outpatient clinic prior to clinical trial:
None
Less than 6 months
More than 6 months

2. Have you participated previously in a clinical trial?
Yes
No

3. Did participation in a previous research project affect your decision to join the trial?
Yes
No

4. What is the level of your education?
Less than 12 years at school
Completed high school
University degree
Higher degree

5. Did you sign a consent form prior to participating in the study?
Yes
No

6. Did you receive an explanation about the trial?
Yes
No

7. If yes to question 6, how was the explanation given?
Oral explanation
Written explanation
Oral and written explanation
Don't recall the explanation that was given

8. How long did the explanation of the study take?
Less than 5 minutes
5–15 minutes
Longer than 15 minutes
Do not recall receiving an explanation

9. Were you given the opportunity to ask questions regarding the research project?
Yes
No

10. Who gave the explanation regarding the project?
Doctor
Nurse/technician
Both doctor and nurse
Do not remember

11. To what extent did you understand the explanation of the research trial?
Very little or not at all
Understood some or most of it (partial understanding)
Understood everything about the project

12. What was the main reason for agreeing to participate in the research trial?
Expectation of better treatment
Expectation of better follow-up
To advance medical research
Don't know (no clear reason)

13. Were you admitted/readmitted to hospital during the research project?
Yes
No

14. If readmitted, did you feel you received better attention from the treating team compared to the other patients?
Yes
No
Don't know

15. Were you receiving chronic drug therapy before the clinical trial?
Yes
No

16. Did you take the test medication throughout the trial?
Yes, regularly
Forgot sometimes
Did not take it at all

17. Do you think your condition improved during the study?
Yes
No

18. If you think you improved, please grade the degree of improvement:
Little/none really
Some (moderate) improvement
Major improvement

19. If you improved (answered yes in Q.17), to which of the following do you ascribe improvement in your condition during the trial (choose one)?
Better follow-up
Greater motivation
Change in medication

20. What was the attitude of your family doctor to your participating in the trial?
Positive
Negative
Don't know

21. What was the attitude of your family to your participating in the trial?
22. Positive
23. Negative
24. Don't know
25. What did you most derive by participating in the trial?
Follow-up
Feeling of security
Interest in the trial
Nothing at all

26. There was a chance that the medication given to you in the trial may have been placebo (dummy). To what extent did this possibility disturb you?
A great deal
Somewhat disturbing
Not at all

27. Would you like to know the result of the study after its completion?
Yes
No

28. Would you be interested in participating in similar future clinical trials?
Yes
No

29. Which of the following most inconvenienced you most during the trial (choose one)?
Distance from the medical center (need to travel)
Blood sampling
Duration of visit(s) at the medical center
Taking an additional drug


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 Appendix A. Patient...
 References
 

  1. Cohn J.N., Archibald D.G., Ziesche S., et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study (V-HeFT). N Engl J Med (1986) 314:1547–1552.[Abstract]
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