Sex and cardiovascular disease status differences in attitudes and willingness to participate in clinical research studies/clinical trials

Sex and cardiovascular disease status differences in attitudes and willingness to participate in... Background: While women are under-represented in research on cardiovascular disease (CVD), little is known about the attitudes of men and women with CVD regarding participation in clinical research studies/clinical trials. Methods: Patients with CVD (and/or risk factors) and patients with other chronic conditions from Iowa were recruited from a commercial panel. An on-line survey assessed willingness to participate (WTP) and other attitudes towards aspects of clinical research studies. Results: Based on 504 respondents, there were no differences in WTP in patients with CVD compared to patients with other chronic diseases. Across all respondents, men had 14% lower WTP (relative risk (RR) for men, 0.86, 95% CI, 0.72–1.02). Among patients with CVD, there was no significant difference in WTP between women (RR for women = 1) and men (RR for men, 0.96, 95% CI, 0.82–1.14). There were no significant differences based on sex or CVD status for attitudes on randomization, blinding, side effects, conflict of interest, experimental treatments or willingness to talk to one’s physician. Women had more favorable attitudes about participants being treated like “guinea pigs” (RR for men, 0.84, 95% CI, 0.73–0.98) and clinical trials being associated with terminally ill patients (RR for men, 0.93, 95% CI, 0.86–1.00). Conclusions: The findings reported here suggest that the observed lower levels of participation by women are due to factors other than a lower WTP or to women having more negative attitudes towards aspects of study participation. Patients with CVD have similar attitudes and WTP as patients with other chronic conditions. Keywords: Clinical trial, Gender, Cardiovascular disease, Participation, Attitudes Background funding mandates [8] and other efforts [9, 10], women Cardiovascular disease (hereafter, CVD) is the leading continue to be under-represented in clinical research cause of death for women in the United States [1]. associated with CVD prevention and treatment [11–14]. Public relations efforts try to raise the awareness of heart Most studies documenting the under-representation of disease in women [2] (e.g., “Go Red for Women”) and women in clinical research on CVD focus on behavior, more research is being done on heart disease in women i.e., enrollment [11–16]. However, research on clinical [3–5]. Clinical research has identified important trials for other conditions (e.g., cancer) suggests that sex-related differences with respect to CVD diagnosis, patient attitudes are an important determinant of par- treatment and outcomes [6]. The guidelines for preven- ticipation. For example, a national survey [17] found that tion and treatment of CVD are based on the results of 45% of respondents felt that cancer patients participating clinical research, especially clinical trials [7]. Despite in clinical trials were “treated like ‘guinea pigs’.” On the other hand, a sample of outpatients collected in a Midwest hospital found a high proportion (68%) inter- * Correspondence: Thomas-gruca@uiowa.edu University of Iowa, Iowa City, USA ested in participating in a clinical trial [18]. Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Gruca et al. Trials (2018) 19:300 Page 2 of 9 Basic psychology suggests that attitudes predict future Methods behavior [19]. Thus, one path to better understanding dif- Study sample ferences in behavior is to explore variations in attitudes. We conducted a cross-sectional, on-line survey of adults Consider, for example, the effect of race on participation (aged 18 years and older). Schlesinger Associates, a com- in cardiology clinical trials. A 2008 study shows that mercial marketing research firm, recruited respondents accounting for race-based variations in distrust and per- from their Inspired Opinions panel. An email invitation ceived harm eliminated the explanatory effect of race on directed interested panel members to an on-line survey willingness to participate (WTP) in a pharmaceutical programmed using Qualtrics. A set of initial questions clinical trial [20]. Another study compared men’sand screened respondents for age and residency in Iowa. women’s WTP in a (hypothetical) CVD prevention clinical Schlesinger Associates compensated respondents upon trial [21]. In the baseline analysis, women had significantly completion of the survey. lower WTP than men. The authors also found that Schlesinger Associates sent a total of 4439 email invita- women also had significantly higher levels of distrust in tions to prospective participants. Of these, 1250 responded medical professionals compared to men. However, ac- and attempted to complete the survey (28% response rate). counting for this difference in attitudes did not eliminate This response rate is consistent the reported response rates the sex-based variations in WTP. for recent general population surveys conducted online Given the continuing lack of success in recruiting (average response rate of 24.6%) [29]. women for clinical research on CVD, there is a need for A total of 744 respondents completed the survey. Of more research on women’s attitudes towards participa- the respondents completing the survey, 197 (26.5%) tion in such research studies. Researchers studying other reported having none of the 16 chronic conditions of patient populations have identified barriers to participation interest (hypertension, diabetes, high cholesterol, heart including attitudes towards study randomization [22, 23], problems, peripheral vascular disease, stroke, asthma, potential side effects [24], conflicts of interest [25], etc. COPD/emphysema/chronic bronchitis, chronic kidney The attitudes of CVD patients towards these aspects of disease, liver disease, arthritis, osteoporosis, depression, clinical research studies are not well-documented in the fibromyalgia and cancer). We excluded these patients academic literature. How female and male patients with from the final sample. CVD might differ with respect to these attitudes is also A total of 43 patients did not disclose their sex. We an understudied area. excluded these respondents from the final sample as well Recruiting patients for clinical research studies/clinical (see Fig. 1). The final sample size was 504 respondents. trials (CRS/CTs) is a challenge not limited to cardiovascu- The survey was in the field between 15 February lar medicine. Researchers studying other chronic diseases and 23 February 2013. also face recruiting difficulties [26–28]. To better under- stand the attitudes of potential participants in Iowa, the Instruments Institute for Clinical and Translational Science (ICTS) at We asked study participants about their knowledge of, the University of Iowa conducted a general population past participation in, and various attitudes towards CRS/ survey focused on the state of Iowa. This survey was part CTs. We adapted some of the attitude measures from a of a larger effort to promote interest in participating in survey conducted by Mayo Clinic [18]. Based on prior clinical trials among potential subjects in Iowa. As a first research, we included additional survey items on general step, the ICTS wanted to better understand attitudes of attitudes towards clinical research studies/clinical trials. potential research subjects towards participating in clinical One such item focuses on the impression that patients in trials and their beliefs about the benefits and harms of clinical trials are “treated like guinea pigs”[17]. Another participating in clinical trials. item inquired whether the participant would be comfort- For the analysis presented in this paper, we limited our able talking to their physicians about enrolling in a CRS/ sample to those patients with at least one of 16 chronic CT [30]. Additional items asked whether CRS/CTs were conditions including CVD. These conditions included sig- for only for terminally ill patients [31] or always involved nificant risk factors for CVD such as diabetes, high choles- experimental treatments. For all attitude items, respon- terol and high blood pressure. Our purpose is to better dents indicated their agreement with this statement on a understand the attitudes of female and male patients with 5-point Likert scale (Strongly agree, Agree, Neither Agree CVD towards various aspects of participation in clinical nor Disagree, Disagree, Strongly disagree). studies. We included patients with other chronic condi- Willingness to participate was measured using a tions to better understand what attitudes towards partici- single item: “I would be interested in participating in pation are specific to CVD patients and which are shared clinical research studies/clinical trials related to med- with other patient groups eligible to participate in clinical ical condition(s) I’m interested in (such as conditions research studies/clinical trials (hereafter CRS/CT). I or my friends/family have or may have).” The WTP Gruca et al. Trials (2018) 19:300 Page 3 of 9 disagree) [14]. The entire survey is included as an on-line appendix (Additional file 1). 4,439 Email Unlike prior research using written survey forms Invitations Sent [14, 18], the location of this item was randomized within the entire set of attitudinal items. This approach re- duces the tendency for order effects, exposure effects and 3,189 Unresponsive other biases associated with written surveys using a single printed form. To internally validate this measure of WTP with actual behavior, we compared the Likert scale response to the 1,250 Responses prior experience of the respondent with respect to CRS/ CTs. In the survey, respondents were asked if they had been asked to participate in a clinical research study/ clinical trial. The possible responses were: “Yes, and I 506 Incomplete participated,”“Yes, and I declined to participate” and Responses “No.” For those who were asked, we correlated their response (participated or declined to participate) with their WTP response on the 5-point Likert scale using the point-biserial correlation. The non-parametric z-score was 2.54 (p < 0.01) which is consistent with past research [14] 744 Completed using WTP measures regarding hypothetical participation Surveys in CRS/CTs. Of the other attitude items, two were reverse coded, i.e., a positive response (Disagree, or Strongly disagree) and a negative response (Neither Agree nor Disagree, 197 Reported no Agree or Strongly agree). These are identified in Table 1. The survey included a question on self-reported health chronic health status and items related to respondent demographic conditions characteristics. This study was approved by the University of Iowa Institutional Review Board (IRB) (#201210760). 547 Reported 1 or Statistical analysis more chronic health Respondents who self-reported having any of the follow- conditions ing medical conditions: heart problems (e.g., heart disease, heart failure, etc.), peripheral vascular disease, stroke, high cholesterol, hypertension, or diabetes were classified into a group labeled “CVD.” 43 Did not indicate Relative risk (RR) analysis was conducted to examine sex or refused to the associations between sex, CVD status and positive answer question WTP. Additional associations between positive WTP and other attitudes related the CRS/CT participation were also estimated. Relative risks were estimated using Poisson regression with robust variance [32]. The baseline sex and CVD status-Stratified Analysis 504 Included in final (model 1) were adjusted first for age (18–24, 25–29, 30– study 39, 40–49, 50–59, 60–64, 65 years and older). An enhanced model (model 2) included age, race (Caucasian (non-Hispanic) or other), household income (US$0– Fig. 1 Flowchart of study completion US$24,999, US$25,000–US$49,999, US$50,000–US$74,999, US$75,000–US$100,000, or ≥ US$100,000), marital status measure was dichotomized into a positive response (with partner or single), education (less than college (Strongly agree or Agree) and a negative response graduate or college graduate) and health status (poor/fair, (Neither Agree nor Disagree, Disagree, or Strongly good, very good, excellent). Gruca et al. Trials (2018) 19:300 Page 4 of 9 Table 1 Responses to survey items on patient attitudes towards and interest in participating in clinical research studies/clinical trials Label Question Positive responses N(%) Random I find it acceptable to be assigned in a random fashion in 372(73.8) a clinical research study/clinical trial. Blinded I find it acceptable to be assigned in a blinded fashion in 388(77.0) a clinical research study/clinical trial Side effects Even if I were told that the treatment prescribed to me 180 (35.7) in a clinical research study/clinical trial has potential side effects, I would still be interested in participating in the clinical research/study Conflict of interest Clinical research studies/clinical trials sponsored by the 143 (28.4) pharmaceutical companies are likely to have a conflict of interest Guinea pigs (reversed) Patients who participate in clinical research studies/ 322 (63.9) clinical trials are treated like guinea pigs Talking to physician I would feel comfortable talking to my physician about 420 (83.3) enrolling in a clinical research study/clinical trial Terminally ill (reversed) Only terminally ill patients participate in clinical research 449 (89.1) studies/clinical trials Experimental treatments All clinical research studies/clinical trials involve 124 (24.6) experimental treatments WTP I would be interested in participating in clinical trial(s) 325 (64.5) related to medical condition(s) I’m interested in (e.g., conditions I or my friends/family have or may have) Further analyses (model 3) examined whether including likely to be a function of the older age distribution of attitudes towards different aspects of CRS/CTs affected the sample as well as the use of an on-line panel [35]. the associations between sex, CVD status and positive There is no significant difference in WTP between men WTP. These included attitudes towards randomization, and women in the age-adjusted model (model 1) or in the blinding, side effects, conflicts of interest, etc. (The items multivariate model adjusted for other demographic vari- are listed in Table 1.) ables (model 2). The results are presented in Table 3. Poisson regression analysis was also used to examine The addition of a sex × CVD status interaction term to the association of sex or CVD status and the attitude the multivariate model (with demographic variables) did items listed in Table 1. not alter the results (model 3). The WTP for men is lower All analyses were conducted using SAS 9.4. All tests but not significantly different from the WTP for women were two-sided. (model 3: RR, 0.86, 95% CI, 0.72–1.09). The WTP for re- spondents in the CVD group was not significantly different. Results Using model 3, we tested for in WTP across sex and Descriptive statistics for the study subjects are provided within CVD status. Within the CVD group, the WTP in Table 2. Our sample is older than the general popula- for men is not significantly different from the WTP for tion. This is likely due to the restriction of this analysis women (model 3, Stratified Analysis: CVD group, RR for to respondents with a self-reported chronic disease. men, 0.96, 95% CI, 0.82–1.14). The results are similar Chronic diseases, including CVD, tend to be associated for the non-CVD group (model 3, Stratified Analysis: with advanced age [33] (the one exception is obesity non-CVD group, RR for men, 0.77, 95% CI, 0.57–1.04). which is not included in this study). The addition of measures of attitudes towards CRS/CTs The sample is also more highly educated than the gen- to model 3 did not affect the difference in WTP for the eral population. The proportion of adults in Iowa (over CVD group compared to those not in the CVD group. 25) holding a bachelor’s degree (or higher) was 26.3% in None of the differences were significantly different. 2015. In our sample, the percentage was more than The addition of two respondent attitudes to the model double at 60%. This higher level of education is likely of WTP had an impact on the difference in WTP between due to having an older population and contacting poten- women and men. The addition of respondent attitudes tial respondents through an on-line survey [34]. Simi- towards study blinding resulted in a significantly lower larly, the median income of the survey respondents is WTP for men compared to women (model 3 + blinded: higher (US$58,880) than the general population of Iowa RR for men, 0.85, 95% CI, 0.72–1.00). Similar results were (median income of US$54,736). This variation is also found for the inclusion of attitudes towards side Gruca et al. Trials (2018) 19:300 Page 5 of 9 Table 2 Descriptive characteristics of participants Characteristic Men Women P value Men Women (n = 195) (n = 309) proportions proportions Age (years) < 0.001 18–29 4 25 2.1 8.1 30–39 9 46 4.6 14.9 40–49 32 41 16.4 13.3 50–59 56 82 28.7 26.6 60–64 42 51 21.5 16.6 65+ 52 63 26.7 20.5 Race 0.15 Caucasian (non-Hispanic) 186 300 95.4 97.7 Other 9 9 4.6 2.3 Education 0.16 College graduate 124 176 63.6 57.3 Not a college graduate 71 131 36.4 42.7 Income < 0.01 Less than US$25,000 12 51 10.8 16.8 US$25,000 to US$49,999 38 93 19.6 30.6 US$50,000 to US$74,999 58 71 29.9 23.4 US$75,000 to US$99,999 47 47 17.5 15.5 US$100,000+ 42 42 22.2 13.8 Marital status < 0.01 With partner (married or domestic partnership) 157 214 80.5 69.5 Without partner 38 95 19.5 30.5 Current health status 0.75 Poor/fair 6 6 3.1 2.0 Good 51 73 26.2 23.8 Very good 114 185 58.5 60.3 Excellent 24 43 12.3 14.0 Cardiovascular disease / risk factors Heart problems 31 15 < .0001 15.9 4.9 Peripheral vascular disease 3 1 .30 1.5 0.3 Stroke 5 4 .32 2.6 1.3 Hypertension 76 102 .17 39.0 33.0 High cholesterol 106 129 < .01 54.4 41.8 Diabetes 31 33 .09 15.9 10.7 Any CVD (or risk factor) 151 191 < .001 77.4 61.8 Using chi-square test unless otherwise noted Fisher’s exact test African-American (non-Hispanic), Asian, Pacific Islanders, Latino or Hispanic, Native American or Aleut, self-reported “other,” or prefer not to answer effects (model 3 + side effects: RR for men, 0.85, 95% Disagree = 1) was significantly lower for the “treated like CI, 0.73–1.00). The results for the other attitudes were guinea pigs” (RR for men, 0.84, 95% CI, 0.73–0.98) and the not statistically significantatthe p<0.05 level. “only for terminally ill patients” RR for men, 0.93, 95% CI, We compared sex and CVS status differences in the 0.86–1.00) items. Both of these are reverse coded which respondents’ attitudes towards CRS/CTs. There were only indicates that men have a significantly less favorable two significant differences (see Table 4). For men, the opinion of CRS/CTs with respect to these factors than do proportion with a positive response (Strongly Disagree and the women in the study. Gruca et al. Trials (2018) 19:300 Page 6 of 9 Table 3 Sex, cardiovascular disease (CVD) status and willingness to participate in clinical research studies/clinical trials Relative risk (95% CI) Relative risk (95% CI) Women Men P value Non-CVD CVD P value Model 1 1 [Reference] 0.93 (0.80–1.07) .28 1 [Reference] 1.00 (0.86–1.16) .95 Model 2 1 [Reference] 0.91 (0.79–1.05) .19 1 [Reference] 0.99 (0.85–1.14) .86 Model 3 1 [Reference] 0.86 (0.72–1.02) .09 1 [Reference] 1.04 (0.88–1.24) .63 Model 3 + random 1 [Reference] 0.85 (0.72–1.01) .07 1 [Reference] 1.05 (0.88–1.24) .60 Model 3 + blinded 1 [Reference] 0.85 (0.72–1.00) .05 1 [Reference] 1.04 (0.88–1.23) .63 Model 3 + side effects 1 [Reference] 0.85 (0.73–1.00) .05 1 [Reference] 1.11 (0.95–1.31) .19 Model 3 + conflict of interest 1 [Reference] 0.85 (0.72–1.01) .06 1 [Reference] 1.02 (0.86–1.21) .81 Model 3 + guinea pigs 1 [Reference] 0.92 (0.78–1.09) .31 1 [Reference] 1.03 (0.87–1.22) .73 Model 3 + talking to physician 1 [Reference] 0.93 (0.80–1.08) .36 1 [Reference] 1.05 (0.91–1.23) .49 Model 3 + terminally ill 1 [Reference] 0.89 (0.75–1.06) .18 1 [Reference] 1.03 (0.87–1.22) .73 Model 3 + experimental treatments 1 [Reference] 0.86 (0.72–1.02) .08 1 [Reference] 1.04 (0.88–1.25) .63 Stratified characteristics, model 3 Non-CVD CVD P value‖ Women 1 [Reference] 1 [Reference] .40 Men 0.77 (0.57–1.04) 0.96 (0.82–1.14) Model 1 is adjusted for age Model 2 is adjusted for the variables in model 1 plus age, education, annual household income, marital status, race and current health status Model 3 is adjusted for the variables in model 2 plus CVD status for the primary sex effect estimates and sex for the primary CVD status estimates; model 3 is also adjusted for sex × CVD status interaction Responses of “Strongly Disagree” and “Disagree” were grouped together ‖P values for stratified models are for sex × CVD status interaction Comparing attitudes between respondents in the CVD WTP for patients in the CVD group was equally high for group and those not in the CVD group, no significant women as for men. This null finding itself was unexpected differences were found. given that women are significantly under-represented in clinical trials [36]. Some authors suggest that the low Discussion enrollment in studies involving CVD is due to patients Our general population survey of prospective CRS/CT having negative attitudes towards various aspects of CRS/ participants in the state of Iowa examined differences in CTs such as fear of randomization, mistrust of the the WTP of men and women, all of whom have a researcher, etc. [13]. We found no significant differences self-reported chronic illness. We found no significant dif- between men and women regarding their attitudes to- ferences between the WTP for men and women. We also wards randomization, blinding, side effects, conflicts of did not find significant differences between respondents interest or the association of CRS/CTs with experimental with CVD and those with one of 10 other chronic ill- treatments. The significant differences in this study were nesses. Most surprising was the finding that the higher associated with participants being treated like guinea pigs Table 4 Sex, cardiovascular disease (CVD) status and positive attitudes associated with participation in clinical trials Relative risk (95% CI) Relative risk (95% CI) Attitude Women Men P value Non-CVD CVD P value Random 1 [Reference] 0.98 (0.88–1.10) .79 1 [Reference] 1.03 (0.92–1.16) .58 Blinded 1 [Reference] 0.99 (0.89–1.20) .85 1 [Reference] 1.05 (0.94–1.17) .35 Side effects 1 [Reference] 1.02 (0.79–1.32) .87 1 [Reference] 0.81 (0.63–1.05) .11 Conflict of interest 1 [Reference] 1.00 (0.74–1.36) .99 1 [Reference] 0.92 (0.67–1.25) .57 Guinea pigs (reversed) 1 [Reference] 0.84 (0.73–0.98) .02 1 [Reference] 1.02 (0.88–1.84) .79 Talking to physician 1 [Reference] 0.95 (0.87–1.04) .25 1 [Reference] 1.00 (0.91–1.09) .92 Terminally ill (reversed) 1 [Reference] 0.93 (0.86–1.00) .05 1 [Reference] 0.98 (0.91–1.05) .57 Experimental treatments 1 [Reference] 0.85 (0.61–1.19) .35 1 [Reference] 0.84 (0.59–1.19) .33 Adjusted for age, marital status, race, education, income and current health status Disagreement with questionnaire prompt Gruca et al. Trials (2018) 19:300 Page 7 of 9 or participation being solely for the terminally ill. How- white population (91.3% in 2010 census). While these re- ever, the results reflected a significantly less positive view sults might not generalizable to other populations, they of CRS/CTs by the men in our study. are of general interest since a recent national study [37] The findings reported here raise some interesting suggests that non-Hispanic whites have the highest pro- questions about why women are under-represented in portion with one or more chronic conditions (63% vs. CRS/CTs especially in the area of CVD prevention and 58% for non-Hispanic black, 50% for non-Hispanic other treatment. The problem does not seem to lie in purely and 49% for Hispanic). sex-based differences or differences in attitudes towards Our sample of survey respondents reported themselves various potentially negative aspects of clinical research; as being healthier than the general United States’ popu- e.g., randomization, potential conflicts of interest, etc. lation. Overall, 73% identified themselves as having very The question is why – if women are favorably predis- good or excellent health. This compares to an expected posed towards participating in CRS/CTs – do so few level of 60% using national data (men and women com- actually enroll in these studies? There does seem to be a bined, weighted by our sample composition) [38]. Prior clear disconnect between the attitudes of women in research suggests that perceived health may be a barrier general (and those with CVD in particular) towards to participation in clinical trials [39]. Consequently, the CRS/CTs and their realized participation. sample of respondents in this study may be more favor- In attempting to explain the continuing failure of ably disposed towards CRS/CT participation than the researchers to recruit women with CVD for clinical general public. research studies, varying theories are advanced. Some of As noted above, sampling prospective CRS/CT partici- these are helpful to researchers. For example, prior re- pants through an on-line panel may limit the number of search suggests that study-based factors account for a less affluent, less well-educated and less technologically great deal of variation in participation [14]. For example, sophisticated respondents. Using a pre-recruited on-line one potential issue is the difference in the age of the on- panels for survey research in medicine is an increasing set of CVD in women. Since the onset of CVD is delayed trend [35]. One concern for using this method to study in women [6] (compared to men), studies excluding eld- prospective participation in clinical research is the po- erly participants would disproportionately affect women. tential for a positive bias towards research in general in There is also a role for physicians in educating and coun- the type of person who would participate in an on-line seling women about participation in clinical trials [6]. panel. While the extent and nature of such a bias is It may appear cliché to suggest further research on unknown, we can compare the overall positive response better understanding women’s attitudes and actions of this study to another survey collected within a single regarding participation in CRS/CTs, especially those in institution with a similar demographic profile of partici- the area of CVD prevention and treatment. Simply doc- pants [18]. A sample of 400 participants recruited umenting the problem and speculating about solutions face-to-face at Mayo Clinic (in 2006) found that 68% is not working. had a positive WTP. This compares to an overall WTP Consider, for example, a recent study of women’s of 64.5%. While the WTP figures are comparable for participation in 15 cardiology clinical trials at Duke these two sampling approaches, it must be noted that University [14]. In the discussion of patient-level barriers face-to-face recruiting of survey participants (which is to participation, it was suggested that, “for women espe- used in both general population [18] and CVD patient cially, there may be a need to arrange child care to studies [21]) has its own potential problems with intro- attend a study visit.” Given that the median age of the ducing bias into survey results. patients in this study was 63 years (I.Q. range of 54–72), At the insistence of the IRB, the sponsorship of the it is highly unlikely that arranging child care was a factor study by the University of Iowa was made known to all for many patients of either gender. Similarly, a recent survey respondents. It is not known whether this infor- review article suggested trying to leverage the success of mation positively or negatively influenced the response clinical trials for other conditions [6]. For example, the rate or the responses by survey participants. recruiting success of a HIV-treatment study was at- Most importantly, the focal measurement of WTP was tributed to, among other factors, the effect of a “fem- based on the response to an attitude scale and not actual inine logo – a butterfly” to increase recognition of enrollment in a clinical research study or clinical trial. female patients. It is unclear how such an insight may No details about the benefits or risks associated with be used to increase women’s participation in clinical clinical research were presented when the WTP measure research for CVD. was collected. There are many reasons that a person in- The findings of this study should be viewed in light of terested in participation does not end up in a clinical its limitations. Our sample was collected from a single trial. Some of these barriers are due to the person (e.g., Midwestern state with a predominantly non-Hispanic access to transportation, mobility), some are associated Gruca et al. Trials (2018) 19:300 Page 8 of 9 with the requirements of the trial (comorbidity exclu- Additional file sions, etc.). Still others are due to the patient’s relation- Additional file 1: Survey ICTS - V2. (DOCX 22 kb) ship with others; e.g., family, spouse, primary care physician. These factors (and more) have been identified in prior research as having an enabling or inhibiting in- Abbreviations CI: Confidence interval; CRS/CT: Clinical research studies/clinical trials; fluence on CRS/CT participation. CVD: Cardiovascular disease; RR: Relative risk; WTP: Willingness to participate To improve participation by women in studies on CVD will require different sorts of research than have Acknowledgements been done to date. Due to the voluntary nature of en- The authors would like to thank Blaine Rourick, James Tabiri and Yun-Chin Yeh for their assistance with the data collection and analysis and Kathleen rollment in CRS/CTs, a positive predisposition towards Lilli for her help with administration. participation is a necessary but not sufficient condition. In other fields, especially cancer care, there has been a Consent to participate All subjects were adults and provided informed consent to participate. concerted effort to study in detail the reasons that patients choose to not enroll in a clinical trial. Some of Funding these qualitative studies [23, 25, 30] served to identify This work was supported by the National Institutes of Health (NIH) Clinical general attitudes that were included in this survey con- and Translational Science Award (CTSA) program, grant U54TR001356. The CTSA program is led by the NIH’s National Center for Advancing ducted among Iowans with chronic diseases. Translational Sciences (NCATS). This publication’s contents are solely the Despite the fact that CVD is the leading cause of death responsibility of the authors and do not necessarily represent the official for women in the United States, to our knowledge, there views of the NIH. been no in-depth qualitative studies of the reasons why Availability of data and materials women do not enroll in CRS/CTs in the same propor- The datasets used during the current study available from the corresponding tions as men. This study suggests that the typical rea- author on reasonable request. sons – concerns with study blinding, randomization, conflicts of interest, etc. – are not different between Authors’ contributions TG worked on the study design, drafted the manuscript and oversaw all data men and women with chronic diseases (or even within analysis. WH analyzed and interpreted the willingness to participate data. JC the sub-sample of those with CVD). Therefore, new worked on data coding, preliminary data analysis and manuscript writing research must be undertaken to determine if there are support. AO oversaw data collection including programming and initial data cleaning. GR worked on the study design and provided critical evaluation of unique and addressable barriers in the population of the manuscript. All authors read and approved the final manuscript. women with CVD that serve as a barrier to participa- tion. Fortunately, there is a recent meta-ethnographic Ethics approval and consent to participate analysis [40] of prior qualitative research (conducted This study was approved by the University of Iowa Institutional Review Board (#201210760). across a range of medical conditions) that identifies several key themes that may be germane to further study Competing interests of this important and underserved patient population. The authors declare that they have no competing interests. Conclusions Publisher’sNote Our study of attitudes towards CRS/CTs among Iowans Springer Nature remains neutral with regard to jurisdictional claims in with chronic conditions shows no significant differences published maps and institutional affiliations. in WTP for women or people with CVD (and/or major Author details risk factors). With respect to attitudes towards various 1 2 University of Iowa, Iowa City, USA. Cognizant Consulting, New York, USA. 3 4 aspects of clinical research, the few observed differences OMD, New York, USA. Department of Internal Medicine, Wake Forest University, Winston-Salem, NC, USA. suggest that women have more favorable attitudes. Simi- larly, patients with CVD have attitudes towards various Received: 23 November 2016 Accepted: 3 May 2018 elements of CRS/CTs similar to those of patients with other chronic conditions. These results contradict the References findings from prior research on patient attitudes on 1. Heron M. Deaths: leading causes for 2013. 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Sex and cardiovascular disease status differences in attitudes and willingness to participate in clinical research studies/clinical trials

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Medicine & Public Health; Medicine/Public Health, general; Biomedicine, general; Statistics for Life Sciences, Medicine, Health Sciences
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Abstract

Background: While women are under-represented in research on cardiovascular disease (CVD), little is known about the attitudes of men and women with CVD regarding participation in clinical research studies/clinical trials. Methods: Patients with CVD (and/or risk factors) and patients with other chronic conditions from Iowa were recruited from a commercial panel. An on-line survey assessed willingness to participate (WTP) and other attitudes towards aspects of clinical research studies. Results: Based on 504 respondents, there were no differences in WTP in patients with CVD compared to patients with other chronic diseases. Across all respondents, men had 14% lower WTP (relative risk (RR) for men, 0.86, 95% CI, 0.72–1.02). Among patients with CVD, there was no significant difference in WTP between women (RR for women = 1) and men (RR for men, 0.96, 95% CI, 0.82–1.14). There were no significant differences based on sex or CVD status for attitudes on randomization, blinding, side effects, conflict of interest, experimental treatments or willingness to talk to one’s physician. Women had more favorable attitudes about participants being treated like “guinea pigs” (RR for men, 0.84, 95% CI, 0.73–0.98) and clinical trials being associated with terminally ill patients (RR for men, 0.93, 95% CI, 0.86–1.00). Conclusions: The findings reported here suggest that the observed lower levels of participation by women are due to factors other than a lower WTP or to women having more negative attitudes towards aspects of study participation. Patients with CVD have similar attitudes and WTP as patients with other chronic conditions. Keywords: Clinical trial, Gender, Cardiovascular disease, Participation, Attitudes Background funding mandates [8] and other efforts [9, 10], women Cardiovascular disease (hereafter, CVD) is the leading continue to be under-represented in clinical research cause of death for women in the United States [1]. associated with CVD prevention and treatment [11–14]. Public relations efforts try to raise the awareness of heart Most studies documenting the under-representation of disease in women [2] (e.g., “Go Red for Women”) and women in clinical research on CVD focus on behavior, more research is being done on heart disease in women i.e., enrollment [11–16]. However, research on clinical [3–5]. Clinical research has identified important trials for other conditions (e.g., cancer) suggests that sex-related differences with respect to CVD diagnosis, patient attitudes are an important determinant of par- treatment and outcomes [6]. The guidelines for preven- ticipation. For example, a national survey [17] found that tion and treatment of CVD are based on the results of 45% of respondents felt that cancer patients participating clinical research, especially clinical trials [7]. Despite in clinical trials were “treated like ‘guinea pigs’.” On the other hand, a sample of outpatients collected in a Midwest hospital found a high proportion (68%) inter- * Correspondence: Thomas-gruca@uiowa.edu University of Iowa, Iowa City, USA ested in participating in a clinical trial [18]. Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Gruca et al. Trials (2018) 19:300 Page 2 of 9 Basic psychology suggests that attitudes predict future Methods behavior [19]. Thus, one path to better understanding dif- Study sample ferences in behavior is to explore variations in attitudes. We conducted a cross-sectional, on-line survey of adults Consider, for example, the effect of race on participation (aged 18 years and older). Schlesinger Associates, a com- in cardiology clinical trials. A 2008 study shows that mercial marketing research firm, recruited respondents accounting for race-based variations in distrust and per- from their Inspired Opinions panel. An email invitation ceived harm eliminated the explanatory effect of race on directed interested panel members to an on-line survey willingness to participate (WTP) in a pharmaceutical programmed using Qualtrics. A set of initial questions clinical trial [20]. Another study compared men’sand screened respondents for age and residency in Iowa. women’s WTP in a (hypothetical) CVD prevention clinical Schlesinger Associates compensated respondents upon trial [21]. In the baseline analysis, women had significantly completion of the survey. lower WTP than men. The authors also found that Schlesinger Associates sent a total of 4439 email invita- women also had significantly higher levels of distrust in tions to prospective participants. Of these, 1250 responded medical professionals compared to men. However, ac- and attempted to complete the survey (28% response rate). counting for this difference in attitudes did not eliminate This response rate is consistent the reported response rates the sex-based variations in WTP. for recent general population surveys conducted online Given the continuing lack of success in recruiting (average response rate of 24.6%) [29]. women for clinical research on CVD, there is a need for A total of 744 respondents completed the survey. Of more research on women’s attitudes towards participa- the respondents completing the survey, 197 (26.5%) tion in such research studies. Researchers studying other reported having none of the 16 chronic conditions of patient populations have identified barriers to participation interest (hypertension, diabetes, high cholesterol, heart including attitudes towards study randomization [22, 23], problems, peripheral vascular disease, stroke, asthma, potential side effects [24], conflicts of interest [25], etc. COPD/emphysema/chronic bronchitis, chronic kidney The attitudes of CVD patients towards these aspects of disease, liver disease, arthritis, osteoporosis, depression, clinical research studies are not well-documented in the fibromyalgia and cancer). We excluded these patients academic literature. How female and male patients with from the final sample. CVD might differ with respect to these attitudes is also A total of 43 patients did not disclose their sex. We an understudied area. excluded these respondents from the final sample as well Recruiting patients for clinical research studies/clinical (see Fig. 1). The final sample size was 504 respondents. trials (CRS/CTs) is a challenge not limited to cardiovascu- The survey was in the field between 15 February lar medicine. Researchers studying other chronic diseases and 23 February 2013. also face recruiting difficulties [26–28]. To better under- stand the attitudes of potential participants in Iowa, the Instruments Institute for Clinical and Translational Science (ICTS) at We asked study participants about their knowledge of, the University of Iowa conducted a general population past participation in, and various attitudes towards CRS/ survey focused on the state of Iowa. This survey was part CTs. We adapted some of the attitude measures from a of a larger effort to promote interest in participating in survey conducted by Mayo Clinic [18]. Based on prior clinical trials among potential subjects in Iowa. As a first research, we included additional survey items on general step, the ICTS wanted to better understand attitudes of attitudes towards clinical research studies/clinical trials. potential research subjects towards participating in clinical One such item focuses on the impression that patients in trials and their beliefs about the benefits and harms of clinical trials are “treated like guinea pigs”[17]. Another participating in clinical trials. item inquired whether the participant would be comfort- For the analysis presented in this paper, we limited our able talking to their physicians about enrolling in a CRS/ sample to those patients with at least one of 16 chronic CT [30]. Additional items asked whether CRS/CTs were conditions including CVD. These conditions included sig- for only for terminally ill patients [31] or always involved nificant risk factors for CVD such as diabetes, high choles- experimental treatments. For all attitude items, respon- terol and high blood pressure. Our purpose is to better dents indicated their agreement with this statement on a understand the attitudes of female and male patients with 5-point Likert scale (Strongly agree, Agree, Neither Agree CVD towards various aspects of participation in clinical nor Disagree, Disagree, Strongly disagree). studies. We included patients with other chronic condi- Willingness to participate was measured using a tions to better understand what attitudes towards partici- single item: “I would be interested in participating in pation are specific to CVD patients and which are shared clinical research studies/clinical trials related to med- with other patient groups eligible to participate in clinical ical condition(s) I’m interested in (such as conditions research studies/clinical trials (hereafter CRS/CT). I or my friends/family have or may have).” The WTP Gruca et al. Trials (2018) 19:300 Page 3 of 9 disagree) [14]. The entire survey is included as an on-line appendix (Additional file 1). 4,439 Email Unlike prior research using written survey forms Invitations Sent [14, 18], the location of this item was randomized within the entire set of attitudinal items. This approach re- duces the tendency for order effects, exposure effects and 3,189 Unresponsive other biases associated with written surveys using a single printed form. To internally validate this measure of WTP with actual behavior, we compared the Likert scale response to the 1,250 Responses prior experience of the respondent with respect to CRS/ CTs. In the survey, respondents were asked if they had been asked to participate in a clinical research study/ clinical trial. The possible responses were: “Yes, and I 506 Incomplete participated,”“Yes, and I declined to participate” and Responses “No.” For those who were asked, we correlated their response (participated or declined to participate) with their WTP response on the 5-point Likert scale using the point-biserial correlation. The non-parametric z-score was 2.54 (p < 0.01) which is consistent with past research [14] 744 Completed using WTP measures regarding hypothetical participation Surveys in CRS/CTs. Of the other attitude items, two were reverse coded, i.e., a positive response (Disagree, or Strongly disagree) and a negative response (Neither Agree nor Disagree, 197 Reported no Agree or Strongly agree). These are identified in Table 1. The survey included a question on self-reported health chronic health status and items related to respondent demographic conditions characteristics. This study was approved by the University of Iowa Institutional Review Board (IRB) (#201210760). 547 Reported 1 or Statistical analysis more chronic health Respondents who self-reported having any of the follow- conditions ing medical conditions: heart problems (e.g., heart disease, heart failure, etc.), peripheral vascular disease, stroke, high cholesterol, hypertension, or diabetes were classified into a group labeled “CVD.” 43 Did not indicate Relative risk (RR) analysis was conducted to examine sex or refused to the associations between sex, CVD status and positive answer question WTP. Additional associations between positive WTP and other attitudes related the CRS/CT participation were also estimated. Relative risks were estimated using Poisson regression with robust variance [32]. The baseline sex and CVD status-Stratified Analysis 504 Included in final (model 1) were adjusted first for age (18–24, 25–29, 30– study 39, 40–49, 50–59, 60–64, 65 years and older). An enhanced model (model 2) included age, race (Caucasian (non-Hispanic) or other), household income (US$0– Fig. 1 Flowchart of study completion US$24,999, US$25,000–US$49,999, US$50,000–US$74,999, US$75,000–US$100,000, or ≥ US$100,000), marital status measure was dichotomized into a positive response (with partner or single), education (less than college (Strongly agree or Agree) and a negative response graduate or college graduate) and health status (poor/fair, (Neither Agree nor Disagree, Disagree, or Strongly good, very good, excellent). Gruca et al. Trials (2018) 19:300 Page 4 of 9 Table 1 Responses to survey items on patient attitudes towards and interest in participating in clinical research studies/clinical trials Label Question Positive responses N(%) Random I find it acceptable to be assigned in a random fashion in 372(73.8) a clinical research study/clinical trial. Blinded I find it acceptable to be assigned in a blinded fashion in 388(77.0) a clinical research study/clinical trial Side effects Even if I were told that the treatment prescribed to me 180 (35.7) in a clinical research study/clinical trial has potential side effects, I would still be interested in participating in the clinical research/study Conflict of interest Clinical research studies/clinical trials sponsored by the 143 (28.4) pharmaceutical companies are likely to have a conflict of interest Guinea pigs (reversed) Patients who participate in clinical research studies/ 322 (63.9) clinical trials are treated like guinea pigs Talking to physician I would feel comfortable talking to my physician about 420 (83.3) enrolling in a clinical research study/clinical trial Terminally ill (reversed) Only terminally ill patients participate in clinical research 449 (89.1) studies/clinical trials Experimental treatments All clinical research studies/clinical trials involve 124 (24.6) experimental treatments WTP I would be interested in participating in clinical trial(s) 325 (64.5) related to medical condition(s) I’m interested in (e.g., conditions I or my friends/family have or may have) Further analyses (model 3) examined whether including likely to be a function of the older age distribution of attitudes towards different aspects of CRS/CTs affected the sample as well as the use of an on-line panel [35]. the associations between sex, CVD status and positive There is no significant difference in WTP between men WTP. These included attitudes towards randomization, and women in the age-adjusted model (model 1) or in the blinding, side effects, conflicts of interest, etc. (The items multivariate model adjusted for other demographic vari- are listed in Table 1.) ables (model 2). The results are presented in Table 3. Poisson regression analysis was also used to examine The addition of a sex × CVD status interaction term to the association of sex or CVD status and the attitude the multivariate model (with demographic variables) did items listed in Table 1. not alter the results (model 3). The WTP for men is lower All analyses were conducted using SAS 9.4. All tests but not significantly different from the WTP for women were two-sided. (model 3: RR, 0.86, 95% CI, 0.72–1.09). The WTP for re- spondents in the CVD group was not significantly different. Results Using model 3, we tested for in WTP across sex and Descriptive statistics for the study subjects are provided within CVD status. Within the CVD group, the WTP in Table 2. Our sample is older than the general popula- for men is not significantly different from the WTP for tion. This is likely due to the restriction of this analysis women (model 3, Stratified Analysis: CVD group, RR for to respondents with a self-reported chronic disease. men, 0.96, 95% CI, 0.82–1.14). The results are similar Chronic diseases, including CVD, tend to be associated for the non-CVD group (model 3, Stratified Analysis: with advanced age [33] (the one exception is obesity non-CVD group, RR for men, 0.77, 95% CI, 0.57–1.04). which is not included in this study). The addition of measures of attitudes towards CRS/CTs The sample is also more highly educated than the gen- to model 3 did not affect the difference in WTP for the eral population. The proportion of adults in Iowa (over CVD group compared to those not in the CVD group. 25) holding a bachelor’s degree (or higher) was 26.3% in None of the differences were significantly different. 2015. In our sample, the percentage was more than The addition of two respondent attitudes to the model double at 60%. This higher level of education is likely of WTP had an impact on the difference in WTP between due to having an older population and contacting poten- women and men. The addition of respondent attitudes tial respondents through an on-line survey [34]. Simi- towards study blinding resulted in a significantly lower larly, the median income of the survey respondents is WTP for men compared to women (model 3 + blinded: higher (US$58,880) than the general population of Iowa RR for men, 0.85, 95% CI, 0.72–1.00). Similar results were (median income of US$54,736). This variation is also found for the inclusion of attitudes towards side Gruca et al. Trials (2018) 19:300 Page 5 of 9 Table 2 Descriptive characteristics of participants Characteristic Men Women P value Men Women (n = 195) (n = 309) proportions proportions Age (years) < 0.001 18–29 4 25 2.1 8.1 30–39 9 46 4.6 14.9 40–49 32 41 16.4 13.3 50–59 56 82 28.7 26.6 60–64 42 51 21.5 16.6 65+ 52 63 26.7 20.5 Race 0.15 Caucasian (non-Hispanic) 186 300 95.4 97.7 Other 9 9 4.6 2.3 Education 0.16 College graduate 124 176 63.6 57.3 Not a college graduate 71 131 36.4 42.7 Income < 0.01 Less than US$25,000 12 51 10.8 16.8 US$25,000 to US$49,999 38 93 19.6 30.6 US$50,000 to US$74,999 58 71 29.9 23.4 US$75,000 to US$99,999 47 47 17.5 15.5 US$100,000+ 42 42 22.2 13.8 Marital status < 0.01 With partner (married or domestic partnership) 157 214 80.5 69.5 Without partner 38 95 19.5 30.5 Current health status 0.75 Poor/fair 6 6 3.1 2.0 Good 51 73 26.2 23.8 Very good 114 185 58.5 60.3 Excellent 24 43 12.3 14.0 Cardiovascular disease / risk factors Heart problems 31 15 < .0001 15.9 4.9 Peripheral vascular disease 3 1 .30 1.5 0.3 Stroke 5 4 .32 2.6 1.3 Hypertension 76 102 .17 39.0 33.0 High cholesterol 106 129 < .01 54.4 41.8 Diabetes 31 33 .09 15.9 10.7 Any CVD (or risk factor) 151 191 < .001 77.4 61.8 Using chi-square test unless otherwise noted Fisher’s exact test African-American (non-Hispanic), Asian, Pacific Islanders, Latino or Hispanic, Native American or Aleut, self-reported “other,” or prefer not to answer effects (model 3 + side effects: RR for men, 0.85, 95% Disagree = 1) was significantly lower for the “treated like CI, 0.73–1.00). The results for the other attitudes were guinea pigs” (RR for men, 0.84, 95% CI, 0.73–0.98) and the not statistically significantatthe p<0.05 level. “only for terminally ill patients” RR for men, 0.93, 95% CI, We compared sex and CVS status differences in the 0.86–1.00) items. Both of these are reverse coded which respondents’ attitudes towards CRS/CTs. There were only indicates that men have a significantly less favorable two significant differences (see Table 4). For men, the opinion of CRS/CTs with respect to these factors than do proportion with a positive response (Strongly Disagree and the women in the study. Gruca et al. Trials (2018) 19:300 Page 6 of 9 Table 3 Sex, cardiovascular disease (CVD) status and willingness to participate in clinical research studies/clinical trials Relative risk (95% CI) Relative risk (95% CI) Women Men P value Non-CVD CVD P value Model 1 1 [Reference] 0.93 (0.80–1.07) .28 1 [Reference] 1.00 (0.86–1.16) .95 Model 2 1 [Reference] 0.91 (0.79–1.05) .19 1 [Reference] 0.99 (0.85–1.14) .86 Model 3 1 [Reference] 0.86 (0.72–1.02) .09 1 [Reference] 1.04 (0.88–1.24) .63 Model 3 + random 1 [Reference] 0.85 (0.72–1.01) .07 1 [Reference] 1.05 (0.88–1.24) .60 Model 3 + blinded 1 [Reference] 0.85 (0.72–1.00) .05 1 [Reference] 1.04 (0.88–1.23) .63 Model 3 + side effects 1 [Reference] 0.85 (0.73–1.00) .05 1 [Reference] 1.11 (0.95–1.31) .19 Model 3 + conflict of interest 1 [Reference] 0.85 (0.72–1.01) .06 1 [Reference] 1.02 (0.86–1.21) .81 Model 3 + guinea pigs 1 [Reference] 0.92 (0.78–1.09) .31 1 [Reference] 1.03 (0.87–1.22) .73 Model 3 + talking to physician 1 [Reference] 0.93 (0.80–1.08) .36 1 [Reference] 1.05 (0.91–1.23) .49 Model 3 + terminally ill 1 [Reference] 0.89 (0.75–1.06) .18 1 [Reference] 1.03 (0.87–1.22) .73 Model 3 + experimental treatments 1 [Reference] 0.86 (0.72–1.02) .08 1 [Reference] 1.04 (0.88–1.25) .63 Stratified characteristics, model 3 Non-CVD CVD P value‖ Women 1 [Reference] 1 [Reference] .40 Men 0.77 (0.57–1.04) 0.96 (0.82–1.14) Model 1 is adjusted for age Model 2 is adjusted for the variables in model 1 plus age, education, annual household income, marital status, race and current health status Model 3 is adjusted for the variables in model 2 plus CVD status for the primary sex effect estimates and sex for the primary CVD status estimates; model 3 is also adjusted for sex × CVD status interaction Responses of “Strongly Disagree” and “Disagree” were grouped together ‖P values for stratified models are for sex × CVD status interaction Comparing attitudes between respondents in the CVD WTP for patients in the CVD group was equally high for group and those not in the CVD group, no significant women as for men. This null finding itself was unexpected differences were found. given that women are significantly under-represented in clinical trials [36]. Some authors suggest that the low Discussion enrollment in studies involving CVD is due to patients Our general population survey of prospective CRS/CT having negative attitudes towards various aspects of CRS/ participants in the state of Iowa examined differences in CTs such as fear of randomization, mistrust of the the WTP of men and women, all of whom have a researcher, etc. [13]. We found no significant differences self-reported chronic illness. We found no significant dif- between men and women regarding their attitudes to- ferences between the WTP for men and women. We also wards randomization, blinding, side effects, conflicts of did not find significant differences between respondents interest or the association of CRS/CTs with experimental with CVD and those with one of 10 other chronic ill- treatments. The significant differences in this study were nesses. Most surprising was the finding that the higher associated with participants being treated like guinea pigs Table 4 Sex, cardiovascular disease (CVD) status and positive attitudes associated with participation in clinical trials Relative risk (95% CI) Relative risk (95% CI) Attitude Women Men P value Non-CVD CVD P value Random 1 [Reference] 0.98 (0.88–1.10) .79 1 [Reference] 1.03 (0.92–1.16) .58 Blinded 1 [Reference] 0.99 (0.89–1.20) .85 1 [Reference] 1.05 (0.94–1.17) .35 Side effects 1 [Reference] 1.02 (0.79–1.32) .87 1 [Reference] 0.81 (0.63–1.05) .11 Conflict of interest 1 [Reference] 1.00 (0.74–1.36) .99 1 [Reference] 0.92 (0.67–1.25) .57 Guinea pigs (reversed) 1 [Reference] 0.84 (0.73–0.98) .02 1 [Reference] 1.02 (0.88–1.84) .79 Talking to physician 1 [Reference] 0.95 (0.87–1.04) .25 1 [Reference] 1.00 (0.91–1.09) .92 Terminally ill (reversed) 1 [Reference] 0.93 (0.86–1.00) .05 1 [Reference] 0.98 (0.91–1.05) .57 Experimental treatments 1 [Reference] 0.85 (0.61–1.19) .35 1 [Reference] 0.84 (0.59–1.19) .33 Adjusted for age, marital status, race, education, income and current health status Disagreement with questionnaire prompt Gruca et al. Trials (2018) 19:300 Page 7 of 9 or participation being solely for the terminally ill. How- white population (91.3% in 2010 census). While these re- ever, the results reflected a significantly less positive view sults might not generalizable to other populations, they of CRS/CTs by the men in our study. are of general interest since a recent national study [37] The findings reported here raise some interesting suggests that non-Hispanic whites have the highest pro- questions about why women are under-represented in portion with one or more chronic conditions (63% vs. CRS/CTs especially in the area of CVD prevention and 58% for non-Hispanic black, 50% for non-Hispanic other treatment. The problem does not seem to lie in purely and 49% for Hispanic). sex-based differences or differences in attitudes towards Our sample of survey respondents reported themselves various potentially negative aspects of clinical research; as being healthier than the general United States’ popu- e.g., randomization, potential conflicts of interest, etc. lation. Overall, 73% identified themselves as having very The question is why – if women are favorably predis- good or excellent health. This compares to an expected posed towards participating in CRS/CTs – do so few level of 60% using national data (men and women com- actually enroll in these studies? There does seem to be a bined, weighted by our sample composition) [38]. Prior clear disconnect between the attitudes of women in research suggests that perceived health may be a barrier general (and those with CVD in particular) towards to participation in clinical trials [39]. Consequently, the CRS/CTs and their realized participation. sample of respondents in this study may be more favor- In attempting to explain the continuing failure of ably disposed towards CRS/CT participation than the researchers to recruit women with CVD for clinical general public. research studies, varying theories are advanced. Some of As noted above, sampling prospective CRS/CT partici- these are helpful to researchers. For example, prior re- pants through an on-line panel may limit the number of search suggests that study-based factors account for a less affluent, less well-educated and less technologically great deal of variation in participation [14]. For example, sophisticated respondents. Using a pre-recruited on-line one potential issue is the difference in the age of the on- panels for survey research in medicine is an increasing set of CVD in women. Since the onset of CVD is delayed trend [35]. One concern for using this method to study in women [6] (compared to men), studies excluding eld- prospective participation in clinical research is the po- erly participants would disproportionately affect women. tential for a positive bias towards research in general in There is also a role for physicians in educating and coun- the type of person who would participate in an on-line seling women about participation in clinical trials [6]. panel. While the extent and nature of such a bias is It may appear cliché to suggest further research on unknown, we can compare the overall positive response better understanding women’s attitudes and actions of this study to another survey collected within a single regarding participation in CRS/CTs, especially those in institution with a similar demographic profile of partici- the area of CVD prevention and treatment. Simply doc- pants [18]. A sample of 400 participants recruited umenting the problem and speculating about solutions face-to-face at Mayo Clinic (in 2006) found that 68% is not working. had a positive WTP. This compares to an overall WTP Consider, for example, a recent study of women’s of 64.5%. While the WTP figures are comparable for participation in 15 cardiology clinical trials at Duke these two sampling approaches, it must be noted that University [14]. In the discussion of patient-level barriers face-to-face recruiting of survey participants (which is to participation, it was suggested that, “for women espe- used in both general population [18] and CVD patient cially, there may be a need to arrange child care to studies [21]) has its own potential problems with intro- attend a study visit.” Given that the median age of the ducing bias into survey results. patients in this study was 63 years (I.Q. range of 54–72), At the insistence of the IRB, the sponsorship of the it is highly unlikely that arranging child care was a factor study by the University of Iowa was made known to all for many patients of either gender. Similarly, a recent survey respondents. It is not known whether this infor- review article suggested trying to leverage the success of mation positively or negatively influenced the response clinical trials for other conditions [6]. For example, the rate or the responses by survey participants. recruiting success of a HIV-treatment study was at- Most importantly, the focal measurement of WTP was tributed to, among other factors, the effect of a “fem- based on the response to an attitude scale and not actual inine logo – a butterfly” to increase recognition of enrollment in a clinical research study or clinical trial. female patients. It is unclear how such an insight may No details about the benefits or risks associated with be used to increase women’s participation in clinical clinical research were presented when the WTP measure research for CVD. was collected. There are many reasons that a person in- The findings of this study should be viewed in light of terested in participation does not end up in a clinical its limitations. Our sample was collected from a single trial. Some of these barriers are due to the person (e.g., Midwestern state with a predominantly non-Hispanic access to transportation, mobility), some are associated Gruca et al. Trials (2018) 19:300 Page 8 of 9 with the requirements of the trial (comorbidity exclu- Additional file sions, etc.). Still others are due to the patient’s relation- Additional file 1: Survey ICTS - V2. (DOCX 22 kb) ship with others; e.g., family, spouse, primary care physician. These factors (and more) have been identified in prior research as having an enabling or inhibiting in- Abbreviations CI: Confidence interval; CRS/CT: Clinical research studies/clinical trials; fluence on CRS/CT participation. CVD: Cardiovascular disease; RR: Relative risk; WTP: Willingness to participate To improve participation by women in studies on CVD will require different sorts of research than have Acknowledgements been done to date. Due to the voluntary nature of en- The authors would like to thank Blaine Rourick, James Tabiri and Yun-Chin Yeh for their assistance with the data collection and analysis and Kathleen rollment in CRS/CTs, a positive predisposition towards Lilli for her help with administration. participation is a necessary but not sufficient condition. In other fields, especially cancer care, there has been a Consent to participate All subjects were adults and provided informed consent to participate. concerted effort to study in detail the reasons that patients choose to not enroll in a clinical trial. Some of Funding these qualitative studies [23, 25, 30] served to identify This work was supported by the National Institutes of Health (NIH) Clinical general attitudes that were included in this survey con- and Translational Science Award (CTSA) program, grant U54TR001356. The CTSA program is led by the NIH’s National Center for Advancing ducted among Iowans with chronic diseases. Translational Sciences (NCATS). This publication’s contents are solely the Despite the fact that CVD is the leading cause of death responsibility of the authors and do not necessarily represent the official for women in the United States, to our knowledge, there views of the NIH. been no in-depth qualitative studies of the reasons why Availability of data and materials women do not enroll in CRS/CTs in the same propor- The datasets used during the current study available from the corresponding tions as men. This study suggests that the typical rea- author on reasonable request. sons – concerns with study blinding, randomization, conflicts of interest, etc. – are not different between Authors’ contributions TG worked on the study design, drafted the manuscript and oversaw all data men and women with chronic diseases (or even within analysis. WH analyzed and interpreted the willingness to participate data. JC the sub-sample of those with CVD). Therefore, new worked on data coding, preliminary data analysis and manuscript writing research must be undertaken to determine if there are support. AO oversaw data collection including programming and initial data cleaning. GR worked on the study design and provided critical evaluation of unique and addressable barriers in the population of the manuscript. All authors read and approved the final manuscript. women with CVD that serve as a barrier to participa- tion. Fortunately, there is a recent meta-ethnographic Ethics approval and consent to participate analysis [40] of prior qualitative research (conducted This study was approved by the University of Iowa Institutional Review Board (#201210760). across a range of medical conditions) that identifies several key themes that may be germane to further study Competing interests of this important and underserved patient population. The authors declare that they have no competing interests. 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