Beliefs about chelation among thalassemia patients

Thalassemia is a congenital blood disorder that is often managed with chronic blood transfusions, typically every 2–4 weeks, which leads to progressive iron overload. Daily iron chelation therapy is prescribed to manage the transfusional iron overload and attempt to prevent progressive organ failure (heart, endocrine, liver). Life expectancy is directly related to the quality of chelation therapy, and poor adherence to treatment increases the risk of complications and shortens survival. Patient adherence practices are generally seen as a singular action, a one-dimensional phenomenon where the patient simply chooses not to do their chelation therapy. In this model, either simpler chelation methods and/or patient education were the defined solutions to failed practice. Until recently, parenteral treatment with nearly daily prolonged infusion of deferoxamine was the only available treatment, However, despite the development of new oral chelators and the development of patient education interventions, patient adherence continues to be a problem in thalassemia. Developing effective adherence interventions requires better analytic models of adherence practice.

Patients’ concerns about their treatments and their beliefs in its necessity appear to be critical in understanding patient adherence practices. The Beliefs about Medicines Questionnaire (BMQ) was designed to examine this and has been used in many disease populations, including asthma, diabetes, renal disease, cardiac disease, oncology, hypertension, arthritis, bowel disease, HIV, migraines, depression, and psychiatric disorders [1‐15]. A second instrument, the Sensitive Soma Assessment Scale (SSAS) is another instrument that is designed to assess a patient’s perceived sensitivity to medicines, and this preconception is likely related to the report of side-effects [16].

The BMQ scales have been found to correlate with adherence to treatment across many diseases and populations [1‐14, 17, 18]. Beliefs that treatment is less necessary or feelings of greater concerns about treatment are associated with lower adherence to that treatment. The necessity-concerns difference score has been found to be especially related to adherence, suggesting that “medication beliefs were more powerful predictors of reported adherence than the clinical and sociodemographic factors” [2]. The SSAS is a new instrument that early use in AIDS, hypertension, travel clinic, and undergraduate students suggests has a strong predictive association with adherence [16]. Given the importance of adherence to thalassemia treatment, understanding how patients’ beliefs in chelation therapy relate to their adherence (or lack thereof) may help providers better assist their patients. This is especially important because chelation therapy has two main forms: subcutaneous slow infusions by a portable pump (deferoxamine) and oral (deferasirox, deferiprone).

The Thalassemia Clinical Research Network (TCRN) is an NIH/NHLBI-funded network composed of five core thalassemia centers in North America, one in London, and their associated satellite sites. In May 2007, the TCRN launched the Thalassemia Longitudinal Cohort (TLC) study with baseline and annual collection of patient questionnaires, clinical history, results of standard-of-care procedures, and data regarding treatments for thalassemia and its complications. The aim of the present study is to summarize Beliefs in Medicine Questionnaire (BMQ) results for patients with thalassemia, compare beliefs in deferoxamine (DFO) vs. oral chelators, and assess effect on quality of life, anxiety, depression, and chelation adherence. This unique large international study of thalassemia patients spanning a wide age range (5–58 years) is the first to examine the medical beliefs of patients with thalassemia. Given the thalassemia literature which has emphasized the need for better education to improve adherence, we hypothesized that patients who viewed chelation as high necessity would show better adherence, and patients with high concern would show poorer adherence.

The TCRN TLC protocol was approved by the TCRN Data and Safety Monitoring Board and by the ethical review boards of all TCRN institutions. Informed consent was obtained for all participants. Eligibility for the TLC study included patients with all thalassemia syndromes who required at least annual monitoring for end-organ injury related to thalassemia. 428 patients were enrolled in the TLC from 2007–2009. Patients with a prior successful hematopoietic stem cell transplant (N=12) were excluded from this analysis. 371 patients completed the BMQ at baseline and were included in this analysis.

At baseline and annually, demographic information was collected and participants (age 14+) and/or their parents (age <16y) asked to complete the BMQ (Appendix 1). Participants were surveyed about their general beliefs in medicine, and also those specific to transfusion and chelation. The BMQ is a validated instrument [1, 19] containing 5 scales (Appendix 1), each with 4–5 items: (1) General-Overuse, (2) General-Harm, (3) General-Benefit, (4) Specific-Necessity, and (5) Specific-Concerns. The first three relate to general beliefs in medicine: (1) the notion that doctors tend to overuse and trust medicines too much, (2) the potential for medicines to be harmful, addictive, and poisonous, and (3) the potential for medicines to be helpful and allow for longer better lives. The last two scales (Specific-Necessity, Specific-Concerns) apply to the particular medicine the person is taking and measure how necessary the patient feels their medicine is for them (necessity), and perceptions of the potential negative consequences of the medication such as long-term effects, dependence, and disruptiveness (concerns). Higher necessity scores indicate higher beliefs that transfusion/chelation is necessary for their health. Higher concern scores indicate higher levels of concern about treatment. Participants not on transfusion or chelation therapy completed only the general scales. Participants on chelation were surveyed about the specific chelator they were using. Participants were using a range of chelators, including deferoxamine (DFO), deferasirox, deferiprone (available only for compassionate use in North America), and combination therapy. Patients on combination chelation (both DFO and an oral chelator) completed the scales twice, once for each chelator. The same survey also included the Sensitive Soma scale [1, 16], 5 items that assess perceptions of personal sensitivity to the potential adverse effects of medication (Appendix 1). In addition, a single item from the original BMQ item pool [1] was added asking how well patients can cope without transfusion/chelation. Finally, one additional item was added asking about unpleasant side effects of transfusion/chelation. All questions were asked on a 5-point Likert scale of strongly disagree to strongly agree (Appendix 1).

Participants aged 14 and older were asked to complete the hospital anxiety and depression scale (HADS) [20], as well as the SF-36v2 health survey [21] which measures health-related quality of life (QOL) in 8 subscales and two summary scores: physical component and mental component. Parents of children <14 years at baseline were asked to complete the PF-28 child health questionnaire (CHQ) [22], which measures quality of life (QOL) in children in 12 subscales and two summary scores (physical and mental). Participants or their parents were surveyed about their chelation use (number of doses taken in the past week and month), and study coordinators recorded the prescribed chelator dosage. Chelation adherence was defined as percent of doses administered in the last four weeks (patient report) out of those prescribed (coordinator chart review). Finally, serum ferritin, liver iron concentration (LIC) by FerriScan®, MRI, SQUID, or liver biopsy, and clinical complications were recorded from chart review. Ferritin ≥2500 ng/ml and LIC ≥15 mg Fe/g dry were considered markers of inadequate chelation. Potential complications included cardiac complications (congestive heart failure, ventricular arrhythmia, low cardiac T2*<12 ms by MRI), endocrine complications (diabetes type I, diabetes type II, growth hormone deficiency, hypothyroidism, hypoparathyroidism, hypogonadotropic hypogonadism), liver disease (cirrhosis), and transfusion related complications and infections (alloimmunization, active hepatitis C, chronic active hepatitis B, HIV).

At baseline, 371 TLC participants/parents completed the BMQ. Surveys were completed by 231 adult participants, 104 parents/guardians (mean age 10.2y, range 5–16) and 49 children (mean age 14.9y, range 10–17), including 30 pairs with forms completed by both child and parent (13 at baseline and 17 at annual follow-up, all ages 14–15). Most participants were on transfusion (93%) and chelation (92%) therapy, with 24% chelating with DFO, 58% on an oral chelator, and 10% on combination therapy (Table 1). Patients from London constituted 53% of TLC participants on deferiprone monotherapy and 27% of those on deferiprone combination chelation. The participants ranged in age from 5–58 years, with an average of 24 years. Approximately 75% of respondents had beta thalassemia major (transfused at least 8 times in the past year). Participants had an average of 1.3 clinical complications (median 1, range 0–8, 21% with >2 complications). Internal consistency (Cronbach’s alpha) for all BMQ scales was within the range reported in scale development [1, 16]: 0.80-0.84 for the Specific-Necessity scales, 0.68-0.73 for the Specific-Concerns scales, 0.63-0.71 for the general scales, and 0.84 for Sensitive Soma.

In this first study to look at beliefs about medication in thalassemia, most participants viewed their thalassemia treatment of transfusion and chelation as very necessary. As expected, their views about concerns were less uniform; having concerns about extensive and invasive treatment can be normal. Nonetheless, these patients generally reported higher beliefs in necessity and lower concerns about their treatment when compared to populations with other diseases [1‐3]. Necessity of chelation was similar to that reported for disease-specific medications by diabetic patients [1] and higher than those of patients with asthma, renal disease, cardiac disease, cancer, psychiatric illness, and rheumatoid arthritis [1‐3]. Concerns about DFO chelation were similar to concerns about medications in diabetic [1] and oncology patients [2], and lower than all other diseases reported [1‐3]; concerns about oral chelation were the lowest of any disease population [1‐3]. As blood transfusions are life-sustaining for patients with the more severe forms of thalassemia, it is perhaps not surprising that they view transfusion as more necessary than chelation. Patients immediately feel their response to transfusion with improvement in physical symptoms (e.g., asthenia, back pain). This is in contrast to iron overload which leads to insidious complications without overt symptoms for years. Nevertheless, the high ratings of necessity of chelation are a positive indication that patients understand the benefit of chelation and/or the health consequences of not chelating. This is important because providers do make the effort to educate patients about the necessity of chelation.

One goal of deploying multiple “quality of life” instruments in the TLC was to measure known social and behavioral factors that influence patient adherence behaviors in order to inform intervention. The data from the deployed set of instruments including the BMQ and Sensitive Soma clearly reinforce the reality that adherence is a complex and multifaceted problem. This study has many strengths and is the first study of beliefs in medications in thalassemia. We were able to analyze a large, racially diverse, international sample of thalassemia patients, almost all on transfusion therapy, mostly using deferoxamine or deferasirox for chelation. This study also had the advantage of descriptively comparing beliefs to other disease populations, as well as investigating associations with QOL, symptoms of anxiety and depression, and adherence. Finally, the longitudinal cohort allowed for exploration of changes in beliefs over time, especially for patients who switched chelators during follow-up. This study also had several limitations that may impact its generalizability. First, less adherent patients may also be less likely to participate in research, and beliefs in medicine may influence decisions to attend study visits, thereby potentially skewing the resulting data towards higher adherence and more positive beliefs in medicine. Second, adherence was measured from patient report, which is likely overestimated. Additionally, the SF-36v2 health survey has only been formally validated in adults, but we chose to use the instrument on participants aged 14–17 as well, in order to assess the adolescent view. Quality of life in children was measured solely by parent report; additional measurement by child report would be instructive. Finally, no information on specific side effects or adherence to transfusion therapy was collected. As non-adherence to transfusion therapy results in lower hemoglobin levels, which generally immediately affects how patients feel, it would be of interest to measure. Additionally, comparison of the beliefs of thalassemia patients to those with other hematological diseases would be worthwhile.

Clinically, these findings are instructive. Data suggests that patients do know about the importance of their medications. Providers do need to continue to reinforce the necessity of the clinical regimens, and manage patient concerns with them. They also need to recognize that patient adherence is not simply predicated on patients being better educated, but also learning how to use that knowledge in the face of other life complications. This assessment of individual beliefs regarding thalassemia treatment can help health providers better motivate their patients. While change in general beliefs may be hard to implement, perceived sensitivity to chelation may represent an opportunity for targeted intervention. Thalassemia patients may benefit from perceiving that their bodies can actually tolerate the prescribed therapy, and continued efforts to find effective chelators that are painless and without significant side effects seem warranted. In the meantime, devising strategies and interventions to help patients effectively cope with side effects might be ultimately beneficial in lowering body iron burden. As beliefs were found to differ by age, sex, and race, support groups mixing patients could be of interest. Despite their requirement for demanding, multimodal therapy, it is encouraging that thalassemia patients have positive views about medicine, with high belief in their necessity and relatively low concerns about their therapy.

The following institutions and researchers contributed to the Thalassemia Clinical Research Network Thalassemia Longitudinal Cohort data reported in this paper.Children’s Hospital, Boston: Ellis Neufeld, MD, PhD, Principal Investigator, Jennifer Braunstein, NP, Research Nurse, Amber Smith, Study Coordinator, Latoya Lashley, Study Coordinator; Satellite: University of Texas Southwestern Medical Center at Dallas, Charles Quinn, MD, MS, Principal Investigator, Deborah Boger, RN, MSN, PNP, Study Coordinator, Leah Adix, Study Coordinator, Sandra Richardson, Study Coordinator; Children's Healthcare of Atlanta, Jeanne Boudreaux, MD, Principal Investigator, Leann Hassen, Study Coordinator; Baylor College of Medicine, Brigitta Mueller, MD, Principal Investigator, Bogden Dino, Study Coordinator. Weill Medical College of Cornell University: Patricia Giardina, MD, Principal Investigator, Dorothy Kleinert, RN, Research Nurse; Satellite: Winthrop University Hospital, Mark Weinblatt, MD, Principal Investigator, Linda Skelly, Study Coordinator. The Children’s Hospital of Philadelphia: Janet Kwiatkowski, MD, Principal Investigator, Marie Martin, RN, Research Nurse, Sage Green, Study Coordinator; Satellite: Children’s Memorial Hospital, Chicago, IL, Alexis Thompson, MD, Principal Investigator, Janice Beatty, RN, Research Nurse, Diane Calamaras, RN, CPNP, Research Nurse, Pauline Hess, study coordinator. Children’s Hospital at Oakland: Elliott Vichinsky, MD, Principal Investigator, Dru Foote, NP, Research Nurse, Nancy Sweeters, Study Coordinator, Olivia Vega, Study Coordinator; Satellites: Children’s Hospital of Los Angeles, Thomas Coates, MD, Principal Investigator, Susan Carson, RN, Research Nurse, Eun Ha Pang, Study Coordinator, Rachna Khanna, Study Coordinator; Stanford Hospital, Michael Jeng, MD, Principal Investigator, Kokil Bakshi, Clinical Research Associate; Children's and Women's Health Center of British Columbia, John Wu, Principal Investigator, Heather McCartney, RN, Research Nurse, Colleen Fitzgerald, Study Coordinator, Stephanie Badour, Study Coordinator. Toronto General Hospital, Toronto, Ontario, Canada: Nancy F. Olivieri, MD, Principal Investigator, Vivek Thayalasuthan, Study Coordinator; Satellite: Hospital for Sick Children, Isaac Odame, MD, Principal Investigator, Manuela Merelles-Pulcini, RN, Study Coordinator. University College London, John Porter, MD, Principal Investigator, Cindy Bhagwandin, Study Coordinator; Satellite: Whittington Hospital, Farrukh Shah, MD, Principal Investigator. NHLBI oversight, Kathryn Hassell, MD. Data Coordinating Center: New England Research Institutes, Sonja McKinlay, PhD, Principal Investigator, Lisa Virzi, RN, MS, MBA, Project Director, Felicia Trachtenberg, PhD, Senior Statistician.

FT is senior statistician for the TCRN. LM, AS, and RY are TCRN consultants with expertise in quality of life and anxiety/depression. JK, EN, ZP, AT, CQ, RG, and NO are hematologists at participating TCRN sites. DH is a hematologist nurse at a participating TCRN site. RH is the developer of the BMQ scales.