Results Summary
What was the research about?
Sickle cell disease, or SCD, causes red blood cells to change shape and block blood flow, causing pain or damage to the body. Hydroxyurea, or HU, is a treatment that helps keep red blood cells healthy. But many patients find it hard to take HU every day. Some worry that it won’t help or will cause side effects.
In this study, the research team looked at whether encouraging adults and children with SCD helped them take HU every day. Patients and parents earned $1 every day that they uploaded a video for the research team of themselves taking an HU pill. The team sent reminders daily and followed up if patients had not uploaded a video three times in the past month. They encouraged patients by phone, text, or in person. Patients received reminders for one year.
The research team compared patients who got encouragement with those who received usual care. In usual care, adults with SCD and children with SCD and their parents received reminders about clinic visits and help paying for transportation.
What were the results?
Patients who got encouragement and patients who received usual care didn’t differ in
- How often they said they took HU
- The proportion of days they had HU pills available from their prescription each month
After six months, patients who received encouragement to take HU had more red blood cells that were healthy than patients who received usual care. But by one year, there was no difference. Compared with children who got usual care, children who got encouragement had less pain and anxiety.
Patients receiving encouragement uploaded videos an average of 34 percent of days. Patients said the video system and reminders worked well, but they sometimes didn’t want to record videos.
Who was in the study?
The study included 79 adults with SCD and 85 children with SCD and their parents. Among adults, 96 percent were black; 4 percent identified as Latino. The adult average age was 24, and 55 percent of adults were men. Among children, 96 percent were black; 2 percent identified as Latino. The average age was 13, and 45 percent of children were boys.
All patients received treatment at one of three hospitals and had a prescription for HU for at least six months before the study.
What did the research team do?
The research team assigned patients by chance to get usual care or encouragement to take HU.
Using pharmacy records, the research team tracked how often patients filled their HU prescriptions and had HU available. Patients or parents completed surveys at the start of the study and 6 and 12 months later. The surveys asked how often patients took HU, and about pain, fatigue, and sleep. The team also looked at hospital records to see how often patients went to the hospital with pain or other problems caused by SCD. Finally, the team interviewed some patients and parents to find out how they felt about uploading the videos.
Youth and adults with SCD, parents of youth with SCD, and SCD community groups helped plan and conduct the study.
What were the limits of the study?
The research team couldn’t get pharmacy records for all patients, and 26 percent of patients stopped taking part in the study. Some patients got HU refills in the hospital. As a result, the patients might have had HU available more, or less, often than the research team knew.
Future research could compare other ways to help people with SCD take HU regularly.
How can people use the results?
Clinics that care for people with SCD can use these results when considering ways to help people take daily treatment.
Professional Abstract
Objective
To determine whether individualized combinations of interventions improve adherence to hydroxyurea treatment for patients with sickle cell disease (SCD)
Study Design
| Design Element | Description |
|---|---|
| Design | Randomized controlled trial |
| Population | 85 children and 79 adults with SCD who had been prescribed hydroxyurea for at least 6 months prior to the study |
| Interventions/ Comparators |
|
| Outcomes |
Primary: medication possession ratio, proportion of days with videos submitted of patient taking medication, patient-reported medication adherence Secondary: change in hemoglobin level; change in mean cell volume; patient-reported outcome measures of physical function, fatigue, pain and interference, pain intensity, sleep disturbance, and sleep-related impairment; use of ED or hospitalization because of vaso-occlusive crisis or acute chest syndrome; acceptability of treatment |
| Timeframe | 1-year follow-up for primary outcomes |
This randomized controlled trial compared individualized interventions with usual care on hydroxyurea therapy adherence in children and adults with SCD who had been prescribed hydroxyurea at least six months before the trial.
Researchers randomly assigned participants to receive usual care or an individualized combination of interventions to increase medication adherence. Usual care included appointment reminders and transportation assistance. Individualized interventions included
- Directly observed therapy in which the patient, or patient’s parent, uploaded a daily video via phone or mobile device of the patient swallowing the medication. Participants chose a time to take medication each day and received up to four text or email reminders. Participants received $1 for each uploaded video. Research coordinators called participants who had not uploaded a video for 3 or more days out of 30.
- Phone, text, or in-person communication with research coordinators to build and maintain a therapeutic relationship through positive feedback, reminders, and follow-up.
The study included 79 adults with SCD and 85 children with SCD and their parents. All patients received treatment at one of three hospitals. Among adults, 96% were black; 4% identified as Latino. Adult patients’ average age was 24, and 55% of adult patients were male. Among children, 96% were black; 2% identified as Latino. Children’s average age was 13, and 45% of children were male.
Using pharmacy data, researchers tracked patients’ medication possession ratio, or the proportion of days that patients had medication available each month for 12 months. Patients or parents completed surveys about medication adherence, physical function, fatigue, pain, and sleep at baseline and at 6 and 12 months. Researchers used hospital records to track emergency department (ED) visits or admissions for SCD-related complications. In interviews, researchers asked participants their views about submitting videos.
Adolescents and adults with SCD, parents of children and adolescents with SCD, and representatives of community-based SCD organizations helped plan and conduct the study.
Results
Participants in the intervention and usual care groups did not differ significantly in medication possession ratio and self-reported medication adherence.
Mean cell volume for participants in the intervention group was significantly higher than for those in the usual care group at 6 months (p=0.017 for adults, p=0.037 for children) but not at 12 months. The two groups showed no significant differences in ED use or hospitalization. Pediatric patients in the intervention group had significantly less pain interference (p=0.05) and anxiety (p=0.04) than patients in the usual care group, but no other patient-reported outcome reached statistical significance.
Participants in the intervention group submitted videos of themselves or their child taking medication an average of 34% of days. They described the video process and reminders positively. Some said it was not always easy to record videos in social settings, and others said they already had reminders, such as phone alarms, to take medicine.
Limitations
Researchers could not obtain all prescription records, and 26% of participants did not complete the study. Some patients received hydroxyurea during hospital visits, which changed how often they needed refills.
Conclusions and Relevance
Encouraging patients with SCD to upload videos of themselves taking medication and efforts to improve therapeutic alliance did not significantly change medication possession or adherence.
Future Research Needs
Future research could investigate factors that improve medication adherence for hydroxyurea.
Final Research Report
View this project's final research report.
Peer-Review Summary
Peer review of PCORI-funded research helps make sure the report presents complete, balanced, and useful information about the research. It also assesses how the project addressed PCORI’s Methodology Standards. During peer review, experts read a draft report of the research and provide comments about the report. These experts may include a scientist focused on the research topic, a specialist in research methods, a patient or caregiver, and a healthcare professional. These reviewers cannot have conflicts of interest with the study.
The peer reviewers point out where the draft report may need revision. For example, they may suggest ways to improve descriptions of the conduct of the study or to clarify the connection between results and conclusions. Sometimes, awardees revise their draft reports twice or more to address all of the reviewers’ comments.
Peer reviewers commented, and the researchers made changes or provided responses. The comments and responses included the following:
- The reviewers asked that the report give more attention to the difficulty of obtaining sufficient data from subjects for this study, noting that the reminder intervention seems a positive tool. However, they explained that the mobile directly observed therapy (MDOT), requiring subjects to submit videos when taking medication, raised issues of privacy, ease of use, and effectiveness. The researchers added discussion to the report about the limitations of the study’s approach and the intrusiveness of MDOT. They noted that adherence to the study protocol of submitting videos may underestimate the participants’ adherence in taking hydroxyurea (HU) therapy because participants did not always send a video when they took HU.
- Reviewers suggested that reframing the research as a mixed-methods study would be beneficial. The reviewers explained that in this type of study, the qualitative findings could better enhance the quantitative results, which the sample size limits. The researchers explained that while they reached thematic saturation in the qualitative analysis, it concerned them that this would be lost when conducting quantitative subgroup analyses, and they preferred to keep the analyses separate.
- Reviewers noted that different types of sickle cell disease (SCD) produce different challenges and needs. They wondered if more insights would have been gleaned if this study identified patients by type of SCD. The researchers agreed that patients with different forms of SCD might have different responses to HU but said that this study did not have the statistical power to distinguish impact in patients with different types of SCD.
- Reviewers noted that the rate of video submission seemed poor, and that the researchers’ use a rate of 25 percent adherence cut point to categorize groups seemed too low. The researchers acknowledged that they did not set a priori an adequate level of adherence for video submission, since there were no previous standards for this. They explained that 25 percent was much lower that what previous research has set as a benchmark for good medication intake adherence (e.g., 80 percent). However, as they learned from qualitative interviews that participants often took medications but did not submit videos, they determined post hoc that the appropriate inflection point categorize groups was 25 percent adherence with video submission.
Conflict of Interest Disclosures
Project Information
Key Dates
Study Registration Information
^Lakshmanan Krishnamurti was affiliated with the University of Pittsburgh when this project was funded.