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Hydroxyurea therapy is effective for reducing complications related to sickle cell disease (SCD) and is recommended by National Health Lung and Blood Institute care guidelines. However, hydroxyurea is underutilized, and adherence is suboptimal. We wanted to test a multilevel mobile health (mHealth) intervention to increase hydroxyurea adherence among patients and improve prescribing among providers in a multicenter clinical trial. In the first 2 study sites, participants were exposed to the early phases of the COVID-19 pandemic, which included disruption to their regular SCD care.
We aimed to describe the impact of the COVID-19 pandemic on the implementation of an mHealth behavioral intervention for improving hydroxyurea adherence among patients with SCD.
The first 2 sites initiated enrollment 3 months prior to the start of the pandemic (November 2019 to March 2020). During implementation, site A clinics shut down for 2 months and site B clinics shut down for 9 months. We used the reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework to evaluate the implementation and effectiveness of the intervention. mHealth implementation was assessed based on patients’ daily app use. Adherence to hydroxyurea was calculated as the proportion of days covered (PDC) from prescription records over the first 12 and 24 weeks after implementation. A linear model examined the relationship between app usage and PDC change, adjusting for baseline PDC, lockdown duration, and site. We conducted semistructured interviews with patients, health care providers, administrators, and research staff to identify factors associated with mHealth implementation and effectiveness. We used a mixed methods approach to investigate the convergence of qualitative and quantitative findings.
The percentage of patients accessing the app decreased after March 15, 2020 from 86% (n=55) to 70% (n=45). The overall mean PDC increase from baseline to week 12 was 4.5% (
We found significant impacts of the early clinic lockdowns, which reduced implementation of the mHealth intervention and led to reduced patient adherence to hydroxyurea. However, disruptions were lower among participants who experienced shorter clinic lockdowns and were associated with higher hydroxyurea adherence. Investigation of added strategies to mitigate the effects of care interruptions during major emergencies (eg, patient coaching and health navigation) may “insulate” the implementation of interventions to increase medication adherence.
ClinicalTrials.gov NCT04080167; https://clinicaltrials.gov/ct2/show/NCT04080167
RR2-10.2196/16319
Sickle cell disease (SCD) is a chronic blood disorder in which acute painful acute events occur on the background of progressive organ dysfunction, leading to premature mortality [
Mobile health (mHealth) apps, for both patients and providers, can be used as a strategy to incorporate behavioral change interventions that can potentially improve medication adoption and effectiveness [
The COVID-19 pandemic has disrupted health care access in unprecedented ways, including reducing patient-provider contact during health maintenance care and reducing medication adherence for chronic diseases [
Because the COVID-19 pandemic lockdown restrictions disrupted the care of the study participants, we sought to evaluate how the implementation and preliminary effectiveness of the patient
Implementation intervention specification. Specification is done according to the action, actor, context, target, and time (AACTT) framework [
In this report, we describe the results of the implementation of the
Patient participants were individuals with a diagnosis of SCD between the ages of 15 and 45 years treated with hydroxyurea and receiving care at the 2 initial participating sites [
This study was approved by the Institutional Review Board at St Jude Children's Research Hospital (19-0159) and Duke University (Pro00073506), and all participants (or their legal guardians) signed consent prior to study participation.
The methods of the study have been published [
As part of the planned approach for the multisite study, we used the reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework to inform the evaluation of the implementation and effectiveness of the
Patient-level data on hydroxyurea adherence provided a measure of effectiveness. Hydroxyurea adherence was measured by calculating the proportion of days covered (PDC), which is the ratio of the number of days the patient is covered by the medication to the number of days in the treatment period. In other words, the PDC is the number of days covered by prescriptions that were filled divided by the length of the study interval. If a prescription was filled just before the start of the study interval, the days between the prescription fill date and start of the interval were excluded. If a prescription was filled near the end of the study interval, the part of the interval covered by the prescription that was after the end of the study interval was also excluded. The PDC was calculated over a 24-week baseline interval and over the first 12 and first 24 weeks after implementation. Provider app use was classified as low (≤1 time on average monthly during the study) and high (>1 time on average monthly during the study).
We compared PDC change over 12 and 24 weeks after mHealth implementation using 1-sample
The association between the use of the
We used the RE-AIM framework to qualitatively identify factors that may have influenced mHealth implementation and effectiveness during the initial phases of the COVID-19 pandemic [
A total of 75 patients (out of 508 eligible) and 42 providers (out of 55 eligible) were enrolled between November 2019 and September 2020 in the first 2 participating SCDIC sites. To characterize the influence of the COVID-19 pandemic shutdowns on app use, we only included 64 patients and all 42 providers enrolled prior to March 15, 2022. Among the patients, 28 were enrolled at site A and 36 at site B. Half (32/64, 50%) were young adults (18-25 years), with almost even gender distribution (
Participant characteristics.
Characteristic | Patients, n (%) | Providers, n (%) | ||||||||||||
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All patients (N=64) | Site A (N=28) | Site B (N=36) | All providers (N=42) | Site A (N=15) | Site B (N=27) | ||||||||
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15-17 | 7 (11) | 0 (0) | 7 (19) | 0 (0) | 0 (0) | 0 (0) | |||||||
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18-25 | 32 (50) | 10 (36) | 22 (61) | 0 (0) | 0 (0) | 0 (0) | |||||||
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26-45 | 25 (39) | 18 (64) | 7 (19) | 29 (69) | 9 (60) | 20 (74) | |||||||
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46-64 | 0 (0) | 0 (0) | 0 (0) | 12 (29) | 5 (33) | 7 (26) | |||||||
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>65 | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | |||||||
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Missing | 0 (0) | 0 (0) | 0 (0) | 1 (2) | 1 (7) | 0 (0) | |||||||
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Male | 31 (48) | 15 (54) | 16 (44) | 12 (29) | 2 (13) | 10 (37) | |||||||
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Female | 33 (52) | 13 (46) | 20 (56) | 30 (71) | 13 (87) | 17 (63) | |||||||
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Black | 64 (100) | 28 (100) | 36 (100) | 8 (19) | 5 (33) | 3 (11) | |||||||
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White | 0 (0) | 0 (0) | 0 (0) | 24 (59) | 7 (47) | 17 (63) | |||||||
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Asian | 0 (0) | 0 (0) | 0 (0) | 9 (22) | 2 (13) | 7 (26) | |||||||
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Missing | 0 (0) | 0 (0) | 0 (0) | 1 (2) | 1 (7) | 0 (0) | |||||||
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Not Hispanic | 64 (100) | 28 (100) | 36 (100) | 41 (98) | 14 (93) | 27 (100) | |||||||
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Hispanic | 0 (0) | 0 (0) | 0 (0) | 1 (2) | 1 (7) | 0 (0) | |||||||
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HbSS/HbSβ0-thalassemia | 56 (88) | 27 (96) | 29 (81) | N/Aa | N/A | N/A | |||||||
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HbSC/HbSβ+-thalassemia/other | 8 (12) | 1 (4) | 7 (19) | N/A | N/A | N/A | |||||||
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Physician | N/A | N/A | N/A | 24 (59) | 9 (60) | 15 (56) | |||||||
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Nurse practitioner or physician assistant | N/A | N/A | N/A | 17 (41) | 6 (40) | 11 (41) | |||||||
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Missing | N/A | N/A | N/A | 1 (2) | 0 (0) | 1 (4) | |||||||
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High | 6 (9) | 6 (21) | 0 (0) | N/A | N/A | N/A | |||||||
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Medium-high | 8 (13) | 5 (18) | 3 (8) | N/A | N/A | N/A | |||||||
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Medium-low | 9 (14) | 2 (7) | 7 (19) | N/A | N/A | N/A | |||||||
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Low | 41 (64) | 15 (54) | 26 (72) | N/A | N/A | N/A | |||||||
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High | N/A | N/A | N/A | 21 (52) | 8 (53) | 13 (48) | |||||||
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Low | N/A | N/A | N/A | 19 (48) | 5 (33) | 14 (52) |
aN/A: not applicable.
bThe
cThe
dTwo providers were removed from the study (moved to a new institution or requested to be withdrawn).
All 64 patient participants downloaded the app, and 58 participants used it at least once during the 6-month study period, representing a 91% reach. On average, patients accessed the app on 42.7 (25.5%) days throughout the 6 months of the study period, and 24 (38%) of the 64 patients accessed it on ≥25% of the total days over 6 months. The percentage of participants accessing the app decreased after March 15, 2020, from 86% (n=55) before that date to 70% (n=45) after that date. However, the average change in app use was very close to 0 (mean change: −0.0016;
Of the 42 providers enrolled, 41 downloaded and used the
Change in InCharge Health app use relative to the COVID-19 pandemic lockdown. March 15, 2020, corresponds to the date when both sites went on lockdown in response to the COVID-19 pandemic. The black diagonal lines represent the boundaries for the maximum that app use can change after March 15, 2020, given app use before March 15, 2020. Since app use is expressed as a proportion of days on which the app is accessed, app use must be ≥0 and ≤1.0. As app use prior to March 15, 2020, increases, the maximum amount by which it can drop after March 15, 2020, increases, while the amount by which it can increase after March 15, 2020, decreases. For example, if app use is 0.25 (25% of days) before March 15, 2020, it can drop by a maximum of 0.25 or increase by a maximum of 0.75, whereas if app use is 0.75 (75% of days) before March 15, 2020, it can drop by a maximum of 0.75 or increase by a maximum of 0.25. There were 2 subgroups. The diagonal line of points along the lower black boundary line indicates the first subgroup consisting of participants whose app use dropped from some use to little or no use after March 15, 2020. On the other hand, the cloud of points from both sites above the line of zero change indicates the second subgroup consisting of patients whose app use increased after March 15, 2020.
The mean increase in the PDC was 4.5% (
Proportion of days covered (PDC) change at 24 weeks of follow-up. PDC increases were observed at site A and PDC decreases were observed at site B, but a lower baseline PDC was associated with a higher PDC change at 24 weeks at both sites. The duration of time from March 15, 2020, to the end of each participant’s follow-up was associated with greater PDC increases at site A (where the lockdown duration after March 15, 2020, was shorter) and greater decreases at site B (where the lockdown duration after March 15, 2020, was longer). BasPDC: baseline proportion of days covered.
App use measured by the number of follow-up days on which the app was used at least once was not statistically significant (
Linear model of the change in the proportion of days covered from baseline to 24 weeks of follow-up.
Parametera | Estimate | SE | |
Intercept | 4.4493 | 11.0926 | .69 |
App use increased after March 15, 2020 | 13.7584 | 6.1096 | .03 |
App use decreased after March 15, 2020 | 0 | N/Ab | N/A |
Baseline PDCc | −0.3928 | 0.0862 | <.001 |
Days from enrollment through March 15, 2020 | −0.0116 | 0.1247 | .93 |
Site A | 53.3618 | 14.3925 | <.001 |
Site B | 0 | N/A | N/A |
Days from enrollment through March 15, 2020, at site A | −0.4695 | 0.1803 | .01 |
Days from enrollment through March 15, 2020, at site B | 0 | N/A | N/A |
aModel variables included baseline proportion of days covered, site, time from March 15, 2020, to the end of each participant’s follow-up, the interaction between site and time from March 15, 2020, to the end of follow-up, and an indicator for increased app use after March 15, 2020.
bN/A: not applicable.
cPDC: proportion of days covered.
Eleven patients (mean age, 26.4 years; 64% [7/11] males; 100% [11/11] Black; 73% [8/11] HbSS; 45% [5/11] low app users) completed interviews across the 2 sites. Site B’s closure during COVID-19 had a greater impact on patients, who had difficulty obtaining hydroxyurea and reaching their providers and the clinic for nonurgent or emergent reasons. One low user from site B stated:
Before COVID-19, I could just call my clinic or doctor and ask if I could come in and it would be a ‘yes’, but now, its [COVID-19] cut down on the days the clinic is open and the time the clinic is open. It's harder to get in.
However, almost all reported that the
I can appreciate it [the app]. It helped me. I think it’s a good thing. I think it makes me better with my hydroxyurea.
Consistent with patients, providers and administrators reported that clinic shutdowns during COVID-19 negatively impacted the ability to care for patients. For example, because fewer patients were coming to the clinic, there was a reduction in the need to use the
It [COVID-19] definitely impacted [app use]. As fellows, we were not coming to the clinic as often for at least two to three months. So, I didn't happen to think about the app or just didn't have an opportunity to use it.
Research staff at both sites also reported that reduced in-person clinic visits was a barrier for implementing the study in general. One staff member stated:
It has been quite difficult during the pandemic. It was easier for us when we were in person. We had that carved out time when [patients] weren't doing anything else, they were specifically focused on what we were doing.
Hydroxyurea is an evidence-based therapy in SCD, with proven clinical benefits, but its uptake is low. In a multicenter NHLBI-funded study, we tested the use of mHealth to improve hydroxyurea use among adolescents and adults with SCD. At the first 2 study sites, participants were exposed to the early phases of the COVID-19 pandemic, which included disruption in their regular SCD care. While the ubiquitous access to mobile technology among patients with SCD represents a unique opportunity to leverage mHealth interventions to support clinical care, the contextual changes, such as those during global emergencies, can affect its implementation. Our study is the first to assess, among individuals with SCD, the impact of the COVID-19 pandemic on the implementation of an mHealth behavioral intervention aimed at improving medication adherence. In the 2 clinical trial sites where study activities happened during the early phases of the pandemic, we found evidence of significant reductions in the implementation of the app relative to the duration of the clinic lockdown in response to the COVID-19 pandemic. While low baseline adherence levels predicted higher improvements in adherence, the pandemic disruptions also affected the adherence to hydroxyurea, which was proportionally reduced to the duration of the clinic lockdown. However, we also found evidence of the benefit of mHealth to improve adherence. Among patients whose mHealth use increased after the start of the lockdown, improvements in hydroxyurea adherence were also observed. Our findings highlight the influence of unplanned contextual changes on the implementation of mHealth behavioral interventions and the potential benefits of investing in strategies to sustain use. These data are key for the future implementation of mHealth behavioral interventions, for both patients and providers, in clinical settings during pandemics or other similar situations.
Earlier studies have demonstrated the potential efficacy of mHealth interventions for enhancing hydroxyurea adherence among patients with SCD [
In our study, the usage of the
During the COVID-19 pandemic, reliance on telehealth exponentially increased, and for some chronic conditions, it not only facilitated care delivery but also improved health outcomes [
The finding that reduced in-person visits was a barrier to study implementation was not surprising, as the impact of COVID-19 on clinical trials is well recognized [
Our study has limitations. Data included in this analysis were from 2 study sites with relatively small sample sizes, which limits the generalizability of our findings. However, they do reflect the impact of the early institutional responses to the COVID-19 pandemic, which also occurred in other health institutions worldwide. Additionally, the results presented are not representative of the full study results, as this study is currently ongoing. Additional data regarding the effectiveness of mHealth for hydroxyurea adherence is, therefore, forthcoming. We also were not able to conduct interviews with all SCD participants to better understand specific barriers to hydroxyurea adherence during the pandemic, but our interview sample was purposefully selected based on the participants’ app use levels and achieved theme saturation. Because of the nature of the pandemic, we were not able to measure the mental health impact of the pandemic in the initial months and how it would have affected app use. Further, there are other possible variables beyond patient-level barriers or characteristics, such as system-level ones, that may have affected the implementation of our app during COVID, including clinics being shut down and limited use of telehealth at one site versus the other. Finally, although the PDC is an indirect measure of adherence, it is considered reliable and reflective of real-world settings (as opposed to adherence measured during clinical trials), and it has been used in many published research studies on SCD and other chronic medical conditions [
In conclusion, mHealth apps are promising tools for improving hydroxyurea adherence among adolescents and adults with SCD. In this preliminary analysis, we found significant impacts of the early clinic lockdowns, which reduced the implementation of the mHealth intervention for increasing hydroxyurea uptake. This disruption led to reduced patient adherence to hydroxyurea. However, disruptions to mHealth implementation were lower among participants who experienced shorter clinic lockdowns and among those who increased mHealth use during the pandemic, and evidence of the benefit was provided by higher hydroxyurea adherence. In qualitative analysis, we found concordance between low app use and perceived barriers to obtaining care early on during the pandemic. Triangulation of our findings suggests the benefit of mHealth for improving medication adherence and indicates that its use may be influenced by frequent contact with health care providers. Patients’ barriers to care access might have hindered app implementation, potentially reducing medication adherence. Investigation of added strategies to mitigate the effects of imposed care interruptions during major emergencies, particularly greater patient touchpoints (eg, patient coaching and health navigation), may “insulate” the implementation of interventions for increasing medication adherence. Future studies are essentially needed to better understand both patient- and system-level barriers in the context of pandemics or other similar situations. A focus on removing barriers to mHealth use during care disruptions will likely improve app implementation and medication adherence, ultimately reducing health inequities for vulnerable populations.
Interview questions to describe app effectiveness and implementation during COVID-19.
Thematic analysis of patient experiences with hydroxyurea adherence and health care access during COVID-19.
Thematic analysis of provider, administrator, and research staff experiences with app implementation during COVID-19.
Sickle Cell Disease Implementation Consortium Members.
mobile health
National Health Lung and Blood Institute
proportion of days covered
reach, effectiveness, adoption, implementation, and maintenance
sickle cell disease
Sickle Cell Disease Implementation Consortium
The Sickle Cell Disease Implementation Consortium (
JSH, NS, and LK designed the research study; LD and DB analyzed the data; SMB, LD, DB, AB, LK, NS, and JSH interpreted the data; SMB and LD drafted the paper; and DB, AB, EB, TDM, SJ, HK, LK, CN, NS, and JSH critically revised the paper. All authors approved the submitted final version of the paper.
None declared.