JMIR FORMATIVE RESEARCH Almonacid et al Original Paper Effectiveness of Text Message Reminders on Adherence to Inhaled Therapy in Patients With Asthma: Prospective Multicenter Randomized Clinical Trial Carlos Almonacid1, MD, PhD; Carlos Melero2, MD, PhD; Antolín López Viña3, MD, PhD; Carolina Cisneros4, MD, PhD; Luis Pérez de Llano5, MD, PhD; Vicente Plaza6, MD, PhD; Juan Luis García-Rivero7, MD, PhD; Auxiliadora Romero Falcón8, MD, PhD; Jacinto Ramos9, MD, PhD; Teresa Bazús González10, MD, PhD; María Andrés Prado11, MD, PhD; Alfonso Muriel12, MD, PhD 1 Department of Respiratory Medicine, Instituto Ramón y Cajal de Investigación Sanitaria, University of Alcala de Henares, Madrid, Spain 2 Department of Respiratory Medicine, Hospital Universitario 12 de Octubre, Institute for Health Research (i+12), Complutense University of Madrid, Madrid, Spain 3 Department of Respiratory Medicine, Hospital Universitario Puerta de Hierro, Autonoma University of Madrid, Majadahonda, Spain 4 Department of Respiratory Medicine, Hospital Universitario La Princesa, Autónoma University of Madrid, Madrid, Spain 5 Department of Respiratory Medicine, Hospital Universitario Lucus Augusti, University of Lugo, Lugo, Spain 6 Department of Respiratory Medicine, Hospital de la Santa Creu i Sant Pau, Institut d’Investigació Biomédica Sant Pau, Autònoma University of Barcelona, Barcelona, Spain 7 Department of Respiratory Medicine, Laredo Hospital, Laredo, Spain 8 Department of Respiratory Medicine, Hospital Universitario Reina Sofia, University of Cordoba, Córdoba, Spain 9 Department of Respiratory Medicine, Hospital Universitario de Salamanca, University of Salamanca, Salamanca, Spain 10 Department of Respiratory Medicine, Hospital Universitario Central de Asturias, University of Oviedo, Oviedo, Spain 11 Department of Health Information Management, Fundación Jimenez Diaz, Madrid, Spain 12 Unit of Clinical Biostatistics, Instituto Ramón y Cajal de Investigación Sanitaria, Consorcio Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, University of Alcala de Henares, Madrid, Spain Corresponding Author: Carlos Almonacid, MD, PhD Department of Respiratory Medicine Instituto Ramón y Cajal de Investigación Sanitaria University of Alcala de Henares Ctra. De Colmenar Viejo, km. 9,100 Madrid, Spain Phone: 34 655 534 475 Email: caralmsan@gmail.com Abstract Background: Poor adherence to inhaled medication in asthma patients is of great concern. It is one of the main reasons for inadequate asthma control. Objective: The goal of the research was to determine if motivational messages using short message service (SMS, or text) improved adherence to inhaled medication in patients with asthma. Methods: A prospective multicenter randomized parallel-group clinical trial was conducted in 10 asthma clinics in Spain. Adherence was assessed with electronic monitors (Smartinhaler, Adherium Ltd) connected to inhalers. Patients in the SMS group received psychologist-developed motivational messages every 3 days for 6 months. Results: There were 53 patients in the SMS group and 88 patients in the control group. After 6 months, mean electronic adherence was 70% (SD 17%) in the intervention group and 69% (SD 17%) in the control group (P=.82). Significant differences between the study groups in morning and evening adherence to inhaled therapy, asthma control, exhaled nitric oxide levels, or improvement of lung functions were not observed. http://formative.jmir.org/2021/2/e12218/ JMIR Form Res 2021 | vol. 5 | iss. 2 | e12218 | p. 1 (page number not for citation purposes) XSL• FO RenderX JMIR FORMATIVE RESEARCH Almonacid et al Conclusions: Motivational messages were not useful to improve adherence to inhaled asthma medication compared with usual care. (JMIR Form Res 2021;5(2):e12218) doi: 10.2196/12218 KEYWORDS asthma; adherence; SMS; control; cell phone; inhaler; Smartinhaler hospitals in Spain. Patients were recruited from 2013 to 2014. Introduction Patients were randomized to an SMS group or a control group; Epidemiological studies show a high prevalence of poor asthma follow-up was for 6 months. control [1-3]. Poor adherence is one of the most frequent causes Participants of this problem [2-18]. The measurement of adherence to The eligibility criteria for participants were (1) aged 18 to 85 inhalers is a complicated task. Different methods have been years, (2) asthma diagnosed according to the Global Initiative used in daily practice, including clinical judgment, response to for Asthma (GINA) criteria [41], (3) all patients treated with treatment, generally validated self-report questionnaires [19], maintenance therapy according GINA guidelines, (4) currently or specifically designed instruments such as the Test of own cell phone, (5) not currently being treated with systemic Adherence to Inhalers [20,21]. All these methods tend to corticosteroids or biologic drugs, (6) not currently participating overestimate treatment adherence [22,23]. Exhaled nitric oxide in another research study. (FeNO) measurement has been proposed as an objective technique to measure treatment compliance [24]. In the last 30 Exclusion criteria were (1) inability to use inhaler devices [30]; years, electronic monitoring devices have been developed with (2) other associated chronic respiratory disease (eg, chronic this proposal [25-28]. These devices can record the time and obstructive pulmonary disease); (3) previous participation in a number of doses taken and remind the patient to take medication. study using SMS-related asthma reminders (4) asthma exacerbation within 3 months of inclusion in the study (defined Adherence to inhaled therapy depends on multiple factors. by oral corticosteroid use, emergency department visit, or Asthma education programs plus information and hospitalization); (5) previous treatment with communication technologies could be more useful to improve budesonide/formoterol as maintenance and reliever therapy; (6) adherence than using them separately. All cell phones can send other uncontrolled severe medical conditions. or receive short message service (SMS, or text) messages, which are a convenient, widely used mode of communication [29-32]. Interventions It has been shown that text messages improve appointment The SMS group received psychologist-developed motivational adherence [10], but very little research has focused on the effect messages every 3 days for 6 months in addition to usual care of messages to reinforce adherence using SMS. recommendations according to GINA guidelines [41]. SMS Several studies reviewed the effect of reminders on asthma messages were not reminders to take a dose of medication. The control and adherence to treatment [33-40]. Only a few studies control group was treated with general care recommendations have used electronic devices to assess adherence to inhalers. In alone according to GINA guidelines [41]. Four study visits were these studies, reminders were also sent through the same required (1 for enrollment and 3 for follow-up) in both groups. electronic device (SmartTrack or Smartinhaler [both Adherium Outcome data were collected at the clinic by study staff in V0, Ltd]) that measured adherence to treatment, not through SMS V1 (1 month later), V3 (3 months later), and V6 (6 months [39,40]. Other studies used self-report questionnaires to measure later—end of study). inhaler adherence, but this leads to decreases the quality of the Medications and Inhaler Monitoring results. To date, a benefit in adherence to treatment from motivational text messages sent to a cell phone has not been All patients received a SmartTrack device (Smartinhaler reported. [Adherium Ltd]; Figure 1) that clipped on their ICS/LABA inhaler. SmartTrack is an electronic device that allows The objective of this study is to measure the effect of measuring adherence to the inhalers. Each puff is recorded in motivational messages designed by a psychologist on treatment the device memory. SmartTrack records the date and time the adherence compared with usual care in patients with moderate inhaler was used and the number of puffs taken. SmartTrack to severe asthma. features include reminders, onscreen questions about asthma control, and medication feedback viewing online, but these have Methods been deactivated. After the device was activated during the enrollment (visit 0), it recorded the date and time of all Trial Design maneuvers to measure adherence to treatment. The data were We conducted a parallel-group randomized controlled trial in uploaded to a secure cloud server with local backup to the patients with moderate or severe asthma at 10 university investigator’s computer. http://formative.jmir.org/2021/2/e12218/ JMIR Form Res 2021 | vol. 5 | iss. 2 | e12218 | p. 2 (page number not for citation purposes) XSL• FO RenderX JMIR FORMATIVE RESEARCH Almonacid et al Figure 1. SmartTrack devices connected to pressurized metered-dose inhaler (left) and Turbuhaler inhalation device (right). Patients were treated with an ICS/LABA inhaler for maintenance Asthma Education therapy (fluticasone propionate/salmeterol Accuhaler/Diskus All patients were provided an asthma action plan on the first inhaler, budesonide/formoterol Turbuhaler inhaler, or day written in accordance with the GINA guidelines. Inhaler beclomethasone/formoterol metered-dose inhaler). They also technique was reviewed, and any problems were corrected. At used albuterol pressurized metered-dose inhaler as rescue each visit, inhaler technique and the asthma action plan were medication. Device reliability and precision have been reported reviewed. according to other publications [38]. Asthma Control SmartTrack Training and Monitoring Asthma control was measured using the Asthma Control Test Electronic monitoring via the Smartinhaler was used to assess (ACT) [42], and a score ≥20 identified well-controlled asthma adherence to inhaled asthma therapy. All patients received brief patients. instructions on the use of the SmartTrack. Patients with adherence higher than 80% were considered regular adherents. Pulmonary Function Electronic monitors were attached to participant controller Spirometry with bronchodilator test was performed according medications in the SMS and control groups. to the European Respiratory Society/American Thoracic Society Text Messages (ERS/ATS) guidelines [43]. Values for the Mediterranean population were used [44]. Forced expiratory volume in 1 Patients assigned to the intervention group only received SMS second (FEV1) pre and postbronchodilator were measured. communications about the importance of asthma medication every 3 days for 6 months; messages were not reminders to take Fractional Exhaled Nitric Oxide a dose of medication. The messages, written by a psychologist An FeNO level was measured before spirometry using the in collaboration with pulmonologists, were randomly switched equipment available in each center. The test was performed every 3 days and include the following: following the ERS/ATS recommendations [45]. • Remember that performing the treatment of inhaled Outcomes medication keeps your asthma controlled. Demographic data, ACT, lung function (spirometry), FeNO • Inhaled medication helps to maintain asthma control. levels, and exacerbation history in the previous year were • Remember to take inhaled medication; it keeps you well. collected at the enrollment visit (V0). ACT, lung function, FeNO • Have you taken your inhaled medication? levels, and exacerbation history were also collected at V1, V3, • Do you take your inhaled medication in the morning and and V6. the evening? • Maybe now is the time to take your inhaled medication. The primary outcome was adherence to inhaled medication. • Remember to take inhaled medication as prescribed by your SmartTrack devices were used to quantify adherence to control doctor. medication. The secondary outcomes were asthma control measured by the ACT, spirometry parameters (FEV1, forced http://formative.jmir.org/2021/2/e12218/ JMIR Form Res 2021 | vol. 5 | iss. 2 | e12218 | p. 3 (page number not for citation purposes) XSL• FO RenderX JMIR FORMATIVE RESEARCH Almonacid et al vital capacity, and FEV1/forced vital capacity ratio), FeNO Ethics Approval and Trial Registration levels, number of asthma exacerbations, visits to the emergency The clinical research ethics committees of the participating department, and hospital admissions due to asthma. centers approved the study. All participants provided written Sample Size informed consent. The study was classified by the Spanish Agency of Medicines and Medical Devices as a The sample size was calculated according to an adherence rate noninterventional imposed postauthorization safety study, and to inhaled asthma therapy between 30% and 70% [9]. On the for this reason we were not required to register the clinical trial. assumption of the maximal uncertainty of 50% and considering a clinically relevant difference of 25%, with a type I error of .05, a power of 80%, and a 20% loss, 73 patients per arm were Results needed (total 146 patients). Patient Participants Randomization, Blinding, and Allocation Concealment Of patients recruited, 63.8% (97/152) were women. At the first We generated the 2 comparison groups using simple data collection time point, the mean age was 48.9 (SD 16.7) randomization with an equal allocation ratio by referring to a years, and the mean duration of asthma was 16.5 (SD 13) years. table of random numbers. A mathematician, also in charge of A total of 6.6% (10/152) of patients were current smokers. Most randomization of the SMS sending, generated the sequences of patients were well controlled at enrollment, with a mean ACT random allocation, who enrolled participants, and who assigned score of 20.2 (SD 4.5) points. The mean FEV1 before the participants to interventions and SMS sending. bronchodilation test was 79% (SD 17.9%) predicted, the mean FEV1 after bronchodilation test was 82.5% (SD 16.2%) Blinding of patients was not possible. To avoid bias and with predicted, and the mean FeNO level was 37.9 (SD 35.9) ppb. ethics approval, physicians were not notified about the A total of 13.2% (20/152) of patients reported one or more SmartTrack recording function or SMS intervention until the exacerbations during the last 12 months, 15.8% (24/152) study ended. reported an episode of asthma-related urgent health care Statistical Methods utilization and prednisone use in the previous year, and 5.9% (9/152) required admission to hospital. Categorical variables were expressed as frequencies and percentages and continuous variables as means and standard A failure with the randomization program unbalanced the deviations. The chi-square or Fisher exact test were used for number of patients in both arms. During the study period, 57 the analysis of categorical variables, and the Student t test or patients were assigned to the intervention group, and 95 to the Mann-Whitney U test were used for the comparison of control group. At follow-up, 11 patients were excluded because quantitative variables according to the standard or nonnormal of the total failure of the electronic monitoring device. The final distribution of variables. Tests were 2-tailed. Statistical analysis included 53 patients in the intervention group and 88 significance was set at P<.05. Statistical analyses were in the control group. The flowchart of the study population is performed using the SPSS Statistics version 20.0 (IBM Corp). shown in Figure 2. Demographic and baseline characteristics were similar between groups, apart from a lower proportion of men and university education in the SMS group (Table 1). http://formative.jmir.org/2021/2/e12218/ JMIR Form Res 2021 | vol. 5 | iss. 2 | e12218 | p. 4 (page number not for citation purposes) XSL• FO RenderX JMIR FORMATIVE RESEARCH Almonacid et al Figure 2. Flow diagram of the progress through the phases of a parallel randomized trial of two groups. http://formative.jmir.org/2021/2/e12218/ JMIR Form Res 2021 | vol. 5 | iss. 2 | e12218 | p. 5 (page number not for citation purposes) XSL• FO RenderX JMIR FORMATIVE RESEARCH Almonacid et al Table 1. Clinical characteristics of patients at baseline. Variable SMSa group (n=57) Control group (n=95) P value Gender, male, n (%) 15 (26) 40 (42) .05 Age in years, mean (SD) 50.4 (16.4) 48 (16.9) .40 Education level, n (%) Primary/secondary studies 47 (82) 61 (64) .40 University degree 7 (12) 20 (21) .40 Working status, n (%) Unemployed 6 (11) 10 (11) .79 Employed 34 (60) 54 (57) .79 Housewife 4 (7) 11 (12) .79 Retired 13 (23) 18 (19) .79 Smoking history, n (%) Current smoker 4 (7) 6 (6) .75 Ex-smoker 17 (30) 34 (36) .75 Never smoker 36 (63) 55 (58) .75 Self-management education program, n (%) 10 (18) 16 (17) .91 Asthma history, mean (SD) Years from diagnosis 16.6 (11.6) 16.5 (14.3) .98 Years from starting treatment 13.3 (10.3) 13.2 (12.1) .10 Years from follow-up in outpatient clinics 7.2 (7) 6.8 (7.8) .78 Inhaler type, n (%) Accuhaler/Diskus 18 (32) 38 (40) .57 Turbuhaler 26 (46) 37 (39) .57 pMDIb 13 (23) 20 (21) .57 Inhalation technique, correct steps, n (%) Acceptable 40 (70) 75 (79) .22 Unacceptable 17 (30) 20 (21) .22 Asthma-related events in the previous 12 months, mean (SD) Exacerbations 0.6 (1.2) 0.4 (0.8) .21 Emergency department visits 0.2 (0.6) 0.2 (0.7) .79 Hospital admission 0.05 (0.2) 0.04 (0.2) .76 Asthma Control Test, mean (SD) 20.3 (4.2) 20.0 (4.8) .69 FeNOc level, ppb, mean (SD) 42.2 (37.5) 33.7 (34.3) .18 FEV1d before bronchodilation test, % predicted, mean (SD) 79.0 (17.5) 79.5 (18.4) .92 FEV1 after bronchodilation test, % predicted, mean (SD) 79.6 (16.7) 85.3 (15.7) .16 a SMS: short message service. b pMDI: pressurized metered-dose inhaler. c FeNO: exhaled nitric oxide. d FEV1: forced expiratory volume in 1 second. http://formative.jmir.org/2021/2/e12218/ JMIR Form Res 2021 | vol. 5 | iss. 2 | e12218 | p. 6 (page number not for citation purposes) XSL• FO RenderX JMIR FORMATIVE RESEARCH Almonacid et al Adherence to Treatment The data transmission software that communicated with the Smartinhaler platform failed throughout the study in most of Primary Outcome the participating centers since it did not work with the hospital Adherence data were recorded throughout the study starting proxy servers. Due to this failure, the backup files generated from enrollment, and 92.8% (141/152) of patients had during each visit were used for the analysis. Differences between analyzable SmartTrack data. No adherence data were available the study groups were not found in SmartTrack failures (P=.51). for 7.2% (11/152) of patients due to device failure; 21.7% After 6 months, the mean electronic adherence was 70% (SD (33/152) of SmartTracks monitored adherence for at least 90 17%) in the intervention group and 69% (SD 17%) in the control days, 11.2% (17/152) operated fine for between 90 and 179 group (P=.82). Adherence to inhalers was higher in both groups days, and 59.9% (91/152) worked precisely until the study in the morning (control group 79% [SD 19%] vs 60% [SD 24%] ended. in the afternoon and SMS group 80% [SD 23%] vs 59% [SD 29%] in the afternoon; Table 2). Table 2. Results at the end of the study. Variables SMSa group (n=53) Control group (n=88) P value Adherence %, mean (SD) 70 (17) 69 (17) .82 Morning adherence %, mean (SD) 80 (23) 78 (19) .44 Evening adherence %, mean (SD) 59 (29) 60 (24) .75 Asthma Control Test score, mean (SD) 21.6 (3.7) 22.1 (3.5) .46 FeNOb level, ppbc, mean (SD) 36.5 (35.5) 28.3 (22.0) .14 FEV1d before bronchodilation test, % predicted, mean (SD) 77.3 (16.2) 80.9 (18.0) .42 FEV1 after bronchodilation test, % predicted, mean (SD) 85.9 (12.4) 84.5 (16.2) .73 Exacerbation episodes , n (%) .22 0 37 (84) 68 (92) — 1 7 (16) 5 (7) — ≥2 0 1 (1) — Visits to emergency department, n (%) .43 0 40 (91) 71 (95) — 1 4 (10) 4 (5) — ≥2 0 0 — Hospital admission for asthma, n (%) 0 0 — a SMS: short message service. b FeNO: exhaled nitric oxide. c ppb: parts per billion. d FEV1: forced expiratory volume in 1 second. Education strategies are useful to improve adherence to asthma Secondary Outcomes therapy [10]. Few studies have examined the effect of SMS At the end of the study (V6), no differences were found between reminders on adherence to asthma treatment. Strandbygaard et the SMS and control group in ACT, FEV1, FeNO levels, al [46] conducted a 12-week study with 26 asthma patients exacerbations, emergency department visits, or hospital randomized to the SMS group (n=12) or control group (n=14). admissions (Table 2). The SMS group received this message daily: “Remember to take your asthma medication morning and evening. From the Discussion Respiratory Unit.” A medicine dose-count for Diskus inhaler was used to assess adherence. The mean adherence rate Principal Findings increased in the SMS group and decreased in controls, with a In this study, motivational SMS was not associated with an difference in mean adherence rate between the 2 groups after improvement in adherence to inhaled medication. We also found 12 weeks of 17.8% (95% CI 3.2%-32.3%; P=.02). Changes in no significant differences in secondary variables, asthma control, adherence in the SMS group, however, were not associated with lung function, exhaled nitric oxide levels, or exacerbations due clinical or functional improvement. Few patients were included to asthma. http://formative.jmir.org/2021/2/e12218/ JMIR Form Res 2021 | vol. 5 | iss. 2 | e12218 | p. 7 (page number not for citation purposes) XSL• FO RenderX JMIR FORMATIVE RESEARCH Almonacid et al in this study, and adherence may have been overestimated due An interesting finding of this study, in which all patients had to the possibility to take actions before the medical visit. twice-daily medication schedules, is that adherence rates were higher in the morning than in the evening. It is possible that in In another study, Charles et al [47] used the audiovisual patients on single-dose inhaled medication regimens, SMS could reminder function on the Smartinhaler metered-dose inhaler have had a more significant impact on adherence. device. After 12 weeks, the absolute difference in the median percentage of medication taken between the intervention (n=55) Although the Smartinhaler is accurate in recording and retaining and control (n=55) groups was 18% (95% CI 10%-26%; actuation data [48,49], potential malfunction during real-life P<.001). But, again, no improvements in clinical or lung use by patients is possible. In our study, failure of functions were observed. communication technology occurred in all centers without differences between the study groups; in these cases, however, In a 6-month cluster-randomized study, Foster et al [35] assessed analyses were performed using backup files. Only 91% (SD the effect of inhaler reminders plus adherence feedback (n=21) 59.9%) of the Smartinhalers worked fine and collected versus usual care or personalized discussion with the general information until the study ended. practitioners (n=22) in the primary care setting. Reminders were associated with improvements in adherence (73% [SD 26%] vs In our study, patients were recruited in specialized asthma units 46% [SD 28%] of prescribed daily doses, P<.001) as well as established in different hospitals throughout Spain for the with an improvement in the ACT but without differences management of patients with severe and difficult-to-control between the study groups. asthma [50]. Therefore, it is possible that this particular circumstance may account for the adequate adherence at baseline In a recent systematic review of interventions aimed at and proper control of asthma before enrollment and at the end improving adherence to inhaled corticosteroids for asthma, 11 of the study. studies assessing electronic trackers or reminders versus control were analyzed [10]. Electronic trackers or reminders led to better Conclusions adherence of 19 percentage points (95% CI 14.47-25.26; 6 In summary, in this prospective randomized clinical study, studies; moderate-quality evidence), but a clear benefit on reinforcement of adherence to inhaled asthma medication using clinical outcomes was not found. motivational SMS via cell phones was not capable of improving Limitations adherence. Mobile health interventions are increasingly popular for implementing on a large scale in different chronic health In our study, a simple intervention based on motivational SMS conditions [51-53], but further research into these issues is sent every 3 days for 6 months was not adequate to improve needed. Despite the negative results that may be justified adherence. Different reasons may account for this adverse because of the study’s limitations as described above, the study’s finding. First, the messages sent were motivational; they were results are not conclusive. However, an interesting fact that can not reminders for taking medication. Second, the pattern of be seen in both groups is that morning adherence to the inhaler nonadherence behavior (eg, erratic, deliberate, unwitting) [21] is much higher than afternoon adherence. These data should be was not evaluated nor were patients stratified according to a verified in a new well-designed clinical trial that could reinforce nonadherent model. Third, asthma was well controlled at the use of ultralong action treatments, which only need to be baseline as shown by high ACT scores and lung function taken once a day, in order to improve the adherence and control parameters; the magnitude of improvement depends to a large of asthma. extent on the degree of control of the disease before the intervention. Acknowledgments This project was funded by Sociedad Española de Neumología y Cirugía Torácica and Pfizer Spain. Authors' Contributions CM and ALV conceived the study. MA and AM verified the analytical methods. CA supervised the findings of this work. All authors discussed the results and contributed to the final manuscript. Conflicts of Interest None declared. References 1. Rabe KF, Adachi M, Lai CKW, Soriano JB, Vermeire PA, Weiss KB, et al. 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JMIR Res Protoc 2017 Oct 23;6(10):e204 [FREE Full text] [doi: 10.2196/resprot.7522] [Medline: 29061556] Abbreviations ACT: Asthma Control Test ERS/ATS: European Respiratory Society/American Thoracic Society FeNO: exhaled nitric oxide FEV1: forced expiratory volume in 1 second GINA: Global Initiative for Asthma ICS/LABA: inhaled combination of corticosteroids and a long-acting beta 2 agonist SMS: short message service Edited by G Eysenbach; submitted 22.09.18; peer-reviewed by R Beasley, M Marcolino; comments to author 01.04.19; revised version received 20.07.19; accepted 28.10.20; published 09.02.21 Please cite as: Almonacid C, Melero C, López Viña A, Cisneros C, Pérez de Llano L, Plaza V, García-Rivero JL, Romero Falcón A, Ramos J, Bazús González T, Andrés Prado M, Muriel A Effectiveness of Text Message Reminders on Adherence to Inhaled Therapy in Patients With Asthma: Prospective Multicenter Randomized Clinical Trial JMIR Form Res 2021;5(2):e12218 URL: http://formative.jmir.org/2021/2/e12218/ doi: 10.2196/12218 PMID: ©Carlos Almonacid, Carlos Melero, Antolín López Viña, Carolina Cisneros, Luis Pérez de Llano, Vicente Plaza, Juan Luis García-Rivero, Auxiliadora Romero Falcón, Jacinto Ramos, Teresa Bazús González, María Andrés Prado, Alfonso Muriel. 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