Study design
It is a randomized controlled trial with a factorial design, four arms, with a double-blinding approach. Intention-to-treat analysis with 12-months of follow-up will be applied to determine the efficacy of Ed-counselling assistance and mHealth intervention on hypertensive patients at four teaching hospitals in Lahore, Pakistan. Lahore is the provincial capital of Punjab (largest province of the country) [21]. It is the world’s eighteenth largest city and Pakistan’s second-largest metropolis. The SPIRIT 2013 Statement (Standard Protocol Items: Recommendations for Interventional Trials) [22] provides the basis for this research. A factorial approach will be used to assign participants to the four groups. The groups will receive standard care, Ed-counselling, mHealth intervention, and combined intervention (Figure 1). All groups will be followed up for a period of total 12-months. Systolic blood pressure, the Self-efficacy for Appropriate Medication Adherence Scale (SEAMS), the number of prescribed tablets taken for a specified period (self-reporting), and health-related quality of life will be measured at least three times: at baseline, 6 months and 12 months after the intervention [23,24].
Study participants and eligibility criteria
The study participants will be hypertensive patients with coronary artery disease as comorbidity registered in the Cardiology Outpatient Departments (OPDs) of four selected public teaching hospitals in Lahore, Pakistan.
Inclusion criteria include men and women over the age of 21 and up to 70 years, who have been registered for the last 30 days or more as hypertensive with comorbidity of coronary artery disease in the OPDs of the selected teaching hospitals in Lahore, Pakistan. These participants will be having stable coronary artery disease; are already on anti-hypertensive medication; are willing to sign a written informed consent form; possess a smartphone with access to internet; and are able to read Urdu/English.
Patients with a history of cancer who may need drug changes; with a blood pressure reading of more than 220/120 mmHg; with any biological condition that makes it difficult for them to read, write, communicate or hear phone calls; with pregnancy and in lactation period; and who are enrolled in some other study will be excluded.
Sample size
For comparing different interventions among the four groups, the sample size is computed through STATA software using a standard deviation of 18.5 in systolic blood pressure taken from Pakistani study [9]; population mean of 148 and 143 respectively; as 5 mmHg reduction in systolic blood pressure is related to clinical importance regarding decreasing risk of coronary artery disease [25]. A two-sided level of significance of 5% and a power of 90% with a 20% attrition rate between baseline and 12-months of intervention period were used. The total sample size calculated is 1440 with 360 in each group.
Recruitment
After screening, the participants fulfilling eligibility criteria will be recruited. For this purpose, a trained doctor in the department of cardiology from each teaching hospital in the study will facilitate and monitor the recruitment process. Each of these doctors will be supported by one research assistant who will act as the project’s focal person in each hospital for the entire study duration. The contact information of participants who have been recruited will be gathered and saved.
After shortlisting, participants will be briefed (written and verbally) about the study and presented with consent forms bearing the option to relinquish their participation from the study at any moment of its duration. Participants will subsequently be enrolled and assigned code numbers by the principal investigator. All these participants will be able to select their communication language of choice (Urdu and/or English), as well as the day and hour of their respective sessions.
Randomization and blinding
To avoid any potential bias, a simple complete randomization procedure will be utilized [26]. A computer-generated, simple complete random approach will be used to divide participants into four groups [27]. To keep their identities hidden, all participants will be assigned an identification number. To keep the allocation of participants into four groups hidden from the research staff, tight concealment of allocation will be observed. Before allotment, written assignments will be sealed in opaque packets with tagged identifying numbers [28].
All subsequent randomization processes will be completed by an independent biostatistician who will no longer be a participant in the trial. Independent personnel will be involved in the randomization, evaluation, and intervention delivery. The staff involved in data collection and outcome assessment will be blinded. They will be unaware of the allocation of any group [29].
The recruitment process will continue until a final sample size of 1440 people from four teaching hospitals is reached. Participants’ follow-up period is 12-months from the point of randomization (Figure 2).
Intervention
The Health Belief Model is used to create the content of the study modules (Table 1). Expert consultations in the domains of behavioral sciences, health education, information technology, cardiac medicine, and hypertension management were sought in the development of these modules. The goal of these interventions is to control systolic blood pressure among study participants after twelve months.
The first group will receive no intervention and only standard hospital care (as per the practice of the hospital); the second group will receive monthly Ed-counselling sessions in addition to standard care; the third group will receive daily written and voice reminders, and once weekly an education-led video in addition to standard care; the fourth group will receive Ed-counselling sessions every month, daily written and voice reminders, and once weekly an education-led video in addition to standard care.
Educational support with peer counseling
Peer counseling sessions will be led by doctors who are specialized in hypertension. Patients and their families will be focused in these sessions. Face-to-face sessions will take roughly 25-30 minutes each. Patients will receive spoken and written instructions based on their abilities during these sessions. Counseling sessions are geared toward overcoming both general and personal obstacles. They will learn about the need of adhering to medicine, nutrition, and exercise regimens, as well as about the possible consequences of failing to do so (heart attack, stroke, nephropathy, retinopathy, and dementia). The counseling component also addresses personal barriers to taking medication and is designed to assist participants in better understanding their drug-taking attitude. The peer counseling sessions will take place monthly for a total of twelve months.
Information on hypertension, blood pressure self-monitoring, and frequent systolic blood pressure tests, as well as body weight and serum cholesterol values, are included in the instructional support. Food control, exercise therapy, hypertension problems, and their management will also be explored as non-pharmacological therapeutic approaches. Furthermore, based on their unique needs, patients will be informed about medicine administration timings and quantities. Finally, all patients will be informed about antihypertensive medications, including indications, side effects, contraindications, warnings/precautions, drug interactions, and pregnancy risks. Educational components will be delivered through educational booklets with animated infographics.
Involvement of patients and their families
A patient companion will be enrolled in the study for the duration of the trial and will participate in educational and counseling sessions. The objective of involving family members is to learn about their experiences with our Ed-counselling sessions.
mHealth intervention
The mHealth intervention will consist of daily written reminder messages and a video once a week. A professional Information and Technology (IT) facilitator will provide this intervention module. The IT facilitator will be responsible for overseeing the overall messaging, keeping track of it on the computer, and ensuring that all of the material for the various interventions is delivered on time. For the duration of the study, all participants will receive a free 12-months “WhatsApp” internet connection.
A skilled IT team collaborated with two experts from one of the study hospital’s cardiology, hypertension, and nutrition departments in Lahore, Pakistan, to create educational animated infographic videos having both educational and counseling content. The content of the video is also based on the Health Beliefs Model. There are three parts to the video; 1) hypertension awareness, 2) uncontrollable hypertension’s consequences, and 3) improved health through medical and lifestyle improvements. The length of the video is 1:30 minutes.
Pilot testing among 10% of the total sample will be undertaken to guarantee that 144 people with hypertension and angina understood the video’s substance and message. These participants will be recruited from two of the study hospitals using the same criteria as indicated above. The results of this sample will not be included in the final analysis. As a result, these can be changed before the study. This will enable testing of the intervention and can establish if any errors occurred during the intervention’s delivery. It will also assist in identifying issues with eligibility requirements and determining the feasibility of obtaining a sufficient sample size.
Follow-up
Subjects in all four arms of the study will be followed up, three times in 12 months following recruitment. Blood pressure measurement for treatment outcome will be done. Self-efficacy for Appropriate Medication Adherence Scale (SEAMS) is an adherence-monitoring scale that will be used to collect information from participants regarding their adherence to medication self-reporting. Apart from SEAMS, self-reporting pill counting for measuring medication adherence will be used and health-related quality of life using EuroQol 5-Dimension-3-level (EQ-5D-3L) and a visual analogue scale (EQ-VAS) will also be assessed. All the above assessments will be done at baseline, six-month, and twelve-month of follow-up (Figure 3).
Outcome measures
The primary outcome measure outcome measure is the change in participants’ systolic blood pressure at 0, 6, and 12 months. It will be recorded by a nurse who will be oblivious to the study participants’ group. Omron M2 (HEM-7121-E), a calibrated upper-arm electronic sphygmomanometer, will be utilized for this purpose. The blood pressure of the participant will be measured according to standard procedures. Two different readings will be collected within 5 minutes; the average measurement will be the final measurement. If the difference between the two measures is greater than 5mmHg, a third evaluation will be performed, with the average of the two closest measurements being used as the final measurement [30].
In accordance to this, we are going to measure the proportion of participants who will achieve a systolic blood pressure ≤140 mmHg, and, in addition, the proportion of participants who will attend timely scheduled clinic appointments. The data regarding clinical appointments will be taken from the prescriptions of the participants.
There are several secondary outcomes to be investigated. Health-related quality of life baseline, 6 months, and 12 months after the intervention will be measures via the EuroQol 5-Dimension- 3-level (EQ-5D-3L) [31,32]. The five dimensions include mobility, self-care, normal activities, pain or discomfort, and anxiety or depression. Each dimension has three levels: no difficulty, moderate problems, and serious problems. In addition, we are using the EQ-VAS to measure the patient’s self-rated health on a vertical visual analogue scale, with two unique endpoints such as “Best imaginable health condition” for a score of 100 and “Worst imaginable health state” for a score of 0 [31].
We assess self-reported information regarding number of patients who took the specified quantity of medicine divided by the number of pills prescribed multiplied with hundred for the last 7 days A rate of ≥80% will be considered adherent [7,8]. In addition, to measure the adherence score at baseline, 6 months, and 12 months post-intervention, an Urdu/English version of the “Self-efficacy for Appropriate Medication Adherence Scale” (SEAMS) will be employed [33,34]. The SEAMS is a 13-item measure for evaluating medication self-efficacy in chronic disease management that looks to be appropriate for people with low literacy abilities [34]. This survey will use a three-point response system, with 1 indicating lack of confidence, 2 indicating moderate confidence, and 3 indicating extreme confidence. The 13-item scale had a range of possible scores from 13 to 39. High scores indicate better adherence.
Statistical analysis
The intention-to-treat analytic method will be conducted [35,36]. Mixed-effects modeling with repeated measures will be employed for the primary outcome change in systolic blood pressure at 0, 6, and 12 months. To estimate treatment effects at each time point, an interaction between time and the groups will be fitted. For the secondary outcome measuring adherence difference at 0, 6, and 12 months, parametric (ANOVA/Repeated measure ANOVA) and non-parametric tests (Kruskal-Wallistest/Friedman test) will be used. The p-value for the significance test will be set at p<0.05. Pill counting data, adherence assessment at dichotomous variables, frequencies, and the chi-square test will all be used. General Estimating Equation will be used among the four groups for the adherence score and socio-demographic variables to see what factors might influence them. The relation between the four groups and treatment outcome will be examined using negative binomial regression, which will account for any socio-demographic and health-related variables. A complete analysis plan will be established for data analysis, including subgroup analyses and sensitivity analyses.
Sub-group analyses of the change in systolic blood pressure, the adherence to medication over the previous 12-months will be conducted by age (21-29 years, 30-49 years, 50 years and above), sex (male, female), adherence (SEAMS, pill-counting), health-related quality of life (using EQ-5D-3L and EQ-VAS).
Data management
Two trained research assistants will gather data under the supervision of a research specialist. In sealed envelopes, all collected data will be delivered to a bio-statistician who will not be involved in any of the research activities and will be unaware of each participant’s assignment. All data must be entered twice, according to institutional regulation. The bio-statistician will clean and analyze the data. Stata version 16 (Stata corp SE) and R (version 4.0.3) will be utilized for all kinds of analysis in this study.
The research staff involved in data collection will include two research assistants and one research specialist. Two research assistants, in partnership with local hospital staff and under the supervision of a research specialist will collect the data. A 2-day on-site training of research assistants on hypertension and its control, treatment, and how to respond to common questions about blood pressure and medication adherence including medication side effects will be conducted using a standard training module developed by a team of specialists from one of the study hospitals. They will also provide counseling and support to participants in filling out surveys. Data collection and randomized controlled trial procedure guidelines will be covered in three training sessions.
Each participant will receive a 5-minute personal consultation to assist them in filling out the questionnaire, measuring their blood pressure, and counting their pills. Systolic blood pressure will be recorded by a nurse who will be oblivious to the study participants’ group. Omron M2 (HEM-7121-E), a calibrated upper-arm electronic sphygmomanometer, will be utilized for this purpose. The blood pressure of the participant will be measured according to conventional procedures. Within 5 minutes, two different readings will be collected, with the average measurement being the final measurement. If the difference between the two measures is greater than 5mmHg, a third evaluation will be performed, with the average of the two closest measurements being used as the final measurement [37].
Each of the participants will be given a paper-based questionnaire. Interviewers will read the questions to the participants and note down their answers if they have difficulty filling out the response. The paper-based questionnaires “Self-efficacy for Appropriate Medication Adherence Scale” (SEAMS) [34] contain socio-demographic, health-related, and adherence-related validated questions which would be employed in Urdu and English. The SEAMS is a 13-item measure for evaluating medication self-efficacy in chronic disease management that looks to be appropriate for people with low literacy abilities [34]. This survey used a three-point response system, with 1 indicating lack of confidence, 2 indicating moderate confidence, and 3 indicating extreme confidence. The 13-item scale had a range of possible scores from 13 to 39. In terms of drug adherence, greater ratings indicated higher levels of self-efficacy and vice versa. It is a dependable and precise device. Principal component factor analysis was used to determine the study’s validity. The researchers established a two-factor solution that accounted for 52.3 percent of the variance. Test-Retest reliability had a moderate level of dependability (Spearman’s r=0.62, p=0.0001). Internal consistency (Cronbach’s alpha = 0.89) is good [34].
The participants will be asked how many tablets they were prescribed for the period in question, as well as how many pills they took and missed during that time. Adherence rates will be calculated by dividing the number of pills ingested during a period by the number of tablets suggested for that period. Based on past research, an 80 percent cut-off value has been developed. Non-adherents will account for less than 80% of the rate, while adherents will account for more than 80% [7].
At the end of the sixth and twelfth months, participants who completed the baseline survey in all four groups will be invited to one of the study institutes to be questioned by qualified interviewers or over the phone who will be unable to come to complete the second round of blood pressure measurement, SEAMS filling, health-related quality of life post-intervention using EQ-5D-3L and EQ-VAS, and pill-counting information (Table 2).
Dissemination and access
After the trial is completed, the study’s final findings will be published in a peer-reviewed journal and shared with participants, health care providers, and various research organizations via a public access database. The results will be posted on clinicaltrials.gov after it is completed.
Even though we will take all possible measures to minimize the negative impacts of our study, any additional adverse events beyond the primary and secondary outcomes will be reported concerning participants and our intervention approach [35].
Ethical considerations
The study protocols were reviewed and approved by the Institutional Ethical Review Board, University of the Punjab (No. IERB/ISCS/674). Additionally, the research protocol has been authorized and approved by the Rehmatul-Lil-Almeen Institute of Cardiology, Employers Social Security teaching hospital in Lahore (Reference number: RAIC-PESSI-1156). The study methods follow the Declaration of Helsinki and Good Clinical Practice, and the trial is registered with ClinicalTrials.gov (NCT05106790).
Trained research assistants will offer informed consent to participants who are voluntarily participating in the study. Confidentiality and privacy will be strictly followed. Participants’ privacy will be protected in a variety of ways: Any personnel participating will be required to sign an agreement guaranteeing the privacy of all information obtained. In addition, interviewers will receive training on the most effective way to maintain confidentiality. No real names or any other identity markers will be used in the study. Members’ names on the patient overview structures will not be referred to. The assent structures of the members will be placed in a secured cabin. Electronic data will be kept private and secure, and only the principal investigator will have access to it. No results will be directly related to the respondents [36].
The study is set up in such a way that the participants and medical workers are in as little danger as feasible. Participants face a minor risk in the form of a few mild psychological discomforts when answering questions about sensitive topics such as their own and their household’s income, and may feel embarrassed when answering a follow-up questionnaire about medicine adherence due to their poor adherence status. To avoid such discomfort, the responder will be interviewed in a different room or at a place away from any witnesses.