Does a nurse-led intervention improve medication adherence among older adults with hypertension in Spanish primary care? Protocol for a pragmatic cluster randomised controlled trial (NURSE-ADHERE-HTN)

Abstract

Introduction

Poor long-term adherence to antihypertensive medication remains a major challenge in hypertension management, particularly among older adults, contributing to suboptimal blood pressure control, cardiovascular morbidity and reduced quality of life. Nurse-led educational and behavioural interventions delivered in primary care may improve medication adherence; however, evidence from pragmatic cluster randomised trials integrated into routine clinical practice remains limited. This study aims to evaluate whether a nurse-led multidimensional educational and behavioural intervention improves adherence to antihypertensive treatment among older adults with hypertension in primary care.

Methods and analysis

NURSE-ADHERE-HTN is an ongoing pragmatic, open-label, cluster randomised controlled trial being conducted in 14 primary care centres of the Navarra Health Service–Osasunbidea, Spain. The trial was prospectively registered in the ISRCTN registry (ISRCTN35559821). Primary care centres were centrally allocated in a 1:1 ratio to the intervention or usual-care group, with seven centres per group and two participating nurses per centre. The target sample size is 280 participants aged 60 years or older with hypertension, prescribed at least one antihypertensive medication and identified as non-adherent using the 4-item Morisky Medication Adherence Scale (MMAS-4).

The intervention consists of a nurse-led multidimensional educational and behavioural programme integrated into routine primary care, comprising individualised education, motivational interviewing, review of antihypertensive treatment and medication-taking routines, Mediterranean diet counselling, physical activity support and telephone reinforcement. The primary outcome will be adherence to antihypertensive treatment at 6 months, assessed using the MMAS-4 in accordance with the licensed wording, structure and standardised scoring method. Adherence will also be assessed at baseline and 12 months, with the 12-month assessment used to evaluate whether any intervention effect observed at 6 months is maintained over time. Electronic prescription dispensing records will provide a complementary measure of adherence.

Secondary outcomes will include blood pressure assessed using 24-hour ambulatory monitoring, health-related quality of life, cardiovascular-related emergency department visits and hospital admissions, symptoms of anxiety and depression, Mediterranean diet adherence, physical activity, reasons for non-adherence, anthropometric and selected laboratory variables, medication burden and concordance between adherence measures. Outcomes will be assessed at baseline, 6 months and 12 months. Prespecified exploratory analyses will assess effect modification by sex. Statistical analyses will account for clustering at the primary care centre level.

Ethics and dissemination

The study was approved by the Navarra Clinical Research Ethics Committee (reference PI_2023/92). Written informed consent is obtained from all participants before enrolment. Findings will be disseminated through peer-reviewed publications, conference presentations and reports to healthcare stakeholders.

Trial registration number

ISRCTN35559821.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• The study uses a pragmatic cluster randomised design across 14 primary care centres, with allocation at the centre level and statistical analyses accounting for centre-level clustering.

• Medication adherence is assessed at baseline, 6 months and 12 months using the MMAS-4 (4-item Morisky Medication Adherence Scale) and electronic prescription dispensing records as complementary measures.

• Blood pressure is assessed using 24-hour ambulatory monitoring with the same validated device model in both study groups and across all participating centres.

• The open-label design and individualisation of the intervention may introduce performance bias and variability in intervention delivery between participants and centres.

• Adherence assessment focuses on antihypertensive treatment and does not separately measure adherence to other medications, while dispensing records indicate medication availability but cannot confirm ingestion.

Introduction

Hypertension is one of the most prevalent chronic conditions worldwide and a leading modifiable risk factor for cardiovascular morbidity and mortality, particularly among older adults. Despite the availability of effective antihypertensive treatments, blood pressure control remains suboptimal in routine clinical practice, partly because of poor long-term medication adherence. Suboptimal adherence has consistently been associated with inadequate blood pressure control and an increased risk of adverse cardiovascular outcomes among people with hypertension.^{1 2}

Medication non-adherence represents a major public health challenge and is associated with increased cardiovascular risk, healthcare utilisation and mortality, as well as a substantial economic burden.^3–5 Systematic reviews and meta-analyses indicate that approximately half of people treated for hypertension do not achieve optimal medication adherence, with particularly low adherence reported among older adults.^{6 7}

In older populations, medication adherence is influenced by multiple interacting factors, including polypharmacy, treatment complexity, adverse drug effects, limited health literacy, cognitive impairment and psychosocial distress.^{6 8} Mental health symptoms and psychosocial factors, such as beliefs about medication and perceived quality of life, may influence adherence and responses to adherence-enhancing interventions among people with hypertension, but these factors are seldom explicitly addressed in adherence-focused primary care interventions.^{9 10}

Primary care plays a central role in the long-term management of hypertension and provides an appropriate setting for implementing adherence-enhancing strategies. Within multidisciplinary primary care teams, nurses are well positioned to deliver educational, behavioural and supportive interventions integrated into routine clinical practice. Evidence from systematic reviews and recent trials suggests that nurse-led interventions, including educational and behavioural approaches, may improve medication adherence and blood pressure control.^11–15 However, existing interventions are heterogeneous, may require substantial resources and are not always integrated into routine primary care workflows.

Potential differences in the effectiveness of adherence interventions according to sex also remain insufficiently explored, despite documented sex-related differences in cardiovascular risk profiles, psychological distress and some health behaviours among older adults.^{6 16} In the present study, sex is recorded in the case report form, whereas gender is not collected as a separate variable; consequently, the planned effect-modification analyses are based on sex.

There is therefore a need to evaluate pragmatic interventions delivered within routine primary care that address adherence to antihypertensive treatment among older adults while considering psychosocial and mental health factors. Cluster randomised controlled trials are appropriate for evaluating complex interventions delivered by healthcare professionals because allocation at the healthcare-centre level can reduce contamination between study groups and reflect routine clinical conditions.^{17 18} Nevertheless, evidence from pragmatic cluster randomised trials evaluating nurse-led adherence interventions in routine primary care remains limited, particularly among older populations within existing and comparable healthcare systems.^{14 19}

The primary aim of this study is to evaluate whether a nurse-led multidimensional educational and behavioural intervention improves adherence to antihypertensive treatment at 6 months among adults aged 60 years or older with hypertension in primary care. Adherence will also be assessed at 12 months to determine whether any intervention effect observed at 6 months is maintained over time. Secondary objectives include evaluating the effects of the intervention on 24-hour ambulatory blood pressure, health-related quality of life, cardiovascular-related emergency department visits and hospital admissions, symptoms of anxiety and depression, adherence to the Mediterranean diet and physical activity. Additional objectives include examining reasons and patterns of non-adherence, medication burden, anthropometric and selected laboratory variables, sociodemographic and clinical factors associated with adherence to antihypertensive treatment, the association between symptoms of anxiety and depression and adherence to antihypertensive treatment, concordance between adherence measures and potential effect modification by sex.

Methods and analysis

Study design

NURSE-ADHERE-HTN is an ongoing pragmatic, open-label, cluster randomised controlled trial conducted in 14 primary care centres of the Navarra Health Service–Osasunbidea, Spain. The primary care centre is the unit of randomisation, while individual participants are the unit of observation. Statistical analyses will account for clustering at the primary care centre level.

The 14 participating primary care centres were centrally allocated in a 1:1 ratio to either the intervention group or the usual-care control group, with seven centres per group. Two nurses participate at each centre, and all participants recruited within the same centre receive the allocation assigned to that centre.

A cluster design was selected because the intervention is delivered by nurses within routine primary care consultations. Randomisation at the primary care centre level reduces the risk of contamination that could arise if nurses working at the same centre delivered both the intervention and usual care and reflects the organisation of routine clinical practice.

Because of the nature of the intervention, participating nurses and patients cannot be blinded to group allocation. Both groups undergo the same standardised outcome assessments. For the prespecified statistical analysis, the study groups will be coded as A and B, and the analysts will remain blinded to group identity until completion of the primary analysis.

The trial was prospectively registered in the ISRCTN registry (ISRCTN35559821) on 2 January 2026, before the first participant was enrolled on 9 February 2026. Participants are being recruited consecutively until the target sample size is reached, with final enrolment planned for 23 August 2026. Each participant will be followed up for 12 months, and overall study completion is planned for 31 August 2027.

The registry record was subsequently updated to ensure consistency with the approved protocol regarding the unit of randomisation, masking, eligibility criteria, intervention procedures, outcome definitions and assessment time points.

Setting

The trial is being conducted in 14 primary care centres within the Navarra Health Service–Osasunbidea, Spain. The Spanish primary care system provides universal, publicly funded healthcare and is organised around multidisciplinary teams that include general practitioners, nurses and other healthcare professionals responsible for the long-term management of chronic conditions such as hypertension. The participating primary care centres constitute the randomisation clusters, with seven centres allocated to the intervention group and seven to the usual-care control group. The intervention is delivered by nurses and integrated into routine primary care consultations.

Participants

Inclusion criteria

Participants are eligible for inclusion if they meet all the following criteria:

• Aged 60 years or older.

• Diagnosed with arterial hypertension, as documented in the electronic health record.

• Prescribed at least one antihypertensive medication at the time of enrolment.

• Identified as non-adherent according to the standardised MMAS-4 (4-item Morisky Medication Adherence Scale) scoring method.

• At least one primary care visit during the previous year.

• Able and willing to provide written informed consent.

Exclusion criteria

Participants are excluded if they meet any of the following criteria:

• Institutionalisation, including residence in a nursing home or long-term care facility.

• Life expectancy of less than 12 months.

• A cognitive or physical condition that prevents participation or completion of the study procedures.

Eligible patients are recruited consecutively within each participating primary care centre until the target sample size is reached. Written informed consent is obtained from each participant before enrolment and before any study-specific procedures are performed (see online supplemental material 1).

Randomisation, allocation and masking

Randomisation was performed at the primary care centre level. The 14 participating primary care centres were centrally allocated in a 1:1 ratio to either the intervention group or the usual-care control group, with seven centres per group. Two nurses participate at each centre, and all participants recruited within the same centre receive the allocation assigned to that centre.

The allocation sequence was generated centrally using a computer-generated random sequence by an independent researcher who was not involved in participant recruitment or intervention delivery. Allocation was concealed until the participating primary care centres had been assigned to their study groups.

Because of the nature of the intervention, participating nurses and patients cannot be blinded to group allocation. No separate blinded outcome assessment is performed; however, both study groups undergo the same standardised assessments using validated questionnaires, 24-hour ambulatory blood pressure monitoring, electronic prescription dispensing records and routinely collected electronic health record data. For the prespecified statistical analysis, the study groups will be coded as A and B, and the analysts will remain blinded to group identity until completion of the primary analysis.

Cluster membership is determined by the participant’s primary care centre at enrolment and remains fixed throughout the study. A change of nurse within the same centre does not constitute a change of cluster. If a participant moves to another primary care centre during the 12-month follow-up period, the participant will not be excluded or change study group but will remain assigned to the original centre for the intention-to-treat analysis. Follow-up data will continue to be collected whenever feasible.

Recruitment

Potentially eligible participants are identified by nurses and general practitioners through electronic health records at the participating primary care centres. Eligibility is confirmed according to the predefined inclusion and exclusion criteria, including non-adherence according to the standardised MMAS-4 scoring method.

Eligible patients are recruited consecutively until the target sample size is reached; therefore, participants do not share a common index date. Each participant’s enrolment date constitutes their individual index date, from which the 12-month follow-up period is calculated.

Eligible patients are informed about the study during routine primary care visits or, when appropriate, are initially contacted by telephone. Patients expressing interest receive detailed verbal and written information about the study and are given the opportunity to ask questions before deciding whether to participate. Written informed consent is obtained by trained healthcare professionals before enrolment and baseline data collection (see online supplemental material 1).

Intervention

The intervention consists of a nurse-led multidimensional educational and behavioural programme designed to improve adherence to antihypertensive treatment and delivered by trained primary care nurses as part of routine clinical practice.

Before study initiation, nurses delivering the intervention attended a standardised 6-hour face-to-face training session conducted over one morning. Training covered medication adherence, motivational interviewing, antihypertensive pharmacotherapy, the Mediterranean diet, healthy lifestyles, physical activity, intervention materials and standardised study procedures.

The intervention includes the following core components:

1. Individualised education on hypertension, cardiovascular risk and antihypertensive treatment, tailored to each participant’s clinical characteristics and information needs.

2. A structured motivational interview to identify individual barriers to adherence to antihypertensive treatment and collaboratively agree on individualised adherence-support strategies.

3. Review of the antihypertensive treatment regimen, including medication-taking routines, dosage schedules, practical barriers and strategies for incorporating medication use into daily activities.

4. Individualised Mediterranean diet and physical activity counselling supported by standardised educational materials and weekly exercise programmes. Recommendations are tailored according to each participant’s clinical characteristics, comorbidities and previous level of physical activity. Every participant in the intervention group receives an elastic resistance band.

5. Two telephone reinforcement contacts planned during the 12-month follow-up period.

The intervention is initiated at baseline and reinforced throughout follow-up. All face-to-face intervention sessions are conducted at the participating primary care centres; home visits are not part of the intervention. Physiotherapy support and pre-existing physical activity promotion programmes are available at all seven intervention centres and may be incorporated according to participants’ clinical characteristics and needs.

The structured medication-adherence component focuses specifically on antihypertensive treatment. Other clinical conditions and treatments continue to be managed as part of usual care. A participant is not withdrawn from the trial if another medication or clinical condition requires priority attention; any necessary clinical care is provided independently of study participation.

Intervention delivery is standardised through the initial nurse training, the structured motivational-interview framework and common educational and exercise materials. Nurses may individualise the content of dietary and physical activity recommendations and adherence-support strategies according to participants’ needs while retaining the intervention’s core components.

The two telephone reinforcement contacts are prespecified components of the intervention. However, the case report form does not systematically record whether each planned call was completed, its duration, the duration of face-to-face intervention contacts or the intensity of physiotherapy support received by individual participants. Available planned intervention inputs, including the standardised 6-hour nurse-training session, educational materials, elastic resistance bands, telephone reinforcement contacts, physiotherapy support and pre-existing physical activity programmes, will be described as part of the assessment of resource use. The ambulatory blood pressure monitoring devices used for outcome assessment in both study groups will be reported separately as study-related resources. Healthcare utilisation will also be considered in the analysis of economic outcomes. Nevertheless, individual-level intervention intensity and additional nursing time cannot be fully quantified, and this will be acknowledged as a limitation of the economic analysis.

The intervention was developed and is reported in accordance with the Template for Intervention Description and Replication checklist. Participants in the control group receive usual care and do not receive the structured multidimensional intervention.

Strategies to promote adherence to the intervention

Strategies to promote adherence to the intervention include individual tailoring of educational content and adherence-support strategies, reinforcement of key messages during follow-up, use of standardised educational and exercise materials, provision of an elastic resistance band and integration of intervention components into routine primary care consultations. Follow-up reinforcement comprises face-to-face nursing consultations conducted at the participating primary care centres and two planned telephone contacts during the 12-month follow-up period. Home visits are not part of the intervention. The case report form does not systematically record completion, attendance or duration of individual intervention contacts; therefore, individual-level exposure to the intervention cannot be fully quantified.

Concomitant care

All participants continue to receive routine medical care for hypertension and other comorbid conditions in accordance with standard clinical practice. No restrictions are imposed on clinically indicated concomitant treatments. The structured medication-adherence component of the intervention focuses specifically on antihypertensive treatment, while other medications and clinical conditions continue to be managed as part of usual care. If another medication or clinical condition requires priority attention, the necessary care is provided and the participant is not withdrawn from the study solely for this reason.

Criteria for discontinuation or modification of the intervention

Participants may discontinue the intervention or withdraw from the study at any time without providing a reason and without any effect on their usual healthcare. The intervention may also be modified or discontinued if the responsible healthcare professional considers that continued delivery is no longer appropriate because of the participant’s clinical or personal circumstances. Individual educational, dietary and physical activity recommendations may be adapted to the participant’s clinical condition and needs while retaining the intervention’s core components. As the intervention is educational and behavioural, medication dose modification does not form part of the study intervention; any clinically indicated changes to pharmacological treatment are made as part of usual care.

Control group

Participants allocated to the control group receive usual care for hypertension in accordance with current clinical guidelines and routine primary care practice. Usual care may include standard clinical follow-up and general advice routinely provided by healthcare professionals but does not include the structured motivational interview, individualised adherence-support strategies, intervention-specific educational and exercise materials, elastic resistance bands or planned telephone reinforcement contacts provided to the intervention group. Participants in the control group undergo the same standardised outcome assessments at baseline, 6 months and 12 months as participants in the intervention group. These assessments are conducted for study purposes and are not considered components of the intervention.

Outcomes

Primary outcome

The primary outcome will be adherence to antihypertensive treatment at 6 months, assessed using the 4-item Morisky Medication Adherence Scale (MMAS-4).^{20 21} The MMAS-4 will be administered at baseline, 6 months and 12 months in accordance with the permission granted for this study, maintaining the licensed wording, structure and standardised scoring method without modification. The 12-month assessment will be used to determine whether any intervention effect observed at the 6-month primary endpoint is maintained over time.

Complementary adherence assessments

Medication availability will be estimated at baseline, 6 months and 12 months using electronic prescription dispensing records by comparing the number of antihypertensive tablets dispensed with the number prescribed during the preceding 180 days. These data will provide a complementary adherence measure to support and contextualise self-reported adherence and to assess concordance with the MMAS-4. Dispensing records indicate medication availability but cannot confirm ingestion.

Reasons and patterns of non-adherence to antihypertensive treatment will be assessed at baseline, 6 months and 12 months using the self-reported EFNA questionnaire. No physical pill count will be performed, and adherence to non-antihypertensive medications will not be measured separately.

Secondary outcomes

Secondary outcomes will be recorded or assessed in both study groups at baseline, 6 months and 12 months, where applicable, and will include:

• Maintenance at 12 months of any intervention effect on adherence to antihypertensive treatment observed at the 6-month primary endpoint.

• Adherence to antihypertensive treatment estimated using electronic prescription dispensing records.

• Concordance between adherence assessed using the MMAS-4 and adherence estimated from electronic prescription dispensing records.

• Blood pressure assessed using 24-hour ambulatory blood pressure monitoring with the Microlife WatchBP O3 AFIB (BP3SZ1-1; Microlife Corporation, Taipei, Taiwan), an automated oscillometric upper-arm device listed by STRIDE BP as equivalent to the validated Microlife WatchBP O3. The latter was validated according to the International Protocol of the European Society of Hypertension. Assessments are performed at baseline, 6 months and 12 months, recording mean systolic and diastolic blood pressure for the overall 24-hour, daytime and night-time periods. The same device model is used in both study groups and across all 14 participating centres.²²

• Health-related quality of life assessed using the EuroQol 5-Dimension 3-Level Questionnaire (EQ-5D-3L) and EuroQol Visual Analogue Scale (EQ-VAS).

• Symptoms of anxiety and depression assessed using the Goldberg Anxiety and Depression Scale.

• Adherence to the Mediterranean diet assessed using Mediterranean Diet Adherence Screener (MEDAS).

• Physical activity assessed using International Physical Activity Questionnaire (IPAQ).

• Cardiovascular-related emergency department visits and cardiovascular-related hospital admissions obtained from electronic health records.

• Anthropometric measurements, including weight, height, body mass index and waist circumference.

• Selected laboratory variables, including haematocrit or haemoglobin, glucose, glycated haemoglobin, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, potassium, sodium, uric acid, creatinine, estimated glomerular filtration rate, calcium, urinary albumin-to-creatinine ratio and microalbuminuria.

• Medication burden, assessed as the total number of prescribed medications recorded in the electronic health record.

Healthcare utilisation and available planned intervention-related resources will be considered in the analysis of economic outcomes. Humanistic outcomes will comprise health-related quality of life and symptoms of anxiety and depression.

Harms

The intervention is considered low risk because it is educational and behavioural and does not involve experimental medication or protocol-mandated changes to pharmacological treatment. Potential minor effects include discomfort associated with 24-hour ambulatory blood pressure monitoring or physical activity. Adverse events are not systematically collected in a separate study safety record; clinically relevant events will be managed and documented in the electronic health record, and any serious and unexpected event potentially related to study participation will be reported to the Navarra Clinical Research Ethics Committee in accordance with applicable requirements.

Participant timeline

Each participant’s enrolment date constitutes their individual index date, from which the 12-month follow-up period is calculated. Assessments are conducted at baseline, 6 months and 12 months in both study groups.

Baseline assessment includes sociodemographic and clinical characteristics, MMAS-4, electronic prescription dispensing records, EFNA, 24-hour ambulatory blood pressure monitoring, EQ-5D-3L and EQ-VAS, the Goldberg Anxiety and Depression Scale, MEDAS, IPAQ, anthropometric measurements, selected laboratory variables, medication burden and cardiovascular-related emergency department visits and hospital admissions obtained from electronic health records.

The same outcome assessments are repeated at 6 months and 12 months, where applicable. The 6-month MMAS-4 assessment constitutes the primary endpoint, while the 12-month assessment evaluates maintenance of any intervention effect. The intervention is initiated at baseline, with two telephone reinforcement contacts planned during the 12-month follow-up period. A schematic overview of enrolment, intervention delivery and assessments is provided in figure 1.

Figure 1. Study design and participant timeline of the NURSE-ADHERE-HTN cluster randomised controlled trial. The 14 participating primary care centres constitute the randomisation clusters and were centrally allocated in a 1:1 ratio to either the nurse-led multidimensional educational and behavioural intervention or usual care, with 7 centres per group and two participating nurses per centre. Participants are recruited consecutively within each centre. Outcomes are assessed in both study groups at baseline, 6 months and 12 months; the 6-month MMAS-4 assessment is the primary endpoint, while the 12-month assessment evaluates maintenance of the intervention effect. MMAS-4, 4-item Morisky Medication Adherence Scale.

Sample size

The target sample size is 280 participants. The initial individual-level calculation assumed adherence rates at the 6-month primary endpoint of 50% in the usual-care group and 70% in the intervention group. The assumed 50% adherence rate in the usual-care group was based on published systematic reviews and meta-analyses indicating that approximately half of patients receiving antihypertensive treatment do not achieve optimal adherence, including evidence specifically concerning older adults.^{3 6 7} With a two-sided significance level of 5%, 80% statistical power and an anticipated 15% loss to follow-up, the individual-level calculation resulted in 238 participants.

The sample size was subsequently increased to 280 participants to account for clustering at the primary care centre level, assuming an intracluster correlation coefficient of approximately 0.01. The trial includes 14 primary care centres, with seven centres per group, two participating nurses per centre and an anticipated mean of 20 participants per centre. The recruitment target therefore corresponds to approximately 140 participants per study group.

Data collection and management

Data are collected using standardised case report forms and routinely recorded electronic health records. Data will be pseudonymised before analysis and stored securely in accordance with European data protection regulations, including the General Data Protection Regulation. Access to identifiable data is restricted to authorised study personnel. Data quality checks are conducted regularly to ensure data completeness and accuracy.

Statistical analysis

Baseline characteristics will be summarised by study group using descriptive statistics. Continuous variables will be reported as means and SD or medians and IQRs, as appropriate, and categorical variables as frequencies and percentages.

The primary analysis will compare adherence to antihypertensive treatment at the 6-month primary endpoint between the intervention and usual-care groups using a generalised mixed-effects regression model appropriate for the standardised MMAS-4 adherence classification. The model will include study group as a fixed effect and primary care centre as a random effect to account for the cluster randomised design. Effect estimates will be reported with 95% CIs. The 12-month MMAS-4 assessment will be analysed as a secondary outcome to evaluate maintenance of any intervention effect observed at 6 months.

Secondary outcomes will be analysed using linear, logistic, Poisson, negative binomial or other appropriate generalised mixed-effects models according to the distribution and nature of each outcome. Repeated assessments at baseline, 6 months and 12 months will be analysed using models incorporating study group, time and the group-by-time interaction, while accounting for clustering by primary care centre and repeated observations within participants.

All analyses comparing the randomised groups will follow the intention-to-treat principle. Participants will be analysed according to the allocation of their primary care centre at enrolment, regardless of any subsequent change of nurse or primary care centre. Where appropriate, adjusted analyses will include prespecified baseline covariates, including age, sex, relevant comorbidities and medication burden.

Prespecified exploratory interaction analyses will assess whether intervention effectiveness differs by sex by including an interaction term between study group and sex. Because of the sample size and number of clusters, analyses of secondary outcomes and effect modification by sex will be considered exploratory.

The extent and patterns of missing data will be described. The primary analysis will use all available outcome data under the assumptions of the selected mixed-effects models. Sensitivity analyses will assess the robustness of the findings using appropriate missing-data methods under plausible missing-at-random assumptions.

For the prespecified statistical analysis, study groups will be coded as A and B, and the analysts will remain blinded to group identity until completion of the primary analysis. Statistical tests will be two-sided, with a significance level of 5% for the primary analysis.

Additional analyses

Concordance between adherence assessed using the MMAS-4 and adherence estimated from electronic prescription dispensing records will be evaluated using appropriate agreement statistics according to the format and distribution of the adherence measures. Reasons and patterns of non-adherence assessed using EFNA will be summarised descriptively and explored in relation to adherence outcomes.

Available planned intervention-related resources and healthcare utilisation will be described and considered in the exploratory analysis of economic outcomes. Individual-level nursing time and intervention intensity cannot be fully quantified because the completion and duration of intervention contacts were not systematically recorded; this limitation will be considered when interpreting the economic findings.

Monitoring

Data monitoring committee

Given the low-risk educational and behavioural nature of the intervention and the absence of investigational medicinal products, no formal data monitoring committee has been established. Trial conduct and data quality are overseen by the principal investigator and research team, with support from the study monitor.

Interim analyses and stopping guidelines

No interim analyses are planned, and no outcome analysis will be conducted before completion of follow-up and database preparation. Given the low-risk nature of the intervention, no formal statistical stopping guidelines have been defined. Any serious and unexpected event considered potentially related to study participation will be assessed and managed in accordance with applicable clinical and ethical requirements.

Trial monitoring

Trial conduct is monitored through regular review of recruitment progress, data completeness, data consistency and adherence to the approved protocol. Participating nurses may contact the principal investigator, research team or study monitor to resolve questions or difficulties related to study procedures. Identified protocol deviations or data-quality issues will be documented, reviewed and addressed as appropriate.

Patient and public involvement

Patients and patient representatives were not involved in the design of the study, development of the intervention or selection of outcomes. Patient groups representing people with previous cardiovascular disease have supported awareness of the study and participant recruitment and will contribute to dissemination of the findings. The study design was informed by existing scientific evidence and the clinical experience of primary care professionals. Study findings will be shared with participating patient groups, primary care centres, healthcare professionals and relevant healthcare stakeholders.

Ethics and dissemination

The study was approved by the Navarra Clinical Research Ethics Committee (Comité de Ética de la Investigación Clínica de Navarra; reference PI_2023/92) and is being conducted in accordance with the principles of the Declaration of Helsinki, Good Clinical Practice guidelines and applicable Spanish and European regulations.

Before enrolment and any study-specific procedures, participants receive verbal and written information about the study objectives, procedures, potential risks and benefits, confidentiality and their right to withdraw at any time without affecting their usual healthcare. Written informed consent is obtained from all participants (see online supplemental material 1).

Study data are handled confidentially and will be pseudonymised before analysis. Access to identifiable information is restricted to authorised study personnel, and personal data are processed in accordance with the General Data Protection Regulation and applicable Spanish data protection legislation.

The trial was prospectively registered in the ISRCTN registry (ISRCTN35559821) on 2 January 2026, before the first participant was enrolled, and the registry record was subsequently updated to ensure consistency with the approved protocol and prespecified study procedures.

The intervention is considered low risk because it is educational and behavioural and does not involve experimental medication or protocol-mandated changes to pharmacological treatment. Clinically relevant adverse events or unintended effects identified during routine care will be assessed, managed and documented in the electronic health record in accordance with standard clinical practice. Any serious and unexpected event considered potentially related to study participation will be reported to the Navarra Clinical Research Ethics Committee in accordance with applicable requirements.

Study findings will be disseminated through peer-reviewed publications and presentations at national and international scientific conferences. Results will also be shared with participating patient groups, primary care centres, healthcare professionals and relevant healthcare stakeholders.

Protocol amendments

Any important modification to the approved study protocol will be submitted to the Navarra Clinical Research Ethics Committee for approval before implementation and communicated to the investigators and participating primary care centres. Relevant amendments will also be entered in the trial registry when applicable. Corrections already made to the registry record were intended to ensure consistency with the approved protocol and prespecified study procedures and did not result from interim findings or outcome analyses.

Ancillary and post-trial care

No specific ancillary or post-trial care is planned beyond routine clinical follow-up. Participation in the study does not alter participants’ access to standard healthcare services, and any clinically indicated care will continue to be provided in accordance with routine practice.

Reporting guidelines

This study protocol is reported in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2025 statement. The completed SPIRIT 2025 checklist is provided as online supplemental material 2.