Design

An 8-week, triple-blind, parallel-group, low-risk, randomized controlled trial (RCT) will be conducted in patients with AMI who underwent revascularization by PCI. This protocol was reported according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT 2013 Statements) [19]. The checklist is available in the supporting information (S1 File). Furthermore, the Consensus on Exercise Reporting Template (CERT) has been included as Supporting Information (S6 File) to provide comprehensive rehabilitation details and guarantee the intervention's replicability.

Participants and the study setting

This study will include patients with AMI who underwent revascularization by PCI. These individuals will be recruited from among patients admitted to a CRP in the Cardiac Rehabilitation Unit (CRU) of the Hospital Universitario Virgen de la Victoria in Málaga (HUVV), Spain. Physicians in charge of potential participants with AMI who underwent revascularization by PCI will propose inclusion in the study by applying the eligibility criteria. The recruitment began on November 11, 2024, and will end on December 31, 2025. Patients will receive general information and written consent forms from their doctors, who will ask them about their interest in participating in the RCT. If the answer is yes, they will be asked to sign the written informed consent form. This will be kept in a safe place by the researchers.

Eligibility criteria

The inclusion criteria will be as follows: a) male and female patients with AMI who underwent emergency revascularization by PCI aged over 18 and under 80 years, and b) with absence of cognitive deficits and/or physical limitations that would prevent them from performing physical exercise or completing the questionnaires necessary for participation in the study. Patients will be excluded if they have undergone revascularization via coronary artery bypass grafting or if they present with one of the main absolute contraindications for initiating cardiac rehabilitation in patients with AMI: unstable angina, decompensated heart failure, severe uncontrolled arrhythmias, severe uncontrolled hypertension, and acute myocarditis or pericarditis [20].

Interventions

Both study groups will undergo 16 intervention sessions (2 times/week) of a CRP, consisting of multicomponent exercise (endurance and strength training), health education, and weekly group psychological therapy sessions. This program includes the core components of CRPs recommended by the American Heart Association and the American Association of Cardiovascular and Pulmonary Rehabilitation [12].

The CRP will be performed and supervised by the usual multidisciplinary team of the HUVV. The team is composed of a cardiologist, rehabilitation physician, endocrinologist, physiotherapist, nurse, and psychologist. The study participants will attend the CRU of the hospital three times per week. Two of these days will be dedicated to physical exercise sessions, and the third will be dedicated to health education and group psychological therapy sessions. The health education session will deal with a different topic each week (basic knowledge of their pathology, proper medication, safe physical exercise, sexual dysfunction, healthy eating, and control of cardiovascular risk factors). Subjects suffering from erectile dysfunction will be offered the possibility of being referred to a urologist. Participants with poorly controlled diabetes and/or morbid obesity will be referred to an endocrinologist on the CRU.

The training sessions will take place in the cardiac rehabilitation room at the HUVV in groups of 8 patients and will last approximately 75 minutes. This space has a rectangular floor plan, measures approximately 100m², and is air-conditioned. It contains the equipment described in Table 1 for conducting exercise sessions, as well as telemetry equipment for monitoring participants during exercise. In addition, it has everything necessary to respond in the event of any adverse effects or cardiopulmonary arrest. This includes a stretcher, wheelchair, sphygmomanometer, stethoscope, electrocardiograph, and a fully equipped crash cart with a defibrillator.

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Table 1. Structure of the cardiac rehabilitation exercise session.

https://doi.org/10.1371/journal.pone.0343947.t001

The training sessions will be led by a physiotherapist with previous experience and training in supervising exercise for people with heart disease. This professional will keep an attendance record on the computer in order to measure and report adherence. In addition, this physiotherapist will encourage patients in each session to continue with the program by reinforcing its benefits. The structure and other details of the sessions are shown in Table 1.

The program will be extended for eight weeks until 16 concurrent training sessions are completed.

In addition to the classic CRP described above, the intervention group will undergo IMT during the same period. The Power Breath model – Medic Classic device will be used. The IMT will be performed by adjusting the device load to 70% of the MIP value measured prior to the start of the program. Participants will complete one daily training session four days a week (Monday, Wednesday, Friday, and Sunday), three sets of 10 repetitions, and a rest of 3-minutes between sets. The MIP value will be measured again halfway through the program to readjust the training load. Previous studies with patients with coronary artery disease have used training protocols that are similar in terms of workload, number of repetitions and sets, and distribution of weekly sessions. These clinical trials reported no adverse events, supporting the safety and tolerability of high-intensity IMT in this study population [22–24]. We hypothesize that high-intensity IMT training may lead to greater inspiratory muscle adaptations, resulting in improved CF and other outcomes compared to lower-intensity training [21–23].

The control group will be given the same device as the experimental group, but the load for all participants in the control group will be 5 cm of H₂O. This load is so low that it cannot induce improvements in the inspiratory musculature. Therefore, it will act as a sham intervention in the control group.

A rehabilitation physician, with prior expertise and training in the practice of the device, will teach participants how to use it on the first day, and they will be instructed to do it individually at home. In order to prevent non-compliance with the IMT by the participants, they will be given a paper log to be filled in daily after the IMT session. At any time, participants may ask the rehabilitation physician who instructed them any questions they may have about using the device. During regular CRP exercise sessions, the physiotherapist will emphasize the importance of completing the prescribed IMT.

Outcomes

To analyze the effectiveness of IMT, several outcomes will be assessed. CF as main outcome, PIM, PEM, peripheral muscle strength, social support, anxiety, depression, coping with the disease, sexual dysfunction, QoL, sleep quality, eating habits, and body composition as secondary outcomes. The following sociodemographic and clinical variables will also be collected to characterize the sample and explore potential associations with the outcomes of interest: age, biological sex, marital status, educational level, profession, and nationality.

In the CRU consultation, an anamnesis will be performed in which the following data will be collected for the clinical history: cardiac comorbidities (revascularization, HF, heart valve surgery), presence of cardiovascular risk factors (current or previous smoking, arterial hypertension, dyslipidemia, diabetes mellitus, sedentary lifestyle, obstructive sleep apnea), locomotor, neurological, vascular, or respiratory comorbidities, physical exercise habits (type and time), and stratification of the patient's cardiac risk (low, medium, or high).

Sample size calculation

The sample size was calculated to detect differences between groups in our main outcome, CF, measured by VO₂max. According to the meta-analysis by Fabero-Garrido et al [16], people with ischemic heart disease who have undergone an IMT program have a mean difference of 2.18 ml O₂/kg/min with respect to the control group, and we want to find a deviation of 1 MET (3.5 ml O₂/kg/min). The calculations were performed using the statistical software G*Power 3.1, considering a confidence level of 95% and a power of 80% in all cases.

Based on the above, a sample size of 33 subjects per group (66 in total) was determined. In addition, to minimize the impact of possible dropouts, the total sample was increased by 10% to 72 patients, which will lead to the final inclusion of 36 patients in each group.

Allocation concealment

Consecutive sampling will be performed by a rehabilitation physician on patients attending the CRU consultation of HUVV who meet the criteria (see Eligibility criteria section) and sign the informed consent. Once included, each patient will be randomly assigned to either the intervention or control group (1:1 ratio) using a random sequence of numbers generated with the Simple Random Sampling module of Epidat 3.1 (open-access epidemiological analysis software developed by the Xunta de Galicia, Dirección Xeral de Saúde Pública). Specifically, to reach a sample size of n = 72, the software will generate a sequence that determines the group for each participant according to their order of enrollment. This simple random assignment will ensure maximum unpredictability in the assignment of participants, preventing any prediction of future assignments. These assignments will be generated in advance by an independent team member who will develop sequentially numbered, truly opaque, and sealed envelopes. Finally, the rehabilitation physician responsible for recruitment will open the corresponding envelope to reveal which group the participant belongs to.

Blinding

Participants will receive instruction about IMT from one of the rehabilitation physicians, who will be different from the one performing the assessments. Furthermore, none of the participants will know to which group they belong, since all of them will be given the same IMT device, but with a different training load. The physiotherapist and nurse who will conduct the CRP training sessions will not be involved in the allocation of participants. The statistical analysis will be carried out by a statistician of the research team who will not participate in the allocation, assessment or intervention process. In addition, the participants’ data will be provided anonymously.

In the event of any adverse effect or circumstance that endangers the health of the participants, the researchers will be unblinded. If such a contingency arises, both a paper-based and an electronic record are always maintained and remain accessible to all authorized investigators.

Data collection

Prior to inclusion in the study, each participant will undergo a simple ergometry test to determine their maximum heart rate (MHR), observe their behavior at maximum effort, and rule out conditions that contraindicate exercise. Besides, the rehabilitation physician will perform a nutritional assessment using bioimpedance analysis and a morphological assessment of the quadriceps and abdominal fat using ultrasonography. Patients will be weighed every week to monitor their evolution and rule out possible adverse effects of training. At the end of the program, ergometry, blood analysis, and the rest of the tests described below will be repeated.

Data management plan.

To ensure the privacy and confidentiality of participants, all clinical data collected in the study will be anonymized prior to analysis. Direct identifiers such as names, identification numbers, and specific dates will be removed, and indirect variables that could allow for the identification of subjects will be grouped and coded. The anonymization process will be carried out in accordance with current ethical and regulatory standards, ensuring that the data retained its validity for statistical analysis without compromising individual privacy. All physical documents (informed consent forms, data of the outcomes of the participants, etc.) will be stored in locked filing cabinets located in a secure area with restricted access. Electronic data will be entered into a secure, password-protected database designed specifically for the study. Only members of the research team listed in the protocol will be granted access to the data. The data that will support the findings of this study will not be openly available due to reasons of sensitivity and will be available from the corresponding author upon reasonable request. Data will be in controlled access data storage at University of Cadiz (Spain).

Participant data and variables will be gathered, as depicted in Figs 1 and 2.

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Fig 1. Schedule of enrolment and interventions.

https://doi.org/10.1371/journal.pone.0343947.g001

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Fig 2. Schedule of assessments.

https://doi.org/10.1371/journal.pone.0343947.g002

Statistical analysis

Descriptive statistics will summarize each variable, reporting means ± standard deviations (SD) or medians (IQR) for continuous data and absolute and relative frequencies for categorical data to verify baseline comparability between groups. Exploratory data analysis (e.g., box-plots, z-scores) will screen for influential outliers; values deemed spurious will be winsorized or, when justified, excluded, and sensitivity analyses will confirm that their treatment does not alter the main findings.

A mixed-design analysis of variance (ANOVA) will be performed to assess differential changes between groups over time (group × time interaction). The primary analysis strategy will depend on the proportion of missing data: if the dropout rate is less than 5%, a complete case analysis will be conducted, as this threshold is generally considered to have a negligible impact on bias. However, if missing data exceeds 5%, an intent-to-treat approach will be implemented, using multiple imputation to handle missing values and ensure that all randomized participants are included in the final model, in accordance with clinical trial standards [42].

All analyses will be performed in IBM SPSS Statistics v.24 (IBM Corp., Armonk, NY, USA), significance level will be set at 5% with 95% confidence intervals; assumptions, model fit, and potential risks (e.g., heteroscedasticity or multicollinearity) will be routinely checked, and predefined contingency strategies (nonparametric alternatives or robust estimators) will be implemented when violations are detected.

Ethics

The present project will follow the ethical principles established for medical research on human subjects, according to the Declaration of Helsinki. The present clinical trial was approved by the Provincial Research Ethics Committee of Malaga (Spain) with Code SICEIA-2024–001869 in session number 9, held on 09/26/2024. Since data from real subjects will be used, it is essential to guarantee their confidentiality, privacy, and data protection. To this end, the participation of the subjects will be voluntary, and it will be an indispensable requirement to sign a written informed consent form for participation in the study. Participants will be able to withdraw from the study whenever they wish to do so. To safeguard the identity of the participants, their names and surnames will be coded in the database. This is a low-intervention clinical trial, since IMT is a very safe intervention, as it is routinely performed in other populations of chronic cardiac and respiratory patients without any relevant adverse effects having been reported. In addition, patients will be scrupulously stratified according to their cardiovascular risk, and the CRU at HUVV has extensive experience in training this type of patient, and its professionals are in constant training. The damages incurred by the participants will be covered by individual or collective self-insurance that the researcher in question has already contracted for the usual practice of his or her profession.

To publish the results of the project in international peer-reviewed journals and present the results at congresses worldwide, the Consolidated Standards of Reporting Trials (CONSORT) statement will be followed. In addition, as part of the knowledge translation strategy, we will disseminate the results on institutional websites and social media, contact news organizations, and identify partner institutions interested in the results. It is not planned to use professional scientific writers because the scientific articles will be written by the researchers of the study.

Strengths and limitations

Our study has some strengths that need to be highlighted. The study is going to be carried out on a very specific population that has a specific pathology and has been treated in the same way, which makes the sample very homogeneous and therefore individuals very comparable with each other. Another strength is that this study will collect many variables, so we expect it to generate a lot of knowledge about this specific group of patients. This study is methodologically robust because it was prospectively registered and complies with the SPIRIT statement. In addition, it incorporates the Consensus on Exercise Reporting Template (CERT) as supporting information (S6 File) to include all the details of the rehabilitation and thus ensure that the exercise intervention can be replicated. It also performed concealed randomization and triple blinding. Additional strengths include a homogeneous, well-characterized sample and delivery within a real-world hospital CR setting supported by an experienced, multidisciplinary team. The primary outcome (VO₂ max) is objective, and all secondary outcomes will be measured with validated instruments, maximizing data quality and interpretability. We also believe that the long experience of the intervention team will contribute to the quality of this clinical trial. Finally, conducting the trial in a real-world hospital setting will facilitate rapid translation into routine cardiac-rehabilitation practice.

As limitations, we believe that the high number of questionnaires that the patients will have to answer could exhaust some of the participants and it could happen that they would not answer all of them. To try to avoid this, at the beginning of the intervention, the CRU nurse will explain to participants the importance of answering all the questionnaires. They will also be told that if they get tired, they can stop answering them and resume at another time of the day or on subsequent days. The fact that the trial is to be conducted in a real clinical setting with its possible errors and setbacks is also a limitation. Although standard operating procedures will be enforced, unexpected workflow disruptions could affect intervention fidelity. We are also aware that having the study subjects perform the IMT at home is not the best option even though we have provided all the necessary means (adequate instruction and performance record sheet) to make it as similar as possible to having it performed in the hospital (which is not possible due to organizational circumstances of the CRU). Because adherence relies on self-reported diaries and lacks electronic dose counters, compliance bias cannot be ruled out. No long-term follow-up beyond the 16 intervention sessions program means the durability of any observed benefits remains unknown.