Dear Editor,
We sincerely thank the authors of the Letter to the Editor about our manuscript. We appreciate their thoughtful and constructive remarks on our recent article entitled "Effectiveness of early cardiorespiratory rehabilitation combined with melatonin supplementation during the inpatient period after acute myocardial infarction: a pilot study"1 and appreciate the opportunity to respond to each of their observations.
First, regarding the sample size calculation, the authors of this letter suggested that we should have based our calculation on the minimal clinically important difference (MCID) of the 6-minute walk distance (6MWD). It is important to clarify that our study was a pilot, exploratory, randomized controlled trial primarily designed to assess feasibility and safety and to estimate preliminary effect sizes to guide the design of a future definitive trial. As stated in the Consolidated Standards of Reporting Trials (CONSORT) 2010 extension for pilot and feasibility trials,2 a formal MCID-based sample size calculation is not typically required for pilot studies. In line with Whitehead et al,3 our sample size was based on a medium anticipated effect size (Cohen’s d=0.5), which recommends 15 participants per group for this type of study design.
Second, concerning the use of absolute 6MWD values rather than percent-predicted values, while we fully recognize the value of standardized reporting in diverse populations, it should be emphasized that existing predictive equations derived from healthy populations are not well adapted to patients with coronary artery disease (CAD). It has been demonstrated that these equations underestimate the 6MWD in patients with CAD by an average of 52 m, leading to potential misclassification.4
Moreover, it has been recommended that prediction models in patients with CAD should incorporate disease-specific variables, such as the New York Heart Association functional class and waist circumference, to enhance their clinical relevance.4 Nevertheless, to address this point, we retrospectively applied Ben Saad et al’s5 prediction equations and a lower limit of normal values to our sample. At baseline, the mean percent-predicted 6MWD was 44% (SD, 10.5%), rising to 50.45% (SD, 10.3%) after the intervention. This finding confirms the significant functional limitation of patients with post-acute myocardial infarction (AMI) and highlights the limitation of relying on prediction equations derived from healthy individuals. Furthermore, it is crucial to note that in clinical practice for cardiac rehabilitation populations, clinically meaningful changes are typically expressed in raw units (meters) rather than percentages. In our study, we observed an average increase of 70.9 m in the group receiving both early rehabilitation and melatonin supplementation versus 40.2 m in the early rehabilitation-only group. The between-group difference of 30.7 m exceeds the MCID threshold of 25 m for patients with acute coronary syndrome,6 reinforcing the potential added benefit of melatonin administration during the inpatient recovery phase after AMI.
Finally, regarding the use of a 450-m cutoff to define impaired functional capacity, we acknowledge that this threshold is traditionally applied in populations with heart failure, atrial fibrillation, and pulmonary hypertension.7, 8, 9 However, in the absence of specific and validated cutoff values for patients with post-AMI during hospitalization, this value has been pragmatically adopted in several cardiology studies as a descriptive benchmark. We concur that future studies should aim to define appropriate and prognostically meaningful thresholds tailored to patients with post-AMI.
Once again, we thank the authors for their valuable remarks, which allowed us to clarify these methodological considerations and underline the clinical relevance of our preliminary findings.
Disclosure
The investigators have no financial or nonfinancial disclosures to make in relation to this project.
References
- 1.Hbaieb M.A., Charfeddine S., Driss T., et al. Effectiveness of early cardiorespiratory rehabilitation combined with melatonin supplementation during the inpatient period following acute myocardial infarction: a pilot study. Arch Rehabil Res Clin Transl. 2025;7(3):100454. doi: 10.1016/j.arrct.2025.100454. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Eldridge S.M., Chan C.L., Campbell M.J., et al. CONSORT 2010 statement: extension to randomised pilot and feasibility trials. BMJ. 2016;24(355):i5239. doi: 10.1136/bmj.i5239. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Whitehead A.L., Julious S.A., Cooper C.L., Campbell MJ. Estimating the sample size for a pilot randomised trial to minimise the overall trial sample size for the external pilot and main trial for a continuous outcome variable. Stat Methods Med Res. 2016;25:1057–1073. doi: 10.1177/0962280215588241. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Lenasi H., Novak A., Jug B., et al. An alternative prediction equation for evaluation of six-minute walk distance in stable coronary artery disease patients. Front Physiol. 2022;13 doi: 10.3389/fphys.2022.844847. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Ben Saad H., Prefaut C., Tabka Z., et al. 6-minute walk distance in healthy North Africans older than 40 years: influence of parity. Respir Med. 2009;103:74–84. doi: 10.1016/j.rmed.2008.07.023. [DOI] [PubMed] [Google Scholar]
- 6.Gremeaux V., Troisgros O., Benaïm S., et al. Determining the minimal clinically important difference for the six-minute walk test and the 200-meter fast-walk test during cardiac rehabilitation program in coronary artery disease patients after acute coronary syndrome. Arch Phys Med Rehabil. 2011;92:611–619. doi: 10.1016/j.apmr.2010.11.023. [DOI] [PubMed] [Google Scholar]
- 7.Kronberger C., Mousavi R.A., Ermolaev N., et al. One-minute sit-to-stand test cut-offs for risk stratification based on six-minute walk test thresholds in pulmonary hypertension. Eur J Prev Cardiol. 2025 doi: 10.1093/eurjpc/zwaf031. zwaf031. [DOI] [PubMed] [Google Scholar]
- 8.Piepoli M.F., Spoletini I., Rosano G. Monitoring functional capacity in heart failure. Eur Heart J Suppl. 2019;21(Suppl M):M9–M12. doi: 10.1093/eurheartj/suz216. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Zelniker T.A., Huscher D., Vonk-Noordegraaf A., et al. The 6MWT as a prognostic tool in pulmonary arterial hypertension: results from the COMPERA Registry. Clin Res Cardiol. 2018;107:460–470. doi: 10.1007/s00392-018-1207-5. [DOI] [PubMed] [Google Scholar]