Response to commentary on sequential nephron blockade vs . renin‐angiotensin system blockade in resistant hypertension: Methodological and safety clarifications

We sincerely thank Dr. Belančić and colleagues for their critical appraisal of our work in ‘Letter to the Editor: Critical Appraisal of the Yugar-Toledo et al. Study on Resistant Hypertension—Practical, Safety, Methodological, and Ethical Concerns’.1 Constructive scientific dialogue is fundamental for the advancement of clinical knowledge, and we appreciate the opportunity to clarify methodological and safety aspects of our study. Below, we respond point by point to the comments regarding our article, ‘Effects of different antihypertensive drug classes on central and ambulatory blood pressure in resistant hypertension: A randomized clinical trial’, published in the British Journal of Clinical Pharmacology (BJCP).2 —Sequential nephron blockade (SNB Group) n = 35 —Dual blockade of the RAAS plus bisoprolol (RASSB Group) n = 37 SNB consists of a progressive increase in sodium depletion. After the administration of a thiazide diuretic (chlorthalidone) and an aldosterone receptor blocker (spironolactone), low doses of furosemide are administered, and subsequently amiloride is prescribed to enhance the natriuretic effect.3, 4 In the BJCP article, hydrochlorothiazide was incorrectly mentioned instead of chlorthalidone, and the diuretics were erroneously described as being introduced simultaneously rather than sequentially. Additionally, valsartan was mistakenly listed instead of losartan.2 The dual blockade of the renin-angiotensin-aldosterone system (RAAS), combined with bisoprolol (RASSB), was employed to potentiate the effects of angiotensin II Type 1 receptor blockers (ARBs). This therapeutic strategy involves the sequential addition of an angiotensin-converting enzyme (ACE) inhibitor to further reduce angiotensin II (Ang II) levels—elevated due to receptor blockade—and subsequently the introduction of a beta-blocker to suppress the compensatory increase in renin secretion induced by both ACE inhibitors and ARBs.3, 4 This study compared two antihypertensive treatment regimens in patients with resistant hypertension (RHTN), aiming to assess the therapeutic efficacy of SNB vs. RASSB, as well as to evaluate side effects and treatment adherence over 20 weeks. Adverse events were prospectively evaluated at each visit, and all were graded according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0).5 The profile events were consistent with the expected pharmacodynamic effects of the respective drug classes. No hospitalizations or withdrawals occurred, and the overall tolerability was excellent. Table 1 lists all adverse events. Laboratory tests—including electrolytes, renal function, hepatic enzymes and thyroid profile—were performed at baseline and at the end of the 20-week treatment period. No clinically significant thyroid or renal disturbances occurred during the study. These results confirm the safety and laboratory stability of both regimens. Upon review, we identified this as a data entry error in the original spreadsheet. The correct TSH value is: RASSB Before Group: 8.08 ± 3.2 mIU/L. Sequentially numbered, opaque and sealed envelopes were prepared by the study coordinator and assigned to participants in the order of enrollment. Envelopes were opened only after definitive inclusion of the participant, ensuring allocation concealment and minimizing selection bias. Although the trial followed an open-label design—where both investigators and participants were aware of the assigned treatment—blinding was rigorously maintained for outcome assessors. Specifically, individuals responsible for evaluating ambulatory blood pressure monitoring (ABPM) and central systolic blood pressure (CSBP) remained blinded to treatment allocation to reduce detection bias and ensure objective assessment of hemodynamic parameters. To further enhance internal validity, baseline therapy was standardized across all participants prior to randomization. The introduction of new pharmacological agents followed a predefined protocol, allowing the randomization process to isolate the effects of the newly implemented therapeutic strategy rather than background treatment variability.3, 4 This design aligns with the CONSORT 2010 guidelines for pragmatic open-label trials and incorporates methodological safeguards to mitigate detection bias and enhance the reliability of outcome assessment.6 Both groups completed their assigned regimens over 20 weeks. All analyses were prespecified in the primary studies.3, 4 To address multiple comparisons, Bonferroni-adjusted significance thresholds were applied. The primary endpoint—reduction in CSBP—was defined at Week 20, coinciding with full treatment exposure. This approach ensures methodological consistency and minimizes type I error risk. The linear mixed-effects model accounted for potential temporal heterogeneity, ensuring analytical equivalence between arms. The study ‘Effect of Sequential Nephron Blockade versus Dual Renin-Angiotensin System Blockade Plus Bisoprolol in the Treatment of Resistant Hypertension, a Randomized Controlled Trial’ determined its a priori sample size using Stata version 13.0. The calculation was based on detecting a minimum difference of 12 mmHg in systolic blood pressure (SBP) between treatment groups, with an alpha error of 5%, statistical power of 80% and an estimated standard deviation of 8 mmHg. Under these parameters, the required sample size was 36 participants per group.4 A post hoc power analysis was subsequently performed using G*Power version 3.1.9.7 to confirm the adequacy of the sample size. Based on the observed difference of 12 mmHg between groups, a standard deviation of 8 mmHg, a significance level of 5% and a sample size of 36 participants per group, the achieved statistical power was approximately 99.4%. These results indicate that the study was highly powered to detect the intended difference in SBP, reinforcing the robustness of its findings (Figure 1). For this study, published in BJCP, the a priori sample size estimation was conducted using G*Power software (version 3.1.9.7) based on the primary endpoint—reduction in CSBP. We assumed an expected between-group mean difference of 5 mmHg and a standard deviation of approximately 7.46 mmHg (and not 10 mmHg), yielding a Cohen's d of 0.67 (and not 0.1). With a two-tailed alpha level of 0.05 and a statistical power of 80%, the required sample size was 72 participants (36 per group) (Figure 2A). These parameters are consistent with previous resistant hypertension trials and support the robustness of our findings.7, 8 We also conducted post hoc analyses, which confirmed that, given the observed effect size (Cohen's d = 0.67), a significance level of α = 0.05, and a sample size of 36 participants per group, the achieved statistical power was approximately 80% (1—β = 0.8005) (Figure 2B). Adherence was monitored through structured, standardized patient interviews at each follow-up visit. Although adherence was high according to structured monitoring, which ensures reliable exposure assessment, future studies will incorporate plasma or urinary drug-level monitoring to strengthen adherence verification. Our study demonstrated that SNB was more effective than RASSB in reducing central systolic pressure and pulse pressure. Furthermore, it provides a valuable foundation for future research in this field. We sincerely apologize for the errors identified in the BJCP manuscript and trust that these clarifications will meaningfully contribute to the ongoing advancement of knowledge in the field of resistant hypertension. We once again thank Dr. Belančić and colleagues for their meticulous analysis. As the required corrections are substantial, we formally agree to the Retraction of the article and will submit a corrected version of the manuscript for future consideration. We remain fully committed to transparency, participant safety and scientific integrity. We sincerely apologize for the incident and remain available for any further clarification. Sincerely, Prof. Dr. Juan Carlos Yugar-Toledo On behalf of all authors We extend our sincere thanks to the British Journal of Clinical Pharmacology, the British Pharmacological Society, and Wiley for their support, as well as to Dr. Belančić and colleagues for enabling constructive dialogue and clarification of our research. The authors declare no conflicts of interest. Not applicable.