In Reply: Time in Target Range, Sex‐Specific Effects, and the Path to Clinical Integration

To the Editor, Garg et al. raise questions that merit further discussion when discussing our recent publication regarding systolic blood pressure (SBP) time in target range (TTR) and incidence of major adverse cardiovascular events (MACE) [1, 2]. The authors hypothesize why men and women demonstrated different associations between SBP TTR and MACE. While baseline risk profiles and physiology differed between sexes due to PRECISION inclusion criteria, it is necessary to consider our findings within the context of the existing literature for BP lowering [3]. The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that intensive SBP control (<120 mmHg) provided significant and comparable benefits for both men and women, and there was no statistical interaction between sex and the treatment effect (p for interaction = 0.45), indicating that the magnitude of benefit from intensive control did not differ between men and women [4]. Therefore, while the target range of 110–130 mmHg may appear to align with average female BP, the therapeutic principle of achieving this target is strongly supported for men as well. The lack of a statistically significant association in men of our cohort may reflect factors beyond the choice of target range, such as differences in medication adherence, underlying pathophysiology, or as the authors mentioned, the differential inclusion criteria. The authors also note the methodological limitations inherent in using office-based BP measurements to calculate SBP TTR, particularly the potential for misclassification in individuals with higher SBP variability due to hypertension. We concur that out-of-office assessment is crucial; however, the prognostic significance of visit-to-visit variability derived from office measurements is well-established and provides independent predictive information for MACE, even beyond mean BP levels [5-7]. Additionally, existing literature demonstrates that patients with hypertension typically have higher office-based BP measurements, which would have placed them in their appropriate TTR group due to their overall higher mean BP despite enhanced variability. The use of office-based measurements for SBP TTR is a well-established approach that reflects the data most commonly available to clinicians and researchers. The fact that this metric yielded significant associations highlights its real-world clinical utility. Further, the authors mention SBP variability as a potential confounder of TTR. Based on the formula used to calculate TTR, visit-to-visit variability, particularly over variable time intervals, is factored into its derivation [8]. Regarding the potential confounding effect of nonsteroidal anti-inflammatory drugs, it is critical to appraise that the PRECISION trial was a randomized controlled trial that inherently minimizes confounding factors, and our statistical models further adjusted for the assigned treatment arm during analysis. Finally, we wholeheartedly agree with the authors’ sentiment that the ultimate goal of this research is to improve clinical practice. We believe that by demonstrating a clear link between the consistency of SBP control over time through TTR with MACE and cardiovascular outcomes, we are providing a compelling rationale for the future clinical and practice guideline-level integration of the TTR metric. Luke J. Laffin has been a consultant and/or served on steering committees for Medtronic, Lilly, Mineralys Therapeutics, AstraZeneca, and CRISPR Therapeutics; has received research funding from AstraZeneca; and has ownership interests in LucidAct Health and Gordy Health. The other authors have no disclosures. Luke J. Laffin has received research funding from AstraZeneca.