Effect Modification of Sex and Hypertension Status on the Association Between Systolic Time-in-Target-Range and Cardiovascular Outcomes

Abstract

To the Editor,

It is with pleasure that we read the work of Agarwal et al. titled “Association of Systolic Blood Pressure Time in Target Range With Cardiovascular Events Among PRECISION Participants” [1], which demonstrated that participants with systolic blood pressure (SBP) within a target range (TTR) of 110–130 mmHg for a longer duration (>75% vs. <25%) had a lower risk of major adverse cardiovascular events (MACE) using both traditional and Rosendaal TTR methods. We were particularly surprised with the significant effect modification of sex and hypertension status on SBP TTR and would like to provide additional insight.

Women had lower risks of MACE at each level of TTR compared to men. Men, in fact, demonstrated no significant association between TTR and MACE. We speculate that this is due to both selection bias and physiologic differences: (1) the PRECISION trial used different inclusion criteria for men and women, including differences in age, insulin use, and cardiometabolic morbidities. This was likely in part due to the high prevalence of women with rheumatoid arthritis necessitating amended criteria to ensure adequate inclusion of men [2]. Such differences may reflect baseline differences in ASCVD risk and an imbalance of comorbidities. For example, women, in general, are less likely to have hypertension and be using antihypertensives for primary prevention rather than secondary prevention. This coincides with lack of significant effects in the subgroup for secondary prevention and with hypertension; (2) secondly, the selected target range (110–130 mm Hg) may have aligned more with average women BP, as women tend to have lower BP than men and only begin approaching that of men in the eighth decade [3].

Hypertension status was also an effect modifier. We speculate that differential misclassification bias from measurement error likely drives some of the lack of difference seen in participants with hypertension. Those with hypertension are more likely to have higher SBP variability, which is not captured from routine office visit-based TTR. Thus, there may be individuals in the >75% TTR group with actual lower TTR, regressing the effect estimates towards the null. Those without hypertension are less likely to have SBP variability, and thus, TTR is likely prone to less misclassification [4]. Additionally, participants in the PRECISION trial were administered nonsteroidal anti-inflammatory drugs (NSAIDs), which are known to increase BP, CKD risk, and may have contributed to elevated MACE risk in participants with hypertension [5].

Future studies should also report diastolic BP TTR and HR TTR to get a more complete picture of hemodynamics. Abnormal DBP patterns may have influenced the effect modifications observed [6]. Furthermore, the study cohort consisted mostly of older adults whose vessels are likely of lower elasticity, leading to lower DBP and higher SBP [7]. Lastly, while TTR has been reasonably well captured, confounding from the white coat effect, situational differences, and time of day cannot be fully excluded.

The clinical implications of TTR and SBP variability are ever-growing yet not mentioned in the 2025 ACC/AHA hypertension guidelines [8]. The United Kingdom's QRisk score accounts for SBP variability by using the standard deviation of SBP readings in a 5-year period to better identify patients who may have a higher CV risk, even if their average BP is under control [9]. This approach highlights how incorporating BPV into risk assessments can improve CV risk predictions by using both mean BP and BPV. Considering BPV measures, including TTR, in clinical practice could lead to more tailored management strategies, such as more intensive BP monitoring or selection of alternate medications that reduce variability, supporting more complete CV risk reduction.

The authors have nothing to report.

The authors declare no conflicts of interest.