All datasets and materials relevant to this study have been made publicly accessible via the BioLINCC data retrieved from https://biolincc.nhlbi.nih.gov/home/.

SPRINT was a multicenter, open-label, randomized controlled trial designed for individuals at increased cardiovascular risk, excluding those with a documented history of diabetes mellitus or stroke. The trial sought to compare the effectiveness of an aggressive systolic blood pressure management strategy (120 mmHg) against a conventional approach (140 mmHg) (NCT01206062). Participants received medications proven to reduce cardiovascular event risk, using the Adherence Scale to assess the medication adherence, along with recommendations for lifestyle modifications, including the Dietary Approaches to Stop Hypertension (DASH) diet and increased physical activity. The protocol and findings have been previously documented [14]. Authorization was secured from the respective institutional review boards, and all participants provided informed consent. This analysis included participants who underwent a minimum of three follow-up measurements within the initial three months after the baseline blood pressure measurement.

BP was measured by trained clinic staff. Values were obtained by averaging three seated measurements and were routinely measured at baseline, monthly for the initial three months, and every three months thereafter. SBP TTR is delineated as the proportion of time during the observation period wherein SBP values remain within the predefined target range. Systolic blood pressure (SBP) values throughout the observation period were derived using the linear interpolation method of Rosendaal which assumes a linear change between consecutive measurements to estimate SBP at each time point [15, 16]. As previously documented, the target range for the intensive group was defined as 110–130 mmHg with the upper limit aligning with current guideline recommendations, and the target range for the standard group was set at 120–140 mmHg [17, 18]. Ultimately, the percentage of time within this target range is calculated as the metric of SBP TTR. The calculation of SBP TTR, mean SBP, and SBP variability were based on all SBP data within the initial three months of the study.

Structured interviews were conducted quarterly with participants to ascertain the occurrence of potential events. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE), comprising stroke, non-fatal myocardial infarction, non-myocardial infarction acute coronary syndrome, cardiac death, and acute decompensated heart failure. Secondary endpoints encompassed the discrete constituents of MACCE.

Quantitative data following a normal distribution were characterized by the mean $\pm$ SD, and differences were assessed through an independent sample t-tests or one-way analysis of variance. Non-normally distributed quantitative data were described using the median (interquartile range) and analyzed for disparities utilizing the Mann-Whitney U test or Kruskal-Wallis test. Qualitative data were delineated by frequencies and percentages, and chi-square test was applied to identify disparities across groups. Cox proportional hazards model was utilized to delineate the association between SBP TTR and cardiovascular events. Two models were applied in this study consistent with previously published literature: (1) a unadjusted model; (2) an adjusted model, accounting for the treatment group, age, race, a 10-year cardiovascular risk score, baseline SBP, body mass index (BMI), and renal insufficiency. Restricted cubic splines (RCS) with 3 knots at the 10th, 50th, and 90th percentiles of TTR were utilized to further explore the relationship between SBP TTR and cardiovascular events, based on the adjusted Cox model. Statistical analyses were conducted utilizing SPSS (version 27.0, IBM Corp, Armonk, NY, USA) and R software (version 4.3.2, R Foundation for Statistical Computing, Vienna, Austria), with a two-sided p-value 0.05 regarded as statistically significant.

8822 patients were included in the final analysis, with the exclusion of 539 participants due to the absence of a minimum of three follow-up SBP measurements within the initial three months or incomplete covariate information.

In the overall population, the mean age was 67.9 $\pm$ 9.4 years, with a median SBP TTR of 38% (14%–64%). In contrast to men, women, who accounted for 35.3% of the overall population, demonstrated a greater mean age (68.6 $\pm$ 9.5 vs 67.6 $\pm$ 9.3, p 0.001), an elevated BMI (30.1 $\pm$ 6.5 vs 29.7 $\pm$ 5.1, p = 0.007), and a lower SBP TTR within the initial three months (37% (14%–61%) vs 39% (16%–67%), p 0.001). No statistically significant difference was observed in the mean SBP between the two groups during the initial three months (129.5 $\pm$ 13.0 vs 129.8 $\pm$ 11.5, p = 0.241). Detailed clinical characteristics of the patients, stratified by sex or jointly by sex and SBP TTR, are available in Table 1 and Supplementary Table 1.

The antihypertensive intervention strategies, stratified by the number of antihypertensive agents, showed no statistically significant differences between men and women, either in total or when categorized by SBP TTR quartile of the overall population. Notably, in patients who were administered a single type of antihypertensive agent, women exhibited a lower SBP TTR compared with men (40% $\pm$ 30% vs 42% $\pm$ 32%, p = 0.054) despite statistical non-significance. Additionally, the SBP TTR for women was significantly lower than that for men among patients receiving two (p 0.001) or more medications (p = 0.016). Additional details are presented in Supplementary Tables 2,3.

There were 673 MACCE in the overall population after a follow-up period of 3.8 (3.3–4.4) years (Supplementary Table 4). The incidence rate of MACCE in the overall population was 20.7 per 1000 person-years (95% confidence interval [CI], 19.1–22.3), which was 17.4 per 1000 person-years (95% CI, 15.0–20.0) for women and 22.5 per 1000 person-years (95% CI, 20.5–24.6) for men (Table 2).

Each increment of one SD in SBP TTR was associated with a reduction in the MACCE risk in the overall population and the women subgroup in the unadjusted model (hazard ratio (HR), 0.84; 95%CI, 0.78–0.91; p 0.001, and HR, 0.83; 95% CI, 0.72–0.96; p = 0.013, respectively) and the adjusted model (adjusted HR, 0.89; 95% CI 0.82–0.97; p = 0.007, and adjusted HR, 0.85; 95% CI, 0.74–0.99; p = 0.039, respectively), but not in the male subgroup. Moreover, the relationship between SBP TTR increases and the risk of acute decompensated heart failure also exhibited significant sex differences (adjusted HR, 0.68; 95% CI, 0.51–0.92; p = 0.011 for women, and adjusted HR, 0.94; 95% CI, 0.78–1.13; p = 0.526 for men). Additional details are provided in Table 2 and Supplementary Fig. 1.

Restricted cubic splines were utilized to investigate the relationship, with the median SBP TTR of the respective population as the reference. As depicted in Fig. 1, an elevation in SBP TTR was inversely correlated with the risk of MACCE for the overall population and the women subgroup. However, for men, an inverse relationship between SBP TTR and MACCE risk was clearly observed only when SBP TTR exceeded 39%. Similar outcomes were observed in the relationship between SBP TTR and acute decompensated heart failure (Supplementary Fig. 2).

Fig. 1.

Relationship between systolic blood pressure time in target range (SBP TTR) and major adverse cardiovascular and cerebrovascular events in (A) the overall population and by sex: (B) women; (C) men. Restricted cubic splines were performed with the median SBP TTR as reference and the model was fully adjusted for age, race, treatment group, 10-year cardiovascular risk score, body mass index, renal insufficiency, and baseline SBP for women and men separately, with an additional adjustment for sex in the overall population.

To further explore this relationship, we stratified the participants via their respective SBP TTR quartiles: the overall population at 38% (14%–64%), women at 37% (14%–61%), and men at 39% (16%–67%). Elevated SBP TTR levels were correlative with a trend for reduced MACCE risk in the overall population and women, but in men, this trend was only observed when SBP TTR exceeded 39% (Fig. 2 and Supplementary Table 5).

Fig. 2.

Systolic blood pressure time in target range (SBP TTR) categories and risk of major adverse cardiovascular and cerebrovascular events in (A) the overall population and by sex: (B) women; (C) men. Kaplan–Meier estimates and adjusted hazard ratios (adjusted HR; with 95% confidence intervals (CIs)) for age, race, treatment group, 10-year cardiovascular risk score, body mass index, renal insufficiency, and baseline SBP for women/men and additionally for sex for the overall population. To accurately reflect the impact of sex differences, our analysis utilized quartile groupings based on the SBP TTR for distinct populations: the overall population at 38% (14%–64%), women at 37% (14%–61%), and men at 39% (16%–67%).

To further validate the sex-specific independent predictive role of SBP TTR on MACCE risk, we additionally adjusted for mean SBP or SBP variability in the adjusted model. After additional adjustment for mean SBP, a reduction in the risk of MACCE was observed with a one SD increment in SBP TTR in the overall population (adjusted HR 0.90; 95% CI, 0.82–0.98; p = 0.016) and women (adjusted HR 0.84; 95% CI, 0.72–0.98; p = 0.030), while for men, the association remained non-significant (adjusted HR 0.93; 95% CI, 0.84–1.04; p = 0.189). Similar sex differences were also seen in the risk for acute decompensated heart failure (adjusted HR, 0.85; 95% CI, 0.72–0.999; p = 0.049 for overall, adjusted HR, 0.64; 95% CI, 0.47–0.87; p = 0.004 for women, and adjusted HR, 0.97; 95% CI, 0.79–1.18; p = 0.732 for men). Similar results were noted after additional adjustment for SBP variability (Supplementary Tables 6,7).

Hypertension serves as a key factor in the pathogenesis of atherosclerosis via increasing vascular shear stress, which leads to arterial wall thickening, development of atherosclerosis, plaque vulnerability, and ultimately an elevated risk of cardiovascular events [19, 20, 21, 22]. SBP TTR serves as an indicator of effective blood pressure control, accounting for levels, stability, and duration of blood pressure. Higher SBP TTR signifies lower and more consistent levels of vascular shear stress, leading to a reduction in arterial medial thickening and preventing tears and fragmentation in the internal elastic lamina [23]. Moreover, higher levels of SBP TTR diminish the mechanical stimulation of the vascular wall, decreasing the activation of intracellular signaling pathways triggered by mechanical factors and stabilizing cellular functions [24]. Eventually, patients with hypertension benefit from more effective blood pressure control which reduces the risk of cardiovascular diseases.

A previous study has demonstrated an inverse relationship between SBP TTR and the risk of MACCE and acute decompensated heart failure in patients with hypertension, and our study has yielded similar results [17]. Notably, when first investigating sex-specific relationships, the trend of reduced MACCE and acute decompensated heart failure risk with increasing SBP TTR was observed only when SBP TTR exceeded 39%. These findings underscore the importance of implementing sex-specific and personalized blood pressure management strategies to improve cardiovascular outcomes.

Our study has elucidated a sex-specific relationship between SBP TTR and cardiovascular risk, which we hypothesize may be due to differences in sex hormones. Endogenous estrogen exerts cardioprotective effects by regulating nitric oxide (NO) biosynthesis and bioavailability, inhibiting the renin-angiotensin-aldosterone system (RAAS), modulating the sympathetic nervous system, and reducing endothelin-1 (ET-1) levels, thereby promoting vasodilation, inhibiting vascular remodeling, and decreasing arterial stiffness and cardiovascular risk [25, 26, 27, 28]. In postmenopausal women, estrogen deficiency also exacerbates endothelial dysfunction, promotes the rupture of arterial elastin, leads to collagen accumulation, and increases arterial stiffness [29]. In addition, estrogen deficiency is associated with the progression of metabolic syndrome, leading to adverse lipid distribution in elderly women [30]. Obesity, particularly a high BMI, is linked to adipose tissue dysfunction, elevated oxidative stress, activation of the RAAS system, and overactivity of the sympathetic nervous system, promoting chronic vascular inflammation and exacerbating cardiovascular risk [31]. These changes collectively result in greater arterial stiffness in postmenopausal women compared to age-matched men, with faster progression of vascular dysfunction, ultimately leading to higher cardiovascular risk.

In a large cross-sectional study involving 18,326 women, the proportion of postmenopausal women was approximately 90% in the 54–55 age group (n = 2324), 96% in the 56–57 age group (n = 2448), and 98% in the 58–59 age group (n = 2621) [32]. This indicates that the women in our study primarily belong to a postmenopausal population characterized by significantly reduced estrogen levels. These women also exhibited higher BMI levels compared to men, potentially due to adverse lipid distribution resulting from estrogen deficiency. The SBP TTR levels in women were also lower than those in men, despite using a consistent number of medications, indicating poorer blood pressure control in women. These findings suggest that the women in our study have a higher risk of hypertension and cardiovascular disease due to decreased estrogen levels. This presents greater challenges for optimizing blood pressure management and improving cardiovascular outcomes. Consequently, they may gain more significant benefits from effective blood pressure control reflected by increased SBP TTR, compared to men. In contrast, men only exhibit significant benefits after achieving higher SBP TTR levels (SBP TTR $>$39%).

The findings of this study underscore the importance of considering sex-specific differences in clinical blood pressure management strategies. Based on the findings of this study, we recommend implementing sex-specific management strategies for hypertensive patients in clinical practice. For female patients, particularly postmenopausal women, higher SBP TTR levels are strongly associated with reduced risks of MACCE and acute decompensated heart failure. Therefore, prioritizing SBP TTR stability at elevated levels is advised. Pharmacologic choices should favor agents proven to enhance blood pressure stability, with regular monitoring to ensure sustained SBP TTR over time. For male patients, while elevated SBP TTR also provides protective benefits, the clinical focus should be placed on maintaining higher thresholds (e.g., above 39%). Implementing sex-specific follow-up intervals and blood pressure monitoring strategies may enhance SBP TTR control, thereby improving cardiovascular outcomes.

Our study has several limitations. First, the population was subject to rigorous blood pressure management, which limited fluctuations in blood pressure and converged the mean blood pressure and time in the target range. Second, the method for SBP TTR calculation is complex and the results are significantly affected by the selection of time periods for the analysis. Finally, this study is a post hoc analysis based on data from the SPRINT trial, a prospective randomized controlled trial that targeted a high cardiovascular risk population without a history of diabetes or stroke, which may have influenced the generalizability of the results to a large population.