Effect of Hypertension Duration on the Associations Between Intensive Blood Pressure Control and Cardiac, Vascular, and Kidney Organ Damage

Abstract

Background

Intensive systolic blood pressure (SBP) treatment could mitigate the increased cardiovascular disease risk associated with long‐standing hypertension. Target organ damage serves as a critical intermediate phenotype in hypertension‐related sequelae. However, the associations of hypertension duration on the cardiac, vascular, and kidney organ damage improvement of intensive SBP treatment remains to be elucidated.

Methods

A total of 8442 STEP (Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients) participants with complete hypertension duration data were categorized by hypertension duration ≤5 years, 5~10 years, 10~15 years, and >15 years. Patients were randomly assigned to intensive or standard SBP treatment groups after enrollment. Odds ratios (ORs) for left ventricular hypertrophy, arterial stiffness, and chronic kidney disease were calculated using a logistic regression model, testing for effect modification by hypertension duration.

Results

For left ventricular hypertrophy, no evidence showed heterogeneity among groups with different hypertension duration in the treatment effect between intensive versus standard treatment for either new‐onset or improvement (both P for interaction >0.05). For arterial stiffness, intensive versus standard SBP treatment showed significantly greater benefits in preventing new‐onset arterial stiffness in early‐stage (≤5 years: 29.46% versus 36.81%; OR, 0.67 [95% CI, 0.47–0.95]) and long‐standing hypertension (>15 years: 30.88% versus 41.23%; OR, 0.62 [95% CI, 0.45–0.84]) compared with the intermediate stage (P for interaction=0.03). For kidney events, no treatment interaction effects or significant associations with hypertension duration were observed (P for interaction >0.05).

Conclusions

Intensive SBP treatment showed greater benefits in preventing new‐onset arterial stiffness in both early‐stage (≤5 years) and long‐standing (>15 years) hypertension, whereas no heterogeneity was identified among groups with hypertension for left ventricular hypertrophy and kidney events.

REGISTRATION

URL: https://www.clinicaltrials.gov; Unique identifier: NCT03015311.

Nonstandard Abbreviations and Acronyms

baPWV

brachial‐ankle pulse wave velocity

STEP

Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients

Clinical Perspective.

What Is New?

• Intensive systolic blood pressure treatment preserved left ventricular hypertrophy regression proportions regardless of hypertension duration.

• Intensive systolic blood pressure treatment showed greater benefits in preventing new‐onset arterial stiffness in both early‐stage (≤5 years) and long‐standing (>15 years) hypertension.

What Are the Clinical Implications?

• Our findings support the use of intensive blood pressure treatment regardless of hypertension duration; early intensive intervention may prevent target organ damage, and aggressive treatment in long‐standing hypertension could overcome the structural resistance typically observed in prolonged disease, suggesting that it is never too early or too late to optimize blood pressure control.

Hypertension is the major modifiable risk factor for cardiovascular morbidity and mortality, accounting for an estimated 10.8 million deaths annually. ¹ High blood pressure (BP) engenders structural alterations in various organs resulting in organ dysfunction, such as heart, vasculature, and kidney, referred to as target organ damage (TOD). ² These functional and structural changes serve as critical intermediate phenotypes in the progression to overt cardiovascular events, leading current guidelines to emphasize TOD evaluation as an essential component of hypertension management. ³ , ⁴ , ⁵

The duration of hypertension exposure represents a crucial yet underexplored determinant of cardiovascular risk. Hypertension duration, which reflects the cumulative exposure to high BP, is independently associated with increased risk of cardiovascular diseases (CVDs). ⁶ , ⁷ This temporal dimension of BP exposure may be particularly relevant for TOD, as prolonged pressure overload can trigger progressive tissue remodeling and potentially irreversible structural changes. ⁸ Intensive systolic BP (SBP) treatment has emerged as a promising strategy to reduce CVD risks ⁹ , ¹⁰ and protect against the development of TOD, including left ventricular hypertrophy (LVH) ¹¹ , ¹² and arterial stiffness. ¹³ , ¹⁴ Based on these rigorous clinical trial results, intensive SBP control has been recommended in current clinical practice as gold‐standard treatment in several guidelines. However, its effectiveness in preventing or reversing TOD across different durations of hypertension remains unknown.

Our previous study demonstrated that the intensive SBP treatment instead of the standard SBP treatment could attenuate the increased cardiovascular risk associated with long‐standing hypertension. ¹⁵ However, the pathophysiological relationships between hypertension duration and treatment response remain unclear, particularly regarding how specific target organs respond to intensive treatment across varying periods of hypertension exposure. This knowledge gap is clinically significant as understanding how the duration of hypertension influences the responsiveness of specific target organs to intensive treatment could provide clues to identify optimal therapeutic windows when intensive therapy might yield the greatest benefit for preventing or reversing organ damage.

Here, using data from the STEP (Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients) trial, ⁹ this study aims to investigate how hypertension duration influences the effect of intensive blood pressure control on 3 key manifestations of TOD: LVH, arterial stiffness, and kidney function. By analyzing hypertension duration as an effect modifier, we seek to determine whether the association between treatment intensity and TOD varies across different durations of hypertension exposure.

Methods

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Study Design and Population

This study was a post hoc analysis of data from the STEP trial. STEP was a multicenter, randomized controlled trial that compared the effects of intensive (SBP target, 110–130 mm Hg) and standard (SBP target, 130–150 mm Hg) SBP control on cardiovascular outcomes in 8511 patients with hypertension at 42 clinical centers in China (Clinical Trial Registration No. NCT03015311). The study design, rationale, and protocol were published previously. ⁹ , ¹⁶ The STEP trial was approved by the Ethics Committee of Fuwai Hospital and all collaborating centers. All study participants provided written informed consent.

The inclusion and exclusion criteria used in the present study were identical to those in the STEP trial. Briefly, participants who were aged 60 to 80 years and had essential hypertension (SBP 140–190 mm Hg or currently taking antihypertensive medication) were included. Patients were excluded if they had a history of ischemic or hemorrhagic stroke. Moreover, 69 patients who had missing hypertension duration data were excluded. Finally, 8442 eligible participants were included in the present study (Figure 1).

Figure 1. Flow diagram showing the study population enrollment and analysis process.

baPWV indicates brachial‐ankle pulse wave velocity; and BMP, basic metabolic panel.

Intervention

Participants were randomly assigned to intensive treatment (SBP target: 110–<130 mm Hg) or standard treatment (SBP target: 130–<150 mm Hg) using a central computerized randomization program. Follow‐up visits were scheduled monthly for the first 3 months and quarterly thereafter until the final visit or death. The detailed antihypertensive treatment algorithm has been previously published. ⁹

Hypertension Duration

Hypertension duration was calculated from the initial diagnosis date to study enrollment. For incomplete dates, January 1 was used when only the year was known, and the first day of the month was used when only month and year were available. Hypertension duration was assessed at study enrollment through participant self‐report during the screening interview, when patients were asked about the time since their initial hypertension diagnosis. This information was collected as part of the standard STEP trial recruitment protocol. A structured questionnaire asked participants (1) hypertension history (yes/no/unclear), (2) specific diagnosis date (year/month/day), (3) BP values at diagnosis and most recent measurements, and (4) antihypertensive medication use and start date. Although self‐reported diagnostic history was the primary source of duration information, participants' medical records were available during the screening process for reference by the enrolling physicians. Given the pragmatic nature of the trial design and the large sample size, formal verification protocols for comparing self‐reported duration against comprehensive medical record history were not implemented. We acknowledge this as a limitation in our discussion, as the accuracy of self‐reported hypertension duration may vary.

Covariates

Sociodemographic characteristics, comorbidities, and medication use were collected by STEP physicians. Body mass index was calculated by dividing weight (kg) by the square of height (m). Smoking and drinking status (current/former/never) were assessed. Current smokers were defined as those who had smoked at least 1 cigarette per day for >6 months. Current alcohol consumption was defined as consuming alcohol at least once per month for >6 months. The 10‐year CVD risk was estimated using the Framingham Risk Score. ¹⁷

Office BP was measured at baseline and every visit, which is monthly for the first 3 months and 3 months afterwards using a validated automated device (HBP‐1100U; Omron Healthcare). A standard cuff size (regular adult) was used for BP measurements. After 5 minutes of rest, 3 measurements were taken 1 to 2 minutes apart and averaged. BP was initially measured in both the left and right arms, and subsequent measurements were taken from the arm with the higher reading. Laboratory tests including creatinine, fasting blood glucose, and lipid profiles were performed at baseline and annually.

Ascertainment of LVH

A standard 12‐lead ECG was obtained at baseline and at the 3‐year follow‐up following standardized procedures across study sites. All ECGs were interpreted centrally by 2 experienced observers blinded to patient characteristics and treatment allocation. LVH was defined by sex‐specific Peguero–Lo Presti criteria (≥2300 μV for women, ≥2800 μV for men). Peguero–Lo Presti value was computed as summing the deepest S wave amplitude of any lead and the S wave amplitude of lead V4 using the PR segment as the baseline. ¹⁸ The sum of S wave amplitude of any lead and S wave amplitude of lead V4 was also examined as a continuous variable (referred to from now onwards as the Peguero–Lo Presti index). New‐onset LVH was defined as patients without LVH at baseline who developed LVH at the 3‐year follow‐up examination. Regression in LVH was defined as patients with LVH at baseline but without LVH at the 3‐year follow‐up.

Ascertainment of Arterial Stiffness

Brachial‐ankle pulse wave velocity (baPWV) was measured at baseline and 3‐year follow‐up using an automated waveform analyzer (BP‐203RPEIII; Omron Healthcare). Participants were examined in supine position after 5 minutes of rest at 22 to 25 °C. Electrodes were placed on wrists, with a microphone at the left sternal edge and pneumatic cuffs on both arms (2–3 cm above cubital fossa) and ankles (1–2 cm above medial malleolus). Volume pulse form and blood pressure were determined using sensors, and pulse volume waveform was recorded using a semiconductor pressure sensor. Two sets of measurements were obtained for each study participant, and the second set was recorded consistent with our institutional protocol to minimize measurement variability associated with initial patient adjustment to the supine position and measurement apparatus. The maximum baPWV value on each side was used for the analyses.

Arterial stiffness was defined as baPWV of ≥1800 cm/s. ¹⁹ New‐onset arterial stiffness was defined as patients without arterial stiffness at baseline who developed arterial stiffness at the 3‐year follow‐up examination. Regression in arterial stiffness was defined as patients with arterial stiffness at baseline but without arterial stiffness at the 3‐year follow‐up.

Definition of the Kidney Event

Creatinine was measured in the central laboratory (Beijing CIC clinical laboratory) using an enzymatic assay. Samples were processed within 2 hours of collection, centrifuged, and the serum was stored at −80 °C until analysis. Results from baseline and the past year were used to evaluate kidney functions at these 2 time points.

The kidney event was defined a composite of a ≥50% decrease in the estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease (CKD) at baseline, a ≥30% decrease in the eGFR to <60 mL/min/1.73 m² in patients without CKD at baseline, or a serum creatinine increase of >1.5 mg/dL in men or >1.3 mg/dL in women, in consistent with the definition in the STEP trial. ⁹ The eGFR was calculated using the Modification of Diet in Renal Disease equation for Chinese patients. ²⁰

Statistical Analysis

Continuous variables are presented as the mean±SD and categorical variables as the number (percentage).

Participants were divided into 4 groups according to the threshold of hypertension duration (≤5 years, 5~10 years [>5 years and ≤10 years], 10~15 years [>10 years and ≤15 years], and >15 years). Baseline characteristics were compared across treatment groups and across hypertension duration groups within each treatment arm using 1‐way ANOVA for continuous variables and chi‐square test for categorical variables. Missing values for smoking status (n=17), alcohol consumption (n=17), laboratory data (fasting blood glucose and lipids, n=213), and CVD history (n=32) were imputed using multiple imputation (mice package, version 3.16.0). This approach was selected over complete‐case analysis to maximize statistical power and minimize potential selection bias from excluding participants with missing data. We acknowledge this approach's limitations, including the assumption that data are missing at random, which cannot be definitively verified. However, it is applied only to the covariates.

To evaluate whether hypertension duration modifies the associations between intensive SBP treatment and TODs, the effects of intensive versus standard SBP control on the aforementioned target organ outcomes (LVH/arterial stiffness development and regression, and kidney events) were also investigated among different hypertension duration groups. All models were presented as crude, and adjusted for clinical centers, age, and sex, baseline SBP level, baseline glucose level, baseline total cholesterol level, baseline triglyceride level, baseline eGFR, history of CVDs, smoking status, drinking status, and proportion of patients achieving SBP targets. The associations were also analyzed using hypertension duration as a continuous variable with cubic spline models. Peguero–Lo Presti value, baPWV, and eGFR were also analyzed on a continuous scale in addition to the categorical analysis. Then, we determined the interaction effect between the SBP treatment and hypertension duration by including the product term (SBP treatment group × hypertension duration group) in the logistic regression models with a likelihood ratio test. P for trend was calculated by applying the hypertension duration groups as continuous variable in the model. Besides, we conducted sensitivity analyses using percentage changes in Peguero–Lo Presti and baPWV values. Based on the distribution of normalized changes (mean±SD: 1.10 ± 0.47 for Peguero–Lo Presti; 1.06 ± 0.18 for baPWV), we defined LVH development/regression as ≥50% change in Peguero–Lo Presti values and arterial stiffness development/regression as ≥20% change in baPWV values. These thresholds were chosen to capture meaningful changes while accounting for natural measurement variability.

All analyses were performed using R version 4.3.1. A 2‐sided P value of <0.05 was considered statistically significant.

Results

Baseline Characteristics

A total of 8442 patients were included in the analyses (mean age 66.24±4.83 years; 53.45% women; average follow‐up time 3.17 years). Participants were divided into 4 groups based on their hypertension duration: 2028 with ≤5 years, 1934 between 5 to 10 years, 1645 between 10 to 15 years, and 2835 >15 years. Baseline characteristics were compared across different hypertension duration groups and SBP treatment groups (Table1). For hypertension duration, patients with a longer duration of hypertension were slightly older and had modestly higher body mass index, higher SBP, higher fasting blood glucose, and lower eGFR, and a higher proportion of patients had a history of diabetes or CVDs at baseline. For SBP treatment groups, patient baseline characteristics were comparable. For the analysis of LVH, arterial stiffness, and kidney events, 7998, 5361, and 8230 participants were included, respectively. Their baseline characteristics were compared across different hypertension duration groups and SBP treatment groups (Table S1–S3), which were similar to the whole population. The prevalence of achievement of intensive target (110–<130 mm Hg) or standard target (130–<150 mm Hg) of SBP in the 4 study groups was provided in Table S4.

Table 1.

Baseline Characteristics

Hypertension duration	≤5 y		5~10 y		10~15 y		>15 y		P value*	P value†	P value‡
SBP treatment	Intensive	Standard	Intensive	Standard	Intensive	Standard	Intensive	Standard
No. (%)	1038 (24.66)	990 (23.39)	948 (22.52)	986 (23.30)	796 (18.91)	849 (20.06)	1428 (33.92)	1407 (33.25)
Age, y	65.7±4.74	65.84±4.68	65.68±4.55	65.79±4.74	65.81±4.79	65.8±4.61	67.11±5.02	67.26±4.9	<0.001	<0.001	0.36
Female sex	531 (51.16)	495 (50.00)	504 (53.16)	515 (52.23)	438 (55.03)	467 (55.01)	756 (52.94)	806 (57.29)	0.43	0.003	0.37
Body mass index, kg/m2	25.17±3.02	25.22±3.14	25.37±3.11	25.46±3.14	25.77±3.2	25.58±3.06	25.78±3.25	26.01±3.25	<0.001	<0.001	0.26
Heart rate, bpm	73.60±10.24	73.35±10.00	73.53±10.03	73.27±10.23	73.63±10.18	72.99±10.03	73.84±10.88	73.72±10.67	0.51	0.40	0.21
Systolic BP, mm Hg	144.45±16.26	143.60±15.85	145.31±16.68	145.86±16.29	146.05±16.68	146.14±16.49	147.90±17.02	147.63±16.91	<0.001	<0.001	0.69
Diastolic BP, mm Hg	82.33±10.36	81.69±10.36	82.85±10.61	82.8±10.63	82.91±10.72	82.82±10.58	82.63±10.83	81.95±10.49	0.58	0.83	0.08
Mean arterial pressure, mm Hg	103.04±10.84	102.33±10.64	103.67±11.09	103.82±10.93	103.96±11.22	103.92±10.89	104.39±11.13	103.84±10.84	0.003	0.002	0.19
Smoking status									0.69	<0.001	0.94
Current	184 (17.73)	191 (19.29)	155 (16.35)	161 (16.33)	127 (15.95)	156 (18.37)	217 (15.20)	174 (12.37)
Former	123 (11.85)	127 (12.83)	106 (11.18)	109 (11.05)	102 (12.81)	103 (12.13)	179 (12.54)	165 (11.73)
Never	731 (70.42)	672 (67.88)	687 (72.47)	716 (72.62)	567 (71.23)	590 (69.49)	1032 (72.27)	1068 (75.91)
Drink status									0.57	0.01	0.74
Current	294 (28.32)	292 (29.49)	255 (26.90)	263 (26.67)	197 (24.75)	229 (26.97)	367 (25.70)	329 (23.38)
Former	49 (4.72)	58 (5.86)	44 (4.64)	41 (4.16)	43 (5.40)	51 (6.01)	80 (5.60)	83 (5.90)
Never	695 (66.96)	640 (64.65)	649 (68.46)	682 (69.17)	556 (69.85)	569 (67.02)	981 (68.70)	995 (70.72)
Fasting blood glucose, mmol/L	6.00±1.50	6.02±1.51	6.06±1.62	6.16±1.69	6.15±1.66	6.18±1.60	6.13±1.55	6.27±1.60	0.03	<0.001	0.02
Total cholesterol, mmol/L	4.89±1.10	4.9±1.01	4.96±1.13	4.89±1.07	4.96±1.12	4.88±1.12	4.8±1.09	4.85±1.06	0.03	0.30	0.58
Low‐density lipoprotein cholesterol, mmol/L	2.7±0.85	2.75±0.84	2.72±0.89	2.68±0.87	2.74±0.88	2.7±0.90	2.62±0.89	2.67±0.87	0.03	0.05	0.68
High‐density lipoprotein cholesterol, mmol/L	1.29±0.33	1.27±0.29	1.27±0.31	1.26±0.31	1.27±0.31	1.25±0.3	1.23±0.3	1.25±0.3	<0.001	0.21	0.55
Triglyceride, mmol/L	1.52±1.08	1.5±0.87	1.62±1.13	1.6±1.16	1.67±1.26	1.64±1.11	1.62±1.05	1.61±0.95	0.03	0.01	0.48
Serum uric acid, mmol/L	340.92±85.33	341.46±87.29	346.75±86.81	343.64±89.13	349.79±93.64	348.85±88.56	352.26±89.46	352.01±91.44	0.002	0.002	0.69
eGFR, ml/(min/1.73 m2)	111.63±22.95	109.50±23.35	110.43±24.19	110.34±23.62	109.11±24.84	109.16±24.44	107.98±24.58	107.11±24.10	<0.001	0.004	0.12
eGFR <60 ml/(min/1.73 m2)	11 (1.09)	12 (1.24)	14 (1.52)	13 (1.35)	14 (1.81)	12 (1.45)	28 (2.01)	33 (2.40)	0.34	0.10	0.89
Medical history
Diabetes mellitus	156 (15.03)	134 (13.54)	162 (17.09)	174 (17.65)	151 (18.97)	168 (19.79)	324 (22.69)	349 (24.80)	<0.001	<0.001	0.46
Cardiovascular disease History	153 (14.74)	157 (15.86)	142 (14.98)	164 (16.63)	133 (16.71)	154 (18.14)	315 (22.06)	271 (19.26)	<0.001	0.13	1.00
Hypertension treatment	968 (93.26)	937 (94.65)	900 (94.94)	925 (93.81)	758 (95.23)	809 (95.29)	1359 (95.17)	1315 (93.46)	0.14	0.28	0.37
No. of antihypertensive agents	1.34±0.66	1.25±0.6	1.43±0.65	1.3±0.63	1.51±0.71	1.41±0.68	1.62±0.72	1.47±0.74	<0.001	<0.001	<0.001
Framinham risk score ≥15%	754 (74.58)	706 (73.54)	704 (76.52)	740 (77.16)	573 (74.22)	622 (75.21)	1118 (80.78)	1107 (80.80)	<0.001	<0.001	0.94

Values are expressed in n (%) or mean ± SD.

BP indicates blood pressure; and eGFR, estimated glomerular filtration rate.

^* P values were calculated for P value for trend for hypertension duration among patients in the intensive treatment group.

^† P values were calculated for P value for trend for hypertension duration among patients in the standard treatment group.

^‡ P values were calculated for between‐group differences in the intensive treatment group and the standard treatment groups.

Duration of Hypertension, SBP Treatment, and LVH

Of 7998 patients analyzed, 1309 (16.37%) had baseline LVH. Among those without baseline LVH, 699 (10.45%) developed new‐onset LVH. Of patients with baseline LVH, 497 (37.97%) showed regression.

We next investigated whether hypertension duration modifies treatment effect on LVH of intensive SBP treatment. First, intensive SBP treatment was associated with a significantly reduced risk of new LVH (adjusted odds ratio [OR], 0.72 [95% CI, 0.62–0.85]) and increased proportion of regression of LVH (adjusted OR, 1.30 [95% CI, 1.03–1.65]). There was no evidence of effect modification by hypertension duration on the treatment effect of intensive versus standard SBP treatment for new and regressed LVH (P for interaction >0.05; Figure 2 and Figure S1).

Figure 2. Forest plot showing the treatment effects on new and regressed LVH of intensive versus standard SBP treatment by hypertension duration groups.

A, New‐onset LVH. B, Regression of LVH. Multivariable model was adjusted for clinical centers, age, and sex, baseline SBP level, baseline glucose level, baseline total cholesterol level, baseline triglyceride level, baseline estimated glomerular filtration rate, history of cardiovascular diseases, smoking status, drinking status, and whether patients achieved SBP targets. New‐onset LVH was compared in those without baseline LVH, and regression of LVH was compared in those with baseline LVH, separately. LVH indicates left ventricular hypertrophy; and SBP, systolic blood pressure.

Duration of Hypertension, SBP Treatment, and Arterial Stiffness

Of 5361 patients analyzed, 2368 (44.17%) showed arterial stiffness at baseline. Among those without baseline arterial stiffness, 1034 (33.55%) developed new‐onset arterial stiffness. Of patients with baseline arterial stiffness, 573 (24.20%) showed regression.

The modification effect of hypertension duration on treatment effect on arterial stiffness of intensive SBP treatment was then analyzed. We observed a significant interaction between hypertension duration groups and SBP treatment groups (P for interaction=0.03). Patients exhibited higher benefit from intensive SBP treatment with hypertension duration ≤5 years (adjusted OR, 0.67 [95% CI, 0.47–0.95]) or >15 years (adjusted OR, 0.62 [95% CI, 0.45–0.84]; Figure 3A and Figure S2). For patients with hypertension duration ≤5 years, those under intensive SBP treatment showed the lowest incidence of new‐onset arterial stiffness (29.46% versus 36.81%). The intermediate duration groups showed comparable proportions between intensive versus standard SBP treatments (5–10 years: 37.46% versus 34.90%; 10–15 years: 32.23% versus 33.67%). For those with duration >15 years, those under standard SBP treatment showed higher incidence of new‐onset arterial stiffness (30.88% versus 41.23%). There was no suggestion of heterogeneous treatment effect of intensive versus standard SBP treatments across different hypertension duration groups for regressed arterial stiffness (P for interaction >0.05; Figure 3B).

Figure 3. Forest plot showing the treatment effects on new and regressed arterial stiffness of intensive versus standard SBP treatment by hypertension duration groups.

A, New‐onset arterial stiffness. B, Regression of arterial stiffness. Multivariable model was adjusted for clinical centers, age, and sex, baseline SBP level, baseline glucose level, baseline total cholesterol level, baseline triglyceride level, baseline estimated glomerular filtration rate, history of cardiovascular diseases, smoking status, drinking status, and whether patients achieved SBP targets. New‐onset arterial stiffness was compared in those without baseline arterial stiffness, and regression of arterial stiffness was compared in those with baseline arterial stiffness, separately. AS indicates arterial stiffness; and SBP, systolic blood pressure.

Duration of Hypertension, SBP Treatment, and Kidney Events

Among 8537 patients analyzed, 137 (1.16%) had CKD at baseline, and 95 (0.64%) developed kidney events.

Intensive or standard SBP treatment did not show a significant effect on the occurrence of kidney events after multivariable adjustment (Figure S3). Also, we observed no evidence suggesting modification of hypertension duration on intensive SBP treatment effect on kidney events (P for interaction >0.05).

Discussion

In the present study, we found that intensive BP treatment effects on TOD varied by hypertension duration for some, but not all, outcomes examined. For LVH, patients receiving intensive BP treatment showed comparable regression proportions across all hypertension duration groups, whereas standard treatment showed progressively reduced regression proportions with longer duration. For arterial stiffness, intensive treatment showed the greatest benefits in preventing new‐onset arterial stiffness in patients with hypertension duration ≤5 years or >15 years compared with standard treatment. For kidney events, no heterogeneous treatment effect of intensive versus standard SBP treatments was observed across different hypertension duration groups. However, the 4‐year follow‐up period may have been relatively short to detect changes in CKD progression.

Recently, Lembo et al. ²¹ found that delayed initiation of antihypertensive therapy is independently associated with worse TOD outcomes. Their study showed that patients with time‐to‐therapy >2 years had significantly higher risks of LVH, carotid plaques, and CKD compared with those who received timely treatment. Although time‐to‐therapy is not exactly the same as hypertension duration, it emphasized that timing of optimal BP management influences target organ outcomes. Our study extends this concept by demonstrating that even among patients with established hypertension of varying durations, intensive BP control can still provide benefits, though the magnitude of benefit may vary by duration and target organ.

The CARDIA (Coronary Artery Risk Development in Young Adults) study showed that early‐onset hypertension was associated with significantly higher risk of LVH compared with late‐onset hypertension, indicating the cumulative burden of high BP on cardiac structure. ²² , ²³ Given that LVH regression has been associated with improved cardiovascular outcomes, ²⁴ the timing of therapeutic intervention may be crucial for cardiovascular risk reduction in patients with hypertension. Notably, we found that intensive BP treatment appeared to preserve LVH regression proportions regardless of hypertension duration, whereas standard treatment showed progressively LVH improvement with longer duration. This suggests that aggressive BP control may overcome the structural resistance typically observed in long‐standing hypertension. This implication is also supported by mechanistic studies that sustained pressure overload leads to progressive myocardial fibrosis and cardiac remodeling. ²⁵ , ²⁶

Previous studies have demonstrated that arterial stiffness progressively increases with age and is accelerated by prolonged exposure to high BP. ²⁷ Notably, intensive BP treatment showed distinct benefits in preventing new‐onset arterial stiffness at different stages of hypertension, with the most pronounced in patients with hypertension duration ≤5 years or >15 years. This differential treatment effect might be explained by distinct pathophysiological mechanisms. In early‐stage hypertension (≤5 years), vascular changes are primarily functional and more responsive to intensive BP control. ²⁸ In line with this, we found that intensive treatment achieved the lowest incidence of new‐onset arterial stiffness in this group. In contrast, long‐standing hypertension is characterized by structural modifications. ²⁸ Patients under standard treatment showed accelerated progression of arterial stiffness, whereas intensive treatment maintained proportions similar to those with shorter disease duration, suggesting that vascular remodeling may continue to progress under standard treatment but could be stabilized through more intensive intervention. ²⁹ These findings highlight the importance of intensive BP control in both preventing arterial stiffness in early‐stage hypertension and stabilizing vascular remodeling in long‐standing disease.

Previous study showed that prolonged hypertension was associated with CKD. ³⁰ We did not observe modification effect of hypertension duration on the treatment effect on kidney events. This suggests that although prolonged hypertension may contribute to the development of CKD, the progression of kidney function might be influenced more by other factors.

Study Strengths and Limitations

To the best of our knowledge, this is the first post hoc analysis to systematically evaluate the effect of hypertension duration on the association between intensive versus standard SBP treatment and TOD. The strengths of our study include the following. First, our analysis leveraged data from the STEP trial, ⁹ a large, well‐designed randomized controlled trial with rigorous BP targets and standardized outcome measurements, providing robust data for examining treatment effects across duration groups. Second, our study provided a systematical investigation on TODs, including LVH assessment via ECG, arterial stiffness evaluation through baPWV, and kidney function monitoring—provided a comprehensive assessment of TOD.

Our study has several limitations. First, hypertension duration was determined through self‐reporting, although verified by medical records, which could introduce recall bias. Second, as ECG and baPWV measurements were available only at baseline and final follow‐up, we were unable to perform time‐to‐event analyses, limiting our ability to examine the temporal progression of LVH and arterial stiffness. Third, LVH was detected by ECG in this study, which has a low sensitivity. Besides, the amplitude of ECG waves is affected by several confounding factor. Fourth, given that the hypertension duration is not primarily involved in the original trial design, this study has the inherent limitations of post hoc analyses, including potential issues with statistical power and bias. Fifth, for PWV measurements, the upper extremity with the larger value was recorded, which can induce measurement bias. Additionally, potential selection bias from participants with missing outcome data was not assessed through sensitivity analyses. Also, we used data from baseline and final year rather than repeated yearly measurements in our analyses, which may have provided more detailed information about the trajectory of kidney function changes over time. However, in this study, we chose to focus on baseline‐to‐final measurements to assess overall changes during the entire follow‐up period. Last but not least, our study lack in data on prior antihypertension treatment type duration, as well as the exact BP levels before the trial entry, which is another important aspect of BP burden.

Conclusions

Our study suggested that intensive SBP treatment showed greater benefits in preventing new‐onset arterial stiffness in both early‐stage (≤5 years) and long‐standing (>15 years) hypertension, whereas no heterogeneity was found among groups with hypertension for LVH and kidney events.

Sources of Funding

This work was supported by Beijing Research Ward Excellence Program, BRWEP(Project ID, BRWEP2024W012060100), National Natural Science Foundation of China (Project ID, 82330013), Beijing Municipal Science & Technology Commission(Project ID, Z231100004623009, Z241100009024041), Beijing Natural Science Foundation(Project ID, L248105), Beijing Hospitals Authority Clinical medicine Development of special funding support(code, ZLRK202511).

Disclosures

None.

Supporting information

Tables S1–S4

Figures S1–S3

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