Abstract
Background:
Arterial stiffening increases with age and blood pressure and is associated with cardiovascular disease (CVD), but the relationship between blood pressure lowering and arterial stiffening is still uncertain, especially in older people. This study aimed to evaluate the effect of intensive blood pressure treatment on the progression of arterial stiffness and risk of CVD in older patients with hypertension.
Methods:
The Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial was a multicenter, randomized, controlled trial performed at 42 clinical centers throughout China, and 8511 patients aged 60–80 years with essential hypertension were enrolled and randomly assigned to systolic blood pressure (SBP) target of 110 mmHg to <130 mmHg (intensive treatment) or 130 mmHg to <150 mmHg (standard treatment). Patients underwent repeated examinations of the brachial-ankle pulse wave velocity (baPWV) and ankle-brachial index (ABI) at baseline, and the arterial stiffness was evaluated at the 3-year follow-up. A total of 5339 patients who had twice repeated measurements were included in this study. Changes in arterial stiffness between the intensive and standard treatment groups were analyzed using a multivariate linear regression model. The Cox proportional hazard regression model was used to evaluate the effect of intensive treatment on primary CVD outcomes.
Results:
The changes in baPWV were 61.5 cm/s (95% confidence interval [CI]: 49.8–73.2 cm/s) in the intensive treatment group and 98.4 cm/s (95% CI: 86.7–110.1 cm/s) in the standard treatment group (P <0.001). Intensive treatment significantly delayed the progression of arterial stiffness, with an annual change of 23.1 cm·s–1·year–1 vs. 36.7 cm·s–1·year–1 of baPWV in the intensive and standard treatment groups, respectively. During a median follow-up period of 3.36 years, primary CVD outcomes occurred in 77 (2.9%) patients in the intensive treatment group compared with 93 (3.5%) in the standard treatment group. Intensive treatment resulted in a significantly lower CVD risk in patients aged 70–80 years or with SBP <140 mmHg.
Conclusion:
Intensive blood pressure control with an SBP target of 110 mmHg to <130 mmHg could delay the progression of arterial stiffness and reduce the risk of CVD in older patients with hypertension.
Clinical trial registration:
Keywords: Hypertension, Arterial stiffness, Cardiovascular disease, Older people, Blood pressure, Pulse wave velocity
Introduction
Aging is a dominant risk factor for cardiovascular disease (CVD) and hypertension.[1,2] The increased arterial stiffness, usually accompanied by the aging of vascu latures and endothelial dysfunctions, plays a central role in CVD among older people.[3] Aortic pulse wave velocity (PWV) elevation has been recognized to correlate significantly with blood pressure progression[4,5] and cardiovascular events.[6,7] Carotid-femoral pulse wave velocity (cfPWV) is the gold standard for the evaluation of arterial stiffness, but it is not applicable to large clinical studies due to technical and equipment limitations. Brachial ankle pulse wave velocity (baPWV) has the advantages of being economical, non-invasive, and reproducible, which has been reported to be significantly correlated with cfPWV.[8,9] Higher baPWV has a reverse relationship with blood pressure control in response to antihypertensive treatments.[10]
The optimal systolic blood pressure (SBP) treatment target in hypertensive patients remains inconsistent according to current clinical guidelines. China has the most population in the world, including about 18.9% of the population older than 60 years, and the problem of aging is inescapable. Recently, the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial showed that intensive treatment (target, 110 mmHg ≤SBP <130 mmHg) resulted in a lower incidence of cardiovascular events than standard treatment (target, 130 mmHg ≤SBP <150 mmHg) among older patients with hypertension.[11] A post-hoc analysis of the STEP trial showed that arterial stiffening preceded blood pressure elevation and led to difficulty in reaching target SBP under intensive treatment.[12] A secondary analysis of the Systolic Blood Pressure Intervention Trial (SPRINT) showed that intensive treatment (target, SBP <120 mmHg) was associated with improvements in estimated aortic stiffness after 12 months of follow-up and improved risk prediction for incident CVD events and mortality.[13] An extended SPRINT-HEART study combined cardiovascular magnetic resonance imaging of aortic stiffness and suggested that improvement in aortic stiffness might be one of the mechanisms contributing to the CVD benefits of intensive blood pressure treatment.[14] However, the relationship between blood pressure and PWV is an interesting but complex topic in its own right, which needs more investigation in older people.
Therefore, in the present study, we used the longitudinal data of baPWV and ankle-brachial index (ABI) from the STEP trial to evaluate whether intensive treatment could delay or reverse the progression of arterial stiffness and to investigate the mechanistic link between blood pressure control, arterial stiffness, and the reduction of cardiovascular events in older hypertensive patients aged 60–80 years.
Methods
Study design and participant population
This study was a post-hoc analysis of the STEP trial, and the details of the study design and rationale for STEP trial have been published previously.[11,15] Briefly, the STEP trial was a prospective, multicenter, randomized controlled trial (No. NCT03015311) aiming to compare two SBP treatment targets (an intensive target of 110 mmHg ≤SBP <130 mmHg vs. a standard target of 130 mmHg ≤SBP <150 mmHg). A total of 8511 patients were enrolled at 42 clinical centers throughout China from January 10 to December 31, 2017, and randomly assigned to the intensive treatment group (n = 4243) or the standard treatment group (n = 4268). The geographical distribution and affiliations of the STEP group members were presented in Supplementary Table 1, http://links.lww.com/CM9/B747. All eligible patients were required to be aged 60–80 years and have hypertension with 140 mmHg ≤SBP ≤190 mmHg during three screening visits or be taking antihypertensive medication. Patients with a history of ischemic or hemorrhagic stroke were excluded. The inclusion and exclusion criteria were shown in Supplementary Methods, http://links.lww.com/CM9/B747. After randomization, all participants were scheduled for follow-up once monthly for the first three months and every three months thereafter until the end of the study (December 31, 2020). This study was approved by the Ethics Committee of the Fuwai Hospital and collaborating centers (No. 2016-838). All participants provided written informed consent.
At baseline and during the 3rd follow-up year (from December 17, 2019 to December 31, 2020) of the STEP trial, enrolled patients underwent repeated measurements of baPWV and ABI to evaluate arterial stiffness. In the present analysis, patients who did not complete arterial stiffness measurements at baseline (n = 799 in the intensive group and n = 847 in the standard group) or at the follow-up year (n = 715 in the intensive group and n = 739 in the standard group), and patients who were lost to follow-up (n = 34 in the intensive group and n = 36 in the standard group) or discontinued interventions (n = 2) were excluded. Finally, a total of 5339 (62.7%) patients were included for analyzing the effects of intensive blood pressure control on progression of arterial stiffness and cardiovascular risk. The flowchart is shown in Figure 1.
Figure 1. Flowchart showing the patient selection process in this study. ABI: Ankle-brachial index; baPWV: Brachial-ankle pulse wave velocity; SBP: Systolic blood pressure; STEP: Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients.
Assessment for arterial stiffness
The baPWV and ABI were examined using an automated waveform analyzer (Omron BP-203RPEIII, Omron Healthcare, Kyoto, Japan) to assess arterial stiffness.[16,17] Measurements were performed from 7:00 to 9:00 in the morning on the examination day by well-trained clinicians. After being seated for at least 5 minutes, participants were asked to lie down on the examination couch in a supine position and remain quiet during measurement. Cuffs were wrapped on both arms and ankles. BaPWV is automatically calculated as the length of an arterial segment between brachium and ankle (which is estimated from body height) divided by the transit time of pulse wave from the brachial to ankle arteries. Examinations were performed on both the left and right sides, and the maximum of the right and left baPWV values was used in the analysis. Values of baPWV ≤1800 cm/s were considered normal, while values of baPWV >1800 cm/s indicated the presence of arterial stiffness.[18] Based on the SBP and diastolic blood pressure (DBP) levels measured by the arterial stiffness detection device, the mean arterial pressure (MAP) was calculated as DBP + 1/3 (SBP–DBP).
The ABI was typically calculated as the ratio of the higher of the dorsal pedis and posterior tibial arterial systolic pressure to the higher of the left and right brachial systolic pressures. The lower of right and left ABI values recorded were considered as the final ABI value. Values of ABI >0.90 and ≤1.40 in both legs were considered normal, while values of ABI ≤0.90 or >1.40 indicate the presence of peripheral arterial disease.[19] Details of baPWV and ABI measurements are described in Supplementary Methods, http://links.lww.com/CM9/B747.
Assessment of covariates
At baseline, all participants completed a standardized questionnaire, including age, sex, weight, height, educational level, smoking status, alcohol intake, medical history, and current medication treatment. In this study, represented antihypertensive drugs were provided to patients free of charge, including angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and thiazide-type diuretics, all of which have robust evidence to reduce blood pressure and prevent cardiovascular events. For all participants, olmesartan medoxomil (Nanjing Chia Tai Tianqing Pharmaceutical Co., Ltd, Nanjing, China) was the preferred ARB at a daily dose of 20 mg (once daily), and amlodipine besylate (China Resources Saike Pharmaceutical Co., Ltd, Beijing) was the preferred CCB at a daily dose of 5–10 mg (once daily), and hydrochlorothiazide was not used as the initial therapy. Other antihypertensive drugs such as beta-adrenergic blockers might also be used when an investigator deemed it necessary and appropriate. A detailed antihypertensive treatment algorithm to reach the SBP targets has been previously published.[11]
Office blood pressure measurements were performed by a trained trial staff member (physician or nurse). Patients were required to rest for at least 5 minutes in a seated position, and then the blood pressure was measured by a staff three times at 1-minute intervals. This process was standardized, and the same validated office blood pressure monitor[20] was used at all participating centers at baseline and follow-up visits.
Assessment of endpoints
The primary outcome was a composite of stroke (ischemic or hemorrhagic), acute coronary syndrome (acute myocardial infarction and hospitalization for unstable angina), acute decompensated heart failure, coronary revascularization, atrial fibrillation, or death from cardiovascular causes. Definitions and evaluation criteria of the endpoints were outlined in Supplementary Methods, http://links.lww.com/CM9/B747. The follow-up time for each patient was determined from the date of cardiovascular events, death, loss to follow-up, or the last follow-up, whichever came first.
Statistical analysis
Clinical characteristics of participants were compared between two treatment groups using Chi-squared tests for categorical variables (expressed as n [%]), and t-tests or Mann–Whitney non-parametric tests for quantitative variables (expressed as mean ± standard deviation or median [interquartile range]). Values of baPWV and ABI were presented as the mean (95% confidence interval [CI]). To evaluate the effect of intensive treatment on arterial stiffness, changes in baPWV and ABI during the follow-up period were compared between the intensive and standard treatment groups by using a multivariate linear regression model, which adjusted for baseline clinical features including age, sex, blood lipid levels, blood glucose, current smoking and drinking status, history of CVD and diabetes, and baseline values of baPWV or ABI when appropriate. In addition, considering that change in PWV has a close association with change in blood pressure,[21,22] and that the MAP calculated as DBP + 1/3 (SBP–DBP) is more accurate for reflection of the peripheral compliance than either SBP or DBP[23,24] and strongly predicts the CVD events,[25] we accordingly also adjusted baseline MAP and change in MAP during follow-up as covariates in the analytical models to analyze arterial stiffness in the present study. The improvement of arterial stiffness was considered when baPWV or ABI values were abnormal at baseline but normal during follow-up. The proportions of patients with arterial stiffness improvement in the two treatment groups were compared using the Chi-squared test.
The incidence of the primary composite CVD outcomes was estimated using Kaplan–Meier curves. The hazard ratio (HR) with 95% CI was calculated using the Cox proportional hazard regression model after adjusting for the covariates mentioned above to evaluate the effect of intensive treatment on the primary outcomes. Subgroup analyses were also conducted, including age (<70 years vs. ≥70 years), sex (male vs. female), SBP at baseline (<140 mmHg, 140–150 mmHg, and >150 mmHg), history of diabetes (yes vs. no), the 10-year risk of CVD based on the Framingham risk score (<15% vs. ≥15%), and baseline baPWV (<1800 cm/s vs. ≥1800 cm/s). For each subgroup analysis, P value for interaction between the treatment effect and the subgroups mentioned above was reported.
All analyses were performed using R software, version 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria). A two-sided P value <0.05 was considered statistically significant.
Results
Clinical characteristics of studied patients
Of 8511 patients in the original STEP trial, 5339 (62.7%) patients who had repeated measurements of arterial stiffness at baseline and during follow-up were included in this study. The included patients were younger (66.0 years vs. 66.7 years), and had a lower proportion of patients ≥70 years (22.2% vs. 27.5%) and current alcohol intake (25.8% vs. 27.4%) compared with the excluded patients (P <0.05) [Supplementary Table 2, http://links.lww.com/CM9/B747]. Among the included patients, 2693 and 2646 patients, respectively, were in the intensive and standard treatment groups. Overall, the mean age of patients was 66.0 ± 4.7 years, 45.9% (n = 2453) were male, 19.7% (n = 1052) had prior diabetes mellitus, 6.0% (n = 320) had prior coronary heart disease, and 65.7% (n = 3510) were at high risk (10-year Framingham risk score ≥15%). There were no statistically significant differences in baseline characteristics between the two treatment groups [Table 1]. All patients were provided antihypertensive drugs free of charge, including olmesartan, amlodipine, and hydrochlorothiazide. In general, patients receiving the intensive treatment had higher proportions of two drugs combination therapy of olmesartan and amlodipine after enrollment (40.2% [n = 1082] in the intensive group and 31.9% [n = 844] in the standard group). A total of 24 (0.4%, 24/5339) patients used other kinds of ARB and CCB.
Table 1.
Baseline characteristics of patients in this study.
| Characteristics | Total (N = 5339) | Intensive treatment (N = 2693) | Standard treatment (N = 2646) | t/χ2/H values | P values |
|---|---|---|---|---|---|
| Age (years) | 66.0 ± 4.7 | 66.0 ± 4.7 | 66.0 ± 4.6 | –0.153‡ | 0.88 |
| Distribution of age | 0.100§ | 0.77 | |||
| 60–69 years | 4155 (77.8) | 2091 (77.6) | 2064 (78.0) | ||
| 70–80 years | 1184 (22.2) | 602 (22.4) | 582 (22.0) | ||
| Male | 2453 (45.9) | 1228 (45.6) | 1225 (46.3) | 0.261§ | 0.62 |
| Body mass index (kg/m2) | 25.6 ± 3.2 | 25.6 ± 3.1 | 25.7 ± 3.2 | –1.595‡ | 0.11 |
| Baseline blood pressure (mmHg) | |||||
| SBP | 146.1 ± 17.0 | 146.4 ± 17.0 | 145.9 ± 16.9 | 1.109‡ | 0.27 |
| DBP | 82.6 ± 10.7 | 82.5 ± 10.7 | 82.6 ± 10.5 | –0.063‡ | 0.95 |
| Distribution of SBP | 4.485§ | 0.11 | |||
| <140 mmHg | 1980 (37.1) | 962 (35.7) | 1018 (38.5) | ||
| 140–150 mmHg | 1330 (24.9) | 691 (25.7) | 639 (24.1) | ||
| >150 mmHg | 2029 (38.0) | 1040 (38.6) | 989 (37.4) | ||
| Fasting serum glucose (mmol/L) | 6.2 ± 1.7 | 6.2 ± 1.7 | 6.2 ± 1.7 | –0.045‡ | 0.96 |
| Lipids profile (mmol/L) | |||||
| Total cholesterol | 4.9 ± 1.2 | 4.9 ± 1.2 | 4.9 ± 1.1 | 0.615‡ | 0.54 |
| Triglycerides | 1.4 (1.0–1.9) | 1.3 (1.0–2.0) | 1.4 (1.0–1.9) | –0.329‖ | 0.74 |
| HDL-C | 1.3 ± 0.3 | 1.3 ± 0.3 | 1.3 ± 0.3 | 0.007‡ | 0.99 |
| LDL-C | 2.7 ± 0.9 | 2.7 ± 0.9 | 2.7 ± 0.9 | –0.441‡ | 0.66 |
| Missing data | 3 (0) | 1 (0) | 2 | ||
| Educational level | 1.480§ | 0.23 | |||
| Middle school or below | 3009 (56.4) | 1496 (55.6) | 1513 (57.2) | ||
| High school or above | 2327 (43.6) | 1196 (44.4) | 1131 (42.7) | ||
| Missing data | 3 (0) | 1 (0) | 2 (0.1) | ||
| Smoking status | 0.379§ | 0.83 | |||
| Never | 3848 (72.1) | 1951 (72.4) | 1897 (71.7) | ||
| Former | 626 (11.7) | 312 (11.6) | 314 (11.9) | ||
| Current | 853 (16.0) | 424 (15.8) | 429 (16.2) | ||
| Missing data | 12 (0.2) | 6 (0.2) | 6 (0.2) | ||
| Alcohol consumption | 1.487§ | 0.48 | |||
| Never | 3694 (69.2) | 1882 (69.9) | 1812 (68.5) | ||
| Former | 257 (4.8) | 123 (4.6) | 134 (5.1) | ||
| Current | 1376 (25.8) | 682 (25.3) | 694 (26.2) | ||
| Missing data | 12 (0.2) | 6 (0.2) | 6 (0.2) | ||
| Medical history | |||||
| Diabetes mellitus | 1052 (19.7) | 535 (19.9) | 517 (19.5) | 0.090§ | 0.78 |
| Hyperlipidemia | 2002 (37.5) | 1029 (38.2) | 973 (36.8) | 1.177§ | 0.28 |
| CVDs | 320 (6.0) | 165 (6.1) | 155 (5.9) | 0.172§ | 0.69 |
| Ten-year risk of CVD ≥15%* | 3510 (65.7) | 1770 (65.7) | 1740 (65.8) | 0.001§ | 0.99 |
| Antihypertensive drug use after enrollment | |||||
| Amlodipine alone | 1677 (31.5) | 766 (28.4) | 911 (34.4) | 22.192§ | <0.001 |
| Olmesartan alone | 993 (18.6) | 456 (16.9) | 537 (20.3) | 9.964§ | 0.002 |
| HCZ alone | 7 (0.1) | 4 (0.1) | 3 (0.1) | 0.126§ | 0.72 |
| Amlodipine and olmesartan | 1926 (36.1) | 1082 (40.2) | 844 (31.9) | 39.688§ | <0.001 |
| Amlodipine and HCZ | 33 (0.6) | 19 (0.7) | 14 (0.5) | 0.676§ | 0.41 |
| Olmesartan and HCZ | 74 (1.4) | 39 (1.4) | 35 (1.3) | 0.154§ | 0.70 |
| Amlodipine, olmesartan and HCZ | 185 (3.5) | 105 (3.9) | 80 (3.0) | 3.059§ | 0.08 |
| Other ARB or CCB | 24 (0.4) | 8 (0.3) | 16 (0.6) | 2.822§ | 0.10 |
| Other drugs† | 253 (4.7) | 124 (4.6) | 129 (4.9) | 0.461§ | 0.67 |
Data are shown as mean ± standard deviation, n (%), or median (Q1–Q3). ARB: Angiotensin receptor blocker; CCB: Calcium channel blocker; CVD: Cardiovascular disease; DBP: Diastolic blood pressure; HCZ: Hydrochlorothiazide; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; SBP: Systolic blood pressure. *Ten-year CVD risk was estimated with Framingham risk scoring, and patients with a ≥15% risk score were considered to be at high risk. †Other drugs included traditional Chinese drugs or polypills, which are a combination of antihypertensive agents. ‡Student's t-test. §Chi-squared test for qualitative variables. ||H values.
Trajectory pattern of blood pressure during the follow-up period
The blood pressure trend in the intensive and standard treatment groups in this post-hoc analysis was consistent with that in the original STEP trial [Figure 2]. The two treatment strategies led to a rapid and sustained between-group difference in SBP in older patients with hypertension. During the median follow-up period of 3.36 years, the mean decreased in SBP from baseline were 20.6 mmHg and 10.4 mmHg in the intensive and standard treatment groups, respectively. Throughout follow-up, the mean SBP values were 127.7 mmHg and 136.2 mmHg, while the mean DBP values were 76.6 mmHg and 79.4 mmHg in the intensive and standard treatment groups, respectively [Supplementary Figure 1, http://links.lww.com/CM9/B747]. Patients in the intensive treatment group had more antihypertensive agents used, and the mean number of antihypertensive agents used per patient was 1.9 in the intensive treatment group and 1.5 in the standard treatment group at 42 months [Figure 2].
Figure 2. Trajectory pattern of office systolic blood-pressure and antihypertensive medications during the follow-up period. The SBP target was 110 mmHg to <130 mmHg in the intensive treatment group and 130 mmHg to <150 mmHg in the standard treatment group. The mean number of medications is based on the number of blood-pressure medications administered at each visit per patient. ISBP: Systolic blood pressure.
Since patients with SBP <150 mmHg in the standard group usually did not require additional antihypertensive medication, and this difference in treatment strategy might be greater in patients without high SBP (<140 mmHg) and affect the clinical benefits from the SBP <140 mmHg subgroup, we compared the number of antihypertensive medications for patients with SBP <140 mmHg or within 140–150 mmHg in the two treatment groups, showing that the number of antihypertensive agents used in the intensive treatment group was significantly higher than that used in the standard treatment group during follow-up [Supplementary Table 3, http://links.lww.com/CM9/B747].
Effect of intensive treatment on the longitudinal changes of arterial stiffness
There were statistically significant differences in baPWV change but not in ABI change between the two treatment groups [Table 2]. The changes in baPWV (∆baPWV) from baseline to the follow-up visit were 61.5 cm/s (95% CI: 49.8–73.2 cm/s) in the intensive treatment group and 98.4 cm/s (95% CI: 86.7–110.1 cm/s) in the standard treatment group (P <0.001), after adjustment for vascular risk factors including age, sex, blood lipid levels, blood glucose, current smoking and drinking status, history of CVD and diabetes, baseline baPWV, MAP, and change in MAP during follow-up. The annual changes of baPWV were 23.1 cm·s–1·year–1 and 36.7 cm·s–1·year–1 in the intensive and standard treatment groups, respectively.
Table 2.
Effect of intensive blood pressure treatment on change in arterial stiffness during the follow-up period.
| Variables | Intensive treatment, mean (95% CI) | Standard treatment, mean (95% CI) | t/F value | P value |
|---|---|---|---|---|
| N of patients | 2693 | 2646 | ||
| baPWV (cm/s) | ||||
| Baseline baPWV | 1781.2 (1768.4, 1793.9) | 1818.3 (1805.7, 1830.9) | –4.053 | <0.001 |
| Follow-up baPWV | 1848.4 (1835.0, 1808.5) | 1912.6 (1899.3, 1925.9) | –6.682 | <0.001 |
| Unadjusted changes in baPWV | 67.2 (54.8, 79.6) | 94.3 (82.0, 106.7) | 0.991 | 0.002 |
| Adjusted changes in baPWV* | 61.5 (49.8, 73.2) | 98.4 (86.7, 110.1) | 17.553 | <0.001 |
| ABI | ||||
| Baseline ABI | 1.10 (1.09, 1.11) | 1.10 (1.09, 1.11) | 0.615 | 0.140 |
| Follow-up ABI | 1.09 (1.09, 1.10) | 1.10 (1.09, 1.10) | 0.277 | 0.190 |
| Unadjusted changes in ABI | –0.004 (–0.009, 0.001) | –0.004 (–0.008, 0.001) | 0.693 | 0.980 |
| Adjusted changes in ABI* | –0.004 (–0.009, 0.0003) | –0.004 (–0.008, 0.001) | 0.060 | 0.810 |
ABI: Ankle-brachial index; baPWV: Brachial ankle pulse wave velocity; CI: Confidence interval; CVD: Cardiovascular disease; MAP: Mean arterial pressure. *Linear regression model was used to compare changes in baPWV and ABI between two treatment groups after adjustment for baseline clinical features of age, sex, blood lipid levels, blood glucose, current smoking and drinking status, history of CVD and diabetes, baseline values of baPWV or ABI, MAP, and changes in MAP during the follow-up.
Subgroup analyses of ΔbaPWV were also conducted according to age, sex, baseline SBP, prior diabetes, and 10-year risk of CVD, showing a beneficial effect on arterial stiffness under intensive SBP control [Supplementary Table 4, http://links.lww.com/CM9/B747]. Particularly, intensive treatment significantly attenuated progression of baPWV in hypertensive patients at high risk (10-year Framingham risk score ≥15%) (P <0.001 and P for interaction = 0.04). For patients with hypertension aged 70–80 years, the effect size of ∆baPWV was 54.6 cm/s and 101.4 cm/s for the intensive and standard treatment groups, respectively (P = 0.03 and P for interaction = 0.21). The power would achieve 67% to detect a difference in ∆baPWV with a two-sided α level of 0.05 among 1184 patients in the subgroup of patients aged over 70 years. And for patients with baseline SBP under 140 mmHg, the effect size of ∆baPWV was 68.3 cm/s and 118.1 cm/s for the intensive and standard treatment groups, respectively (P <0.001 and P for interaction = 0.07). The power would achieve 95% to detect a difference in ∆baPWV with a two-sided α level of 0.05 among 1980 patients in the subgroup of patients with baseline SBP <140 mmHg. For patients with arterial stiffness (baPWV ≥1800 cm/s) at baseline, intensive treatment could significantly reverse the progression of arterial stiffness, showing ∆baPWV to be –48.5 (95% CI: –69.6 to 27.5) cm/s vs. –16.1 (95% CI: –36.1 to 3.9) cm/s in the intensive and standard treatment groups (P = 0.04), respectively. Patients who had baseline baPWV ≥1800 cm/s but regressed to be baPWV <1800 cm/s during follow-up accounted for 25.2% (287/1139) and 20.4% (254/1248), respectively, in the intensive and standard treatment groups (P = 0.005) [Supplementary Table 5, http://links.lww.com/CM9/B747]. We compared the clinical characteristics of patients according to ∆baPWV and found that in the intensive treatment group, patients who achieved a reduction in arterial stiffness (∆baPWV ≤0) had a higher proportion of prior diabetes or were at high risk of CVD [Supplementary Table 6, http://links.lww.com/CM9/B747].
Occurrence of cardiovascular events
In this study, primary CVD outcomes occurred in 77 (2.9%) patients in the intensive treatment group compared with 93 (3.5%) patients in the standard treatment group during a median follow-up period of 3.36 years [Table 3]. In a prespecified subgroup analysis, intensive SBP treatment resulted in a significantly lower CVD risk in patients aged 70–80 years (HR: 0.52, 95% CI: 0.29–0.95) and patients with baseline SBP <140 mmHg (HR: 0.51, 95% CI: 0.29–0.87), as compared with standard treatment. Comparisons of clinical characteristics of patients aged 70–80 years showed that the standard treatment group had a higher proportion of current alcohol drinkers than the intensive treatment group (24.4% vs. 22.8%, P = 0.01) [Supplementary Table 7, http://links.lww.com/CM9/B747]. Comparisons of clinical characteristics of patients with baseline SBP <140 mmHg showed that patients in the intensive treatment group had a slightly lower body mass index but were more likely to have hyperlipidemia as compared with patients in the standard treatment group [Supplementary Table 8, http://links.lww.com/CM9/B747]. We also compared the risk of incident CVD between patients with or without baseline arterial stiffness. Interestingly, the risk of primary CVD outcomes among patients without arterial stiffness (baPWV <1800 cm/s) was significantly lower in the intensive treatment group than in the standard treatment group [Supplementary Figure 2, http://links.lww.com/CM9/B747], however, after adjustment for the covariates mentioned above, the statistically significant difference of CVD risk was not observed [Table 3].
Table 3.
HRs for the primary outcomes.
| Outcomes | Intensive treatment | Standard treatment | HR (95% CI)* | P for interaction | |||||
|---|---|---|---|---|---|---|---|---|---|
| N of patients | N of events (%) | N of patients | N of events (%) | Model I | Model II | ||||
| Primary composite outcome | 2693 | 77 (2.9) | 2646 | 93 (3.5) | 0.81 (0.60–1.10) | 0.84 (0.62–1.15) | – | ||
| Age (years) | |||||||||
| 60–69 | 2091 | 60 (2.9) | 2064 | 61 (3.0) | 0.98 (0.69–1.40) | 0.96 (0.64–1.44) | 0.25 | ||
| 70–80 | 602 | 17 (2.8) | 582 | 32 (5.5) | 0.49 (0.27–0.89) | 0.52 (0.29–0.95) | |||
| Sex | |||||||||
| Male | 1228 | 37 (3.0) | 1225 | 44 (3.6) | 0.84 (0.54–1.31) | 0.84 (0.51–1.39) | 0.60 | ||
| Female | 1465 | 40 (2.7) | 1421 | 49 (3.4) | 0.79 (0.52–1.20) | 0.78 (0.51–1.19) | |||
| SBP (mmHg) | |||||||||
| <140 | 962 | 19 (2.0) | 1018 | 41 (4.0) | 0.50 (0.29–0.86) | 0.51 (0.29–0.87) | 0.01 | ||
| 140–150 | 691 | 17 (2.5) | 639 | 10 (1.6) | 1.58 (0.72–3.44) | 1.49 (0.67–3.28) | |||
| >150 | 1040 | 41 (3.9) | 989 | 42 (4.2) | 0.93 (0.60–1.43) | 0.99 (0.62–1.60) | |||
| History of diabetes | |||||||||
| Yes | 535 | 21 (3.9) | 517 | 21 (4.1) | 1.02 (0.96–1.09) | 0.84 (0.44–1.62) | 0.77 | ||
| No | 2158 | 56 (2.6) | 2129 | 72 (3.4) | 0.77 (0.54–1.09) | 0.82 (0.57–1.17) | |||
| Ten-year risk of CVD | |||||||||
| <15% | 923 | 22 (2.4) | 906 | 25 (2.8) | 0.87 (0.49–1.54) | 0.83 (0.47–1.48) | 0.92 | ||
| ≥15% | 1770 | 55 (3.1) | 1740 | 68 (3.9) | 0.79 (0.56–1.13) | 0.84 (0.59–1.21) | |||
| Baseline baPWV (cm/s) | |||||||||
| <1800 | 1554 | 36 (2.3) | 1398 | 46 (3.3) | 0.69 (0.45–1.07) | 0.74 (0.47–1.15) | 0.12 | ||
| ≥1800 | 1139 | 41 (3.6) | 1248 | 47 (3.8) | 0.95 (0.63–1.45) | 0.98 (0.62–1.55) | |||
baPWV: Brachial ankle pulse wave velocity; CI: Confidence interval; CVD: Cardiovascular disease; HR: Hazard ratio; MAP: Mean arterial pressure; SBP: Systolic blood pressure. The primary outcome was a composite of acute coronary syndrome, stroke, acute decompensated heart failure, coronary revascularization, atrial fibrillation, or mortality from cardiovascular cause. *HR (95% CI) and P value were calculated using Cox proportional hazard regression model; Model I was adjusted for age at baseline and sex (except for the sex-stratified analysis), and model II was further adjusted for baseline clinical features of blood lipid levels, blood glucose, current smoking and drinking status, history of CVD and diabetes, baseline baPWV, MAP, and changes in MAP during the follow-up.
Discussion
In this post-hoc analysis of the STEP trial, a total of 5339 patients with hypertension aged 60–80 years underwent arterial stiffness examinations at baseline and repeated measurement during follow-up. Intensive treatment (target, 110 mmHg ≤SBP <130 mmHg) significantly attenuated the progression of arterial stiffness evaluated by ∆baPWV as compared with standard treatment (target, 130 mmHg ≤SBP <150 mmHg). Even though there was a reduction in the HR of the primary outcome (HR: 0.84), the difference between the two treatment groups was not statistically significant. Subgroup analysis found that intensive SBP treatment not only slowed the progression of arterial stiffness, but also decreased the risk of CVD events among older hypertensive patients (aged ≥70 years) or patients with a lower baseline SBP (<140 mmHg).
The strength of this prespecified sub-study included repeated assessments of arterial stiffness and office blood pressure monitoring from a randomized controlled trial, which gave new insights into antihypertensive treatment for older patients. It remains undetermined whether the reversibility of vessel changes is attributable to blood pressure lowering alone, local effects of antihypertensive agents on the vessel wall, or a combination of both. The stiffness of the central artery plays an important role in the pathophysiology of CVD.[26] BaPWV increases with age and blood pressure and is associated with more advanced organ damage. Our current findings showed that intensive SBP lowering <130 mmHg could wind down the progression of baPWV. A prerequisite for meaningful baPWV measurements is that the blood circulation is not disturbed during pulse propagation, and thus clarifying whether the lower extremity arterial circulation between the ilium and the tibia is normal by ABI is essential for the effectiveness of baPWV measurements.[27] In this study, we also compared the change in ABI under intensive blood pressure control, although the change in ABI was not statistically significant, it further corroborated the reliability of our conclusion. A previous study found that baPWV accelerated at a greater rate in uncontrolled hypertensive patients compared to those in controlled hypertensive patients and normotensive subjects.[28] Together, these findings suggested that continuous hypertension control among patients with SBP <140 mmHg might be more effective in attenuating arterial stiffness and preventing adverse cardiovascular events than that in patients with uncontrolled BP. The intensive treatment group had more antihypertensive agents used during follow-up among patients with SBP <140 mmHg, and additional antihypertensive medication in the intensive treatment group might partially mediate the slowing progression of arterial stiffening. The Multi-Ethnic Study of Atherosclerosis (MESA) study has shown weak effects of different types of antihypertensive drugs on progressive arterial stiffness, however, blood pressure control, regardless of medications used, was proved to be associated with a slower progression of arterial stiffness.[29] Lowering SBP to <130 mmHg is an efficacious strategy to attenuate baPWV progression along with aging, especially for patients at high risk of CVD or with the presence of arterial stiffness. Early identification and blood pressure intervention for these patients is of clinical importance, which could help prevent the onset and slow the target damage.
The STEP trial is designed to conduct an intervention to lower SBP to 110–130 mmHg in elderly hypertensive patients aged 60–80 years, and the main results have shown that the annual event rates for the primary outcome in the intensive and standard treatment groups are lower (1.0% per year and 1.4% per year, respectively),[11] when compared with the SPRINT trial (1.77% per year and 2.40% per year, respectively).[30] This finding is consistent with previous investigations that have shown lower cardiovascular risk in Asian populations than in the American and European populations.[31,32] Overall, the participants of the STEP trial are a diverse patient population at high cardiovascular risk and comorbid with chronic diseases, such as diabetes mellitus, coronary heart disease, and hyperlipidemia. SPRINT excluded persons with diabetes mellitus, whereas the STEP trial did not; and both trials excluded persons with a history of stroke. Thus, the differences in the trial design, eligibility criteria, and racial/ethnic background may also partially explain the different rates of primary CVD outcomes between the STEP trial and SPRINT.
The intensive treatment group in this study showed a trend toward lower incidence of cardiovascular events compared to the standard treatment group, but no statistically significant difference was obtained. This might be explained in several aspects involving patient characteristics and study design. First, the present study was a post-hoc analysis of the STEP trial, including a subgroup of 5339 (62.7%) patients who had arterial stiffness measurements both at baseline and during follow-up and excluding 3172 (37.3%) patients lacking arterial stiffness data. This limited sample size might not be fully representative of the overall cohort and thus underestimated the cardiovascular risk due to the small number of incident cardiovascular events. Second, the overall age of the included patients was >60 years, but the proportion of patients ≥70 years was still low (n = 1184, 22.2%) and the overall follow-up period was shorter. In addition, more cardiovascular events occurred in the excluded patients (173 events/3172 patients) than in the included patients (170 events/5339 patients), which could be partially attributed to a greater proportion of current alcohol intake (25.8% vs. 27.4%) and history of CVD (6.0% vs. 6.9%) in the excluded patients. In the subgroup analysis of this study, we observed that intensive BP control (target SBP <130 mmHg) slowed down the progression of arterial stiffness and resulted in a significantly lower incidence of CVD events among patients aged 70–80 years. This post-hoc analysis needs to be interpreted cautiously because of insufficient statistical power. However, a previous study has shown that aortic stiffening was associated with a higher rate of CVD in a cohort of community-dwelling older adults aged 70–79 years.[33] These findings indicated that efforts to prevent age-associated arterial stiffening would help improve the health status of older adults.
Meta-analyses have demonstrated that there existed a strong relationship between baPWV and CVD.[34,35] In a subgroup analysis of the China Stroke Primary Prevention Trial (CSPPT), baPWV and BP control independently and jointly affected the risk of first stroke among patients with hypertension. When baPWV and hypertension control were examined jointly, participants in the highest baPWV quartile and with inadequate hypertension control had the highest risk of stroke compared with their counterparts.[36] Our findings showed that intensive treatment (target SBP <130 mmHg) significantly attenuated the progression of arterial stiffness evaluated by the baPWV, consistent with an improvement in arterial stiffness by intensive treatment (target SBP <120 mmHg) after 12 months of follow-up in the secondary analysis of the SPRINT.[13,14] This might be one of the mechanisms underlying the cardiovascular benefit obtained from intensive SBP intervention.
It should be noted that our study has some potential limitations. First, we did not use cfPWV because it is not applicable in large clinical studies, although it is considered the gold standard for assessing arterial stiffness status. BaPWV reflects structural and functional stiffness of the arterial wall and can be applied to assess arterial stiffness simply, reproducibly, and non-invasively.[26] Previous studies reported a strong association between baPWV and cfPWV, suggesting that baPWV could be used as an evaluation index for the degree of arterial stiffness.[8,9] Second, the present study was a post-hoc analysis of the STEP trial, which excluded 3172 (37.3%) patients lacking baseline arterial stiffness data or follow-up arterial stiffness data and included a subgroup of 5339 (62.7%) patients with completed arterial stiffness data. This may lead to selection bias and insufficient statistical power, thus we cannot evaluate whether arterial stiffness changes assessed by baPWV may have mediated the reduction in risk of CVD following intensive SBP treatment. In a recent small randomized clinical trial, the Strategy for Preventing Cardiovascular and Renal Events based on ARTErial Stiffness (SPARTE) study showed that an intensive PWV-driven strategy did not result in a statistically significant reduction in CVD events despite leading to a statistically significant reduction in office blood pressure.[37] Since these studies are exploratory researches, new studies with extension of the follow-up time and large numbers of primary outcomes will be helpful for understanding the relationships between intensive blood pressure control, arterial stiffness, and CVD benefits. In addition, a limitation of our study is the inclusion of only ethnic Han Chinese, which limits the generalizability of our findings.
In this sub-study analysis of the original STEP trial, intensive blood pressure control with an SBP target of 110 mmHg to <130 mmHg could delay the progression of arterial stiffness and lower the risk of CVD in older patients with hypertension, particularly in patients aged 70–80 years and patients with controlled SBP <140 mmHg, as compared with standard treatment to reach a target of 130 mmHg to <150 mmHg.
Acknowledgments
We thank all the collaborating physicians and staffs for their efforts in collecting data. We greatly appreciate all participants for their contribution. We also thank John Holmes, MSc, from Liwen Bianji (Edanz) (www.liwenbianji.cn) for editing the English text of a draft of this manuscript.
Funding
This work was supported by grants from the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (Nos. 2016-I2M-1-006 and 2021-I2M-1-011).
Conflicts of interest
None.
Supplementary Material
Footnotes
Shuyuan Zhang and Yixuan Zhong contributed equally to this work.
How to cite this article: Zhang SY, Zhong YX, Wu SL, Wu HL, Cai J, Zhang WL, On behalf of the STEP Study Group. Intensive blood pressure control on arterial stiffness among older patients with hypertension. Chin Med J 2024;137:1078–1087. doi: 10.1097/CM9.0000000000002868
References
- 1.Paneni F, Diaz Cañestro C, Libby P, Lüscher TF, Camici GG. The aging cardiovascular system: Understanding it at the cellular and clinical levels. J Am Coll Cardiol 2017;69:1952–1967. doi: 10.1016/j.jacc.2017.01.064. [DOI] [PubMed] [Google Scholar]
- 2.Wu S Jin C Li S Zheng X Zhang X Cui L, et al. Aging, arterial stiffness, and blood pressure association in Chinese adults. Hypertension 2019;73:893–899. doi: 10.1161/HYPERTENSIONAHA.118.12396. [DOI] [PubMed] [Google Scholar]
- 3.Donato AJ, Machin DR, Lesniewski LA. Mechanisms of dysfunction in the aging vasculature and role in age-related disease. Circ Res 2018;123:825–848. doi: 10.1161/CIRCRESAHA.118.312563. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Najjar SS Scuteri A Shetty V Wright JG Muller DC Fleg JL, et al. Pulse wave velocity is an independent predictor of the longitudinal increase in systolic blood pressure and of incident hypertension in the Baltimore Longitudinal Study of Aging. J Am Coll Cardiol 2008;51:1377–1383. doi: 10.1016/j.jacc.2007.10.065. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Kaess BM Rong J Larson MG Hamburg NM Vita JA Levy D, et al. Aortic stiffness, blood pressure progression, and incident hypertension. JAMA 2012;308:875–881. doi: 10.1001/2012.jama.10503. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Laurent S Boutouyrie P Asmar R Gautier I Laloux B Guize L, et al. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 2001;37:1236–1241. doi: 10.1161/01.hyp.37.5.1236. [DOI] [PubMed] [Google Scholar]
- 7.Blacher J, Asmar R, Djane S, London GM, Safar ME. Aortic pulse wave velocity as a marker of cardiovascular risk in hypertensive patients. Hypertension 1999;33:1111–1117. doi: 10.1161/01.hyp.33.5.1111. [DOI] [PubMed] [Google Scholar]
- 8.Yamashina A Tomiyama H Takeda K Tsuda H Arai T Hirose K, et al. Validity, reproducibility, and clinical significance of noninvasive brachial-ankle pulse wave velocity measurement. Hypertens Res 2002;25:359–364. doi: 10.1291/hypres.25.359. [DOI] [PubMed] [Google Scholar]
- 9.Tanaka H Munakata M Kawano Y Ohishi M Shoji T Sugawara J, et al. Comparison between carotid-femoral and brachial-ankle pulse wave velocity as measures of arterial stiffness. J Hypertens 2009;27:2022–2027. doi: 10.1097/HJH.0b013e32832e94e7. [DOI] [PubMed] [Google Scholar]
- 10.Zheng M Huo Y Wang X Xu X Qin X Tang G, et al. A prospective study on pulse wave velocity (PWV) and response to anti-hypertensive treatments: PWV determines BP control. Int J Cardiol 2015;178:226–231. doi: 10.1016/j.ijcard.2014.10.049. [DOI] [PubMed] [Google Scholar]
- 11.Zhang W Zhang S Deng Y Wu S Ren J Sun G, et al. Trial of intensive blood-pressure control in older patients with hypertension. N Engl J Med 2021;385:1268–1279. doi: 10.1056/NEJMoa2111437. [DOI] [PubMed] [Google Scholar]
- 12.Ling Q Song Q Bai J Wu S Zhang W Chen M, et al. Temporal relationship between arterial stiffness and systolic blood pressure under intensive or standard control: A post hoc analysis of the STEP trial. Hypertension 2022;79:2755–2763. doi: 10.1161/HYPERTENSIONAHA.122.20022. [DOI] [PubMed] [Google Scholar]
- 13.Vlachopoulos C Terentes-Printzios D Laurent S Nilsson PM Protogerou AD Aznaouridis K, et al. Association of estimated pulse wave velocity with survival: A secondary analysis of SPRINT. JAMA Netw Open 2019;2:e1912831. doi: 10.1001/jamanetworkopen.2019.12831. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Upadhya B Pajewski NM Rocco MV Hundley WG Aurigemma G Hamilton CA, et al. Effect of intensive blood pressure control on aortic stiffness in the SPRINT-HEART. Hypertension 2021;77:1571–1580. doi: 10.1161/HYPERTENSIONAHA.120.16676. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Zhang S Wu S Ren J Chen X Zhang X Feng Y, et al. Strategy of blood pressure intervention in the elderly hypertensive patients (STEP): Rational, design, and baseline characteristics for the main trial. Contemp Clin Trials 2020;89:105913. doi: 10.1016/j.cct.2019.105913. [DOI] [PubMed] [Google Scholar]
- 16.Tomiyama H, Matsumoto C, Shiina K, Yamashina A. Brachial-ankle PWV: Current status and future directions as a useful marker in the management of cardiovascular disease and/or cardiovascular risk factors. J Atheroscler Thromb 2016;23:128–146. doi: 10.5551/jat.32979. [DOI] [PubMed] [Google Scholar]
- 17.Sheng CS Li Y Li LH Huang QF Zeng WF Kang YY, et al. Brachial-ankle pulse wave velocity as a predictor of mortality in elderly Chinese. Hypertension 2014;64:1124–1130. doi: 10.1161/HYPERTENSIONAHA.114.04063. [DOI] [PubMed] [Google Scholar]
- 18.Tanaka A Tomiyama H Maruhashi T Matsuzawa Y Miyoshi T Kabutoya T, et al. Physiological diagnostic criteria for vascular failure. Hypertension 2018;72:1060–1071. doi: 10.1161/HYPERTENSIONAHA.118.11554. [DOI] [PubMed] [Google Scholar]
- 19.Aboyans V Criqui MH Abraham P Allison MA Creager MA Diehm C, et al. Measurement and interpretation of the ankle-brachial index: A scientific statement from the American Heart Association. Circulation 2012;126:2890–2909. doi: 10.1161/CIR.0b013e318276fbcb. [DOI] [PubMed] [Google Scholar]
- 20.Meng L Zhao D Pan Y Ding W Wei Q Li H, et al. Validation of Omron HBP-1300 professional blood pressure monitor based on auscultation in children and adults. BMC Cardiovasc Disord 2016;16:9. doi: 10.1186/s12872-015-0177-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Gow BS. The influence of vascular smooth muscle on the viscoelastic properties of blood vessels. London: Academic; 1972:66–110. [Google Scholar]
- 22.Gribbin B, Steptoe A, Sleight P. Pulse wave velocity as a measure of blood pressure change. Psychophysiology 1976;13:86–90. doi: 10.1111/j.1469-8986.1976.tb03344.x. [DOI] [PubMed] [Google Scholar]
- 23.Finnegan TP, Spence JD, Wong DG, Wells GA. Blood pressure measurement in the elderly: Correlation of arterial stiffness with difference between intra-arterial and cuff pressures. J Hypertens 1985;3:231–235. doi: 10.1097/00004872-198506000-00006. [DOI] [PubMed] [Google Scholar]
- 24.Boutouyrie P, Chowienczyk P, Humphrey JD, Mitchell GF. Arterial stiffness and cardiovascular risk in hypertension. Circ Res 2021;128:864–886. doi: 10.1161/CIRCRESAHA.121.318061. [DOI] [PubMed] [Google Scholar]
- 25.Sesso HD Stampfer MJ Rosner B Hennekens CH Gaziano JM Manson JE, et al. Systolic and diastolic blood pressure, pulse pressure, and mean arterial pressure as predictors of cardiovascular disease risk in Men. Hypertension 2000;36:801–807. doi: 10.1161/01.hyp.36.5.801. [DOI] [PubMed] [Google Scholar]
- 26.Tsuchikura S Shoji T Kimoto E Shinohara K Hatsuda S Koyama H, et al. Brachial-ankle pulse wave velocity as an index of central arterial stiffness. J Atheroscler Thromb 2010;17:658–665. doi: 10.5551/jat.3616. [DOI] [PubMed] [Google Scholar]
- 27.Li B, Gao H, Li X, Liu Y, Wang M. Correlation between brachial-ankle pulse wave velocity and arterial compliance and cardiovascular risk factors in elderly patients with arteriosclerosis. Hypertens Res 2006;29:309–314. doi: 10.1291/hypres.29.309. [DOI] [PubMed] [Google Scholar]
- 28.Benetos A Adamopoulos C Bureau JM Temmar M Labat C Bean K, et al. Determinants of accelerated progression of arterial stiffness in normotensive subjects and in treated hypertensive subjects over a 6-year period. Circulation 2002;105:1202–1207. doi: 10.1161/hc1002.105135. [DOI] [PubMed] [Google Scholar]
- 29.Gepner AD Tedla Y Colangelo LA Tattersall MC Korcarz CE Kaufman JD, et al. Progression of carotid arterial stiffness with treatment of hypertension over 10 years: The Multi-Ethnic Study of Atherosclerosis. Hypertension 2017;69:87–95. doi: 10.1161/HYPERTENSIONAHA.116.08402. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.SPRINT Research Group; Wright JT Jr. Williamson JD Whelton PK Snyder JK Sink KM, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103–2116. doi: 10.1056/NEJMoa1511939. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Yusuf S Bosch J Dagenais G Zhu J Xavier D Liu L, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016;374:2021–2031. doi: 10.1056/NEJMoa1600176. [DOI] [PubMed] [Google Scholar]
- 32.Qi Y Han X Zhao D Wang W Wang M Sun J, et al. Long-term cardiovascular risk associated with stage 1 hypertension defined by the 2017 ACC/AHA hypertension guideline. J Am Coll Cardiol 2018;72:1201–1210. doi: 10.1016/j.jacc.2018.06.056. [DOI] [PubMed] [Google Scholar]
- 33.Sutton-Tyrrell K Najjar SS Boudreau RM Venkitachalam L Kupelian V Simonsick EM, et al. Elevated aortic pulse wave velocity, a marker of arterial stiffness, predicts cardiovascular events in well-functioning older adults. Circulation 2005;111:3384–3390. doi: 10.1161/CIRCULATIONAHA.104.483628. [DOI] [PubMed] [Google Scholar]
- 34.Ohkuma T Ninomiya T Tomiyama H Kario K Hoshide S Kita Y, et al. Brachial-ankle pulse wave velocity and the risk prediction of cardiovascular disease: An individual participant data meta-analysis. Hypertension 2017;69:1045–1052. doi: 10.1161/HYPERTENSIONAHA.117.09097. [DOI] [PubMed] [Google Scholar]
- 35.Sang T, Lv N, Dang A, Cheng N, Zhang W. Brachial-ankle pulse wave velocity and prognosis in patients with atherosclerotic cardiovascular disease: A systematic review and meta-analysis. Hypertens Res 2021;44:1175–1185. doi: 10.1038/s41440-021-00678-2. [DOI] [PubMed] [Google Scholar]
- 36.Song Y Xu B Xu R Tung R Frank E Tromble W, et al. Independent and joint effect of brachial-ankle pulse wave velocity and blood pressure control on incident stroke in hypertensive adults. Hypertension 2016;68:46–53. doi: 10.1161/HYPERTENSIONAHA.115.07023. [DOI] [PubMed] [Google Scholar]
- 37.Laurent S Chatellier G Azizi M Calvet D Choukroun G Danchin N, et al. SPARTE Study: Normalization of arterial stiffness and cardiovascular events in patients with hypertension at medium to very high risk. Hypertension 2021;78:983–995. doi: 10.1161/HYPERTENSIONAHA.121.17579. [DOI] [PMC free article] [PubMed] [Google Scholar]