Study design and population
This study was a post hoc analysis of the STEP trial (STEP ClinicalTrials.gov number, NCT03015311). Details regarding the design, rationale and key results of the STEP trial have been published previously. [3, 5]. Briefly, the STEP trial was a randomized, multicenter, open-label controlled trial that compared the effects of intensive (target SBP 110 to
The inclusion and exclusion criteria were identical to those of the STEP trial. Eligible participants included people aged 60 to 80 with essential hypertension, defined as a SBP of 140 to 190 mmHg, or currently taking antihypertensive medications. Patients with a history of ischemic or hemorrhagic stroke were excluded. Additionally, in the present analysis, 1646 patients with missing baseline baPWV data and 8 patients with missing BP data during follow-up were excluded. In addition, 760 patients with a DBP
Randomization and intervention
Eligible participants were randomly assigned to either the intensive treatment group (SBP goal 110 to
Make sure of the AS
To assess AS at baseline, baPWV was measured with an Omron BP-203RPEIII automatic waveform analyzer (Omron Healthcare, Kyoto, Japan). After the participants had rested for at least 5 minutes in the supine position at an ambient temperature of 22°C to 25°C, the trial-trained personnel placed electrodes on the participants’ wrists, placed a microphone on the left edge of the sternum, and placed pneumatic cuffs on the arms and ankles. The lower edge of the brachial cuff was positioned 2 to 3 cm above the transverse stria of the cubital fossa and the lower edge of the ankle cuff was positioned 1 to 2 cm above the superior surface of the medial malleolus. Sensors were used to determine volume pulse shape and blood pressure, and a solid-state pressure sensor was used to record pulse volume waveforms. For each participant, measurements were performed twice, and the last measurement was recorded. Maximum left and right baPWV values were used for analysis.
Patients were divided into AS and non-AS groups based on their baseline baPWV. The AS group included patients with a baseline baPWV of ≥ 1800 cm/s, and the non-AS group included patients with a baseline baPWV of
Sociodemographic characteristics of each participant were collected by trained STEP physicians at baseline, including age, gender, body mass index, physical activity (never, 1-2 times/week, or ≥ 3 times/week) and the frequency of smoking and alcohol (never, never or in progress). The 10-year risk of cardiovascular disease was estimated using the Framingham risk score . Current smokers were defined as those who smoked at least one cigarette a day for more than 6 months. Current alcohol drinkers were defined as those who drank at least once a month for more than 6 months. Physical activity was assessed by type and frequency of physical activity at work and during leisure time and was categorized as never, 1–2 times/week, or ≥ 3 times/week. Body mass index was calculated by dividing weight (kg) by the square of height (m).
Clinical information, including office blood pressure, was collected at baseline and every 3 months during the follow-up period. At each visit, office blood pressure was measured using the same validated automatic blood pressure monitoring device (Omron HBP-1100U; Omron Healthcare). Participants had to rest for at least 5 minutes before the blood pressure measurement. A trained physician or nurse took three blood pressure measurements at an interval of 1-2 minutes, and the average value was recorded. Laboratory tests, including measurement of creatinine, fasting blood glucose, triglycerides, total cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol concentrations, were performed at baseline and annually thereafter.
Definition of results
The primary endpoint of the present study was an incident cardiovascular event, including a composite of first stroke (ischemic or hemorrhagic), acute coronary syndrome (myocardial infarction and hospitalization for unstable angina), acute decompensated heart failure, coronary revascularization (percutaneous coronary intervention or coronary artery bypass graft), atrial fibrillation or death from cardiovascular causes. This primary outcome was identical to that of the STEP trial . Secondary outcomes were stroke, major cardiovascular events (MACE), acute coronary syndrome (ACS), and death from any cause. MACE was defined as a composite of first occurrence of acute coronary syndrome, acute decompensated heart failure, coronary revascularization, and death from cardiovascular causes. The BP outcome in this study was the risk of low BP during treatment, which was defined as an average BP reached of
Safety outcomes were hypotension, dizziness, syncope, fracture, and renal outcome. The renal outcome was a composite of a ≥50% decrease in estimated glomerular filtration rate (eGFR) in patients with chronic renal failure (CKD) at baseline, a ≥30% decrease in eGFR at 2 in patients without CKD at baseline, or an increase in serum creatinine > 1.5 mg/dL in men or > 1.3 mg/dL in women. eGFR was calculated using the equation Diet modification in kidney disease . CRI was defined as an eGFR 2.
Of the 6865 patients in this study, 3047 patients were allocated to the AS group and 3818 patients were allocated to the non-AS group. The absolute risk of the primary endpoint in the non-AS group was 3.06%. Using this number of patients and a two-sided alpha of 0.05, this study had 80% power to detect a 26% relative change in the hazard ratio of the AS group compared to the non-AS group. Additionally, based on 3444 patients in the intensive treatment group and 3421 patients in the standard treatment group enrolled in this study and an absolute risk of 4.24% in the standard group for the primary outcome, this post hoc analysis provided 80% power to detect a 20% relative risk reduction of primary events between intensive treatment and standard PAS treatment. Statistical power was calculated using PASS (version 15).
Continuous variables are presented as mean ± standard deviation, and categorical variables are presented as not (%). Baseline characteristics were compared between baPWV baseline groups (AS and non-AS) and between SBP treatment groups stratified by baPWV baseline groups using one-way analysis of variance for continuous variables and chi square (χ2) test for categorical variables. The mean BP follow-up status was calculated for each patient by averaging their BP measurements from month 3 to the last visit.
We analyzed the association between baseline baPWV groups (AS and non-AS) and primary and secondary outcomes using Cox proportional hazards regression. We then used the Fine-Gray sub-distribution risk model to calculate hazard ratios (RR) with 95% confidence intervals (CI) for the primary outcome and secondary outcomes, at the exception of death from any cause associated with intensive treatment of SBP compared with standard treatment of SBP (reference) among participants in the AS or non-AS group. For deaths from all causes, the Cox regression model was used. To assess the interaction effect of SBP treatment group in SA and non-SA patients, the product term (SBP × SA or non-SA treatment group) was included in the Cox proportional hazards regression models with a likelihood ratio test. The proportional hazards hypothesis was tested by Schoenfeld residuals for AS status, SBP intervention, and all covariates, and no violations were observed. All multivariate models were adjusted for SBP intervention, clinical centers, age and sex, baseline mean arterial pressure (MAP) level, baseline glucose level, baseline LDL cholesterol level , type of baseline antihypertensive agent, frequency of physical activity, smoking status, and alcohol status. . In addition, cumulative incidence curves were performed using a Kaplan-Meier survival curve to compare the incidence of primary outcome and stroke between the intensive and standard treatment arms in the groups AS and not AS.
We analyzed the effect of baseline AS status on the incidence of on-treatment low DBP (
All analyzes were performed using R version 4.1.2. A double sided P a value