Introduction

Hypertension is one of the major risk factors for cardiovascular events. Blood pressure-lowering treatment has been shown to significantly reduce cardiovascular morbidity and mortality in hypertensive patients regardless of a history of cardiovascular disease (CVD) [1,2,3,4]. Recent meta-analyses have revealed that achievement of blood pressure <130/80 mmHg is associated with greater reductions in major cardiovascular events without increases in all-cause death and cardiovascular death in hypertensive patients with a history of coronary artery disease (CAD) [5, 6]. Therefore, in recently updated major hypertension guidelines, the blood pressure target has been lowered from <140/90 mmHg to <130/80 mmHg for the treatment of hypertension in patients with a history of CAD [7,8,9].

Arterial stiffness increases with the progression of arteriosclerotic change. Conversely, increased arterial stiffness is closely associated with the progression and maintenance of these conditions, leading to target organ damage and cardiovascular complications [10]. Therefore, an index of arterial stiffness may serve not only as a marker of arteriosclerotic change but also as a prognostic marker for cardiovascular complications. Recently, measurement of brachial–ankle pulse wave velocity (baPWV) has been widely performed for noninvasive assessment of arterial stiffness. Several lines of evidence have shown that increased baPWV is significantly associated with an increased risk of cardiovascular events independent of other cardiovascular risk factors in patients without CVD, including hypertensive patients without CVD [11,12,13]. However, there is little information on the predictive value of baPWV in hypertensive patients with a history of CAD. baPWV is profoundly affected by blood pressure regardless of the severity of arterial sclerotic change. Therefore, it is hypothesized that baPWV would be more useful for cardiovascular risk assessment in hypertensive patients with controlled blood pressure.

The purposes of this study were to determine whether the newly recommended blood pressure target of <130/80 mmHg is associated with a lower risk of cardiovascular events in treated hypertensive patients with a history of CAD and to determine whether baPWV can be used as an independent marker to predict the risk of recurrent cardiovascular events in treated hypertensive patients with CAD who have well-controlled blood pressure <130/80 mmHg.

Methods

Study design

We analyzed data from Flow-mediated Dilation Japan (FMD-J) Study A. The rationale and design of FMD-J Study A have been described previously [14]. This study was a prospective multicenter observational cohort study conducted at 22 university hospitals and affiliated clinics in Japan to examine the usefulness of noninvasive vascular function tests for the management of Japanese patients with CAD with a 3-year follow-up period [14]. The main results were reported previously [15]. The study protocol was approved by the Institution’s ethics committee on research on humans. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki. Written informed consent was obtained from each patient included in the study. The protocol was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000012950).

Study patients

Patients aged 20–74 years with a diagnosis of CAD who had been under regular follow-up at any of the participating institutions for at least 6 months were eligible for enrollment in FMD-J Study A. A total of 679 patients were registered from May 2010 to September 2012. CAD was defined as myocardial infarction, angina pectoris with organic stenosis of at least one coronary artery confirmed by diagnostic imaging (i.e., coronary angiography, cardiac nuclear scintigraphy, or coronary-computed tomography), or previous percutaneous coronary intervention (PCI). The exclusion criteria were as follows: history of coronary bypass surgery; severe valvular heart disease; arrhythmia requiring treatment (i.e., atrial fibrillation, atrial flutter, permanent pacemaker implantation, or frequent ventricular premature beats); severe chronic heart failure (New York Heart Association level greater than Level III); malignancy; current treatment with steroids, nonsteroidal anti-inflammatory drugs, or immunosuppressive drugs; serum creatinine level greater than 2.5 mg/dL; history of stroke, aortic disease (except peripheral artery disease), or serious liver disease; and judgment of an attending physician that an individual is ineligible for inclusion in the study.

Study procedures

baPWV measurement and blood examinations were conducted at the start of the study. Cardiovascular events were monitored annually during the 3-year follow-up period. The participants were managed by their attending physicians, who were encouraged to treat cardiovascular risk factors, including hypertension, dyslipidemia, and diabetes mellitus, to achieve the best available standard of care in accordance with guidelines.

Measurement of baPWV and assessment of cardiovascular risk factors

Subjects fasted the previous night and abstained from consuming alcohol, smoking, consuming caffeine, and taking antioxidant vitamins on the day of the examination. Each subject was kept in the supine position in a quiet, dark, and air-conditioned room (constant temperature of 23–26 °C) throughout the study. A 23-gauge polyethylene catheter was inserted into the left deep antecubital vein to obtain blood samples. baPWV was measured after the subjects maintained the supine position for at least 20 min. Blood samples were collected on the same day as the baPWV measurement. The observers were blind to the form of examination. Detailed information on the study protocol and measurement of baPWV is provided in the online-only Data Supplement. baPWV was measured using a vascular testing device (Form/ABI, Omron Health Care Co., Kyoto, Japan). The higher value of either side was used for analysis. Office blood pressure was measured in accordance with the Japanese Society of Hypertension Guidelines for the Management of Hypertension [16]. Diabetes was defined according to the American Diabetes Association recommendation [17]. Dyslipidemia was defined according to the third report of the National Cholesterol Education Program [18]. We defined smokers as those who were current smokers.

Study outcomes

The primary outcome was a composite of coronary events, including fatal, or nonfatal myocardial infarction, coronary artery restenosis, and de novo coronary artery stenosis as confirmed by diagnostic imaging (i.e., coronary angiography, cardiac nuclear scintigraphy, or coronary-computed tomography), stroke, heart failure, or sudden death. Coronary artery restenosis was defined as ≥75% luminal narrowing or repeat revascularization at a previous PCI site, and de novo coronary artery stenosis was defined as the progression of luminal narrowing ≥75% or revascularization at a non-PCI site. Heart failure was defined as a requirement for hospitalization due to hypoxia with congestion caused by cardiac dysfunction. Definitions of the clinical outcomes have been provided previously [14, 15].

Statistical analysis

The results are presented as the means ± SD for continuous variables and as percentages for categorical variables. All reported probability values were two-sided, and a probability value <0.05 was considered indicative of statistical significance. Categorical variables were compared by means of the chi-square test. Continuous variables were compared by using unpaired Student’s t test. Receiver–operator characteristic (ROC) curve analysis was performed to assess the sensitivity and specificity of measurements of baPWV for predicting the composite outcome. Time-to-event end-point analyses were performed by using the Kaplan–Meier method. We categorized subjects into two groups according to the cutoff value of baPWV. The cutoff value was determined according to the highest Youden index from the ROC curve for predicting the composite outcome. The log-rank test was used to compare the groups. Cox proportional hazard regression analyses were performed to evaluate the association of blood pressure control and baPWV with the composite outcome with adjustments for age, sex, and cardiovascular risk factors. The data were processed using JMP version 11 (SAS Institute, Cary, NC) and R software (R version 3.6.2, R Foundation for Statistical Computing, Vienna, Austria).

Results

Blood pressure control and clinical outcomes

A total of 679 patients were enrolled, and 662 patients (97.4%) completed the study. Of those patients, 447 treated hypertensive patients with a history of CAD were included in the analysis after excluding patients with no organic coronary artery stenosis (n = 32), those without measurement of baPWV (n = 104) in whom assessment of arterial stiffness was performed by the cardio–ankle vascular index using Vasera (Fukuda Denshi Co., Ltd, Tokyo, Japan) instead of baPWV, those with ankle–brachial pressure index values less than 0.9 (n = 29), and those without antihypertensive drug treatment (n = 50) (Fig. 1). The baseline clinical characteristics are summarized in Table 1. During a median follow-up period of 47.6 months (interquartile range, 41.8–54.1 months), 11 subjects had myocardial infarction, 30 had de novo coronary artery stenosis, 14 had coronary artery restenosis, 3 had stroke, 4 had heart failure, and 2 died suddenly (Supplementary Table 1). We divided the subjects into two groups according to blood pressure: patients with systolic blood pressure ≥130 mmHg and/or diastolic blood pressure ≥80 mmHg (n = 246) and patients with systolic blood pressure <130 mmHg and diastolic blood pressure <80 mmHg (n = 201). Clinical characteristics of the patients and clinical events on the basis of blood pressure are summarized in Table 1 and Supplementary Table 1. Kaplan–Meier analysis showed that patients with blood pressure <130/80 mmHg had significantly fewer composite outcomes than those with blood pressure ≥130/80 mmHg (log-rank P = 0.04; Fig. 2). Multivariate Cox proportional hazard analyses revealed that blood pressure <130/80 mmHg was a significant predictor of a lower risk of the composite outcome after adjustments for other cardiovascular risk factors and coronary lesions (Supplementary Table 2).

Fig. 1
figure 1

Flow chart of the study design from screening to completion of the trial. CAD indicates coronary artery disease, baPWV brachial–ankle pulse wave velocity, ABI ankle–brachial pressure index

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Table 1 Clinical characteristics of the subjects on the basis of blood pressure control in the total population
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Fig. 2
figure 2

Kaplan–Meier curves of cumulative event-free survival of the composite outcome in subgroups of subjects categorized according to blood pressure with a cutoff at 130/80 mmHg in treated hypertensive patients with coronary artery disease. The P value was calculated from the log-rank test

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baPWV and clinical outcomes

A cutoff value of baPWV derived from the ROC curve for predicting the composite outcome was 1726 cm/s with an area under the curve (AUC) value of 0.57 (95% confidence interval (CI), 0.49–0.64) in the total population (Supplementary Fig. 1). We divided the subjects into two groups according to the cutoff value of baPWV of 1726 cm/s derived from the ROC curve. Clinical characteristics of the patients and clinical events on the basis of baPWV are summarized in Supplementary Table 3 and Supplementary Table 4. Kaplan–Meier analysis showed that patients with baPWV ≥ 1726 cm/s had significantly more composite outcomes than those with baPWV < 1726 cm/s (log-rank P = 0.01; Supplementary Fig. 2). Multivariate Cox proportional hazard analyses revealed that baPWV ≥ 1726 cm/s was a significant predictor of a higher risk of the composite outcome after adjustments for other cardiovascular risk factors and coronary lesions except blood pressure (hazard ratio, 1.79; 95% CI, 1.06–3.05; P = 0.03; Supplementary Table 5). However, a baPWV ≥ 1726 was not significantly associated with the composite outcome when blood pressure control was entered into the model (hazard ratio, 1.62; 95% CI, 0.94–2.78; P = 0.08; Supplementary Table 5).

baPWV and clinical outcomes in patients with blood pressure <130/80 mmHg

Next, we investigated the association between baPWV and cardiovascular events in treated hypertensive patients with CAD who had blood pressure <130/80 mmHg. The cutoff value of baPWV derived from the ROC curve for predicting the composite outcome was 1731 cm/s with an AUC value of 0.59 (95% CI, 0.45–0.72) in patients with blood pressure <130/80 mmHg (Fig. 3). Therefore, we divided 201 patients with blood pressure <130/80 mmHg into two groups according to the cutoff value of baPWV of 1731 cm/s. The clinical characteristics of the patients and clinical events according to the cutoff value of baPWV are summarized in Table 2 and Supplementary Table 6. Kaplan–Meier analysis showed that patients with baPWV ≥ 1731 cm/s had significantly more composite outcomes than those with baPWV < 1731 cm/s (log-rank P = 0.01; Fig. 4). Multivariate Cox proportional hazard analyses revealed that baPWV ≥ 1731 cm/s was a significant predictor of a higher risk of the composite outcome after adjustments for other cardiovascular risk factors and coronary lesions (Table 3).

Fig. 3
figure 3

Receiver operating characteristic curve of baPWV for predicting the composite outcome in treated hypertensive patients with coronary artery disease with blood pressure less than 130/80 mmHg

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Table 2 Clinical characteristics of the subjects on the basis of cutoff value of baPWV in patients with blood pressure <130/80 mmHg
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Fig. 4
figure 4

Kaplan–Meier curves of cumulative event-free survival of the composite outcome in subgroups of subjects categorized according to the cutoff value of brachial–ankle pulse wave velocity (baPWV) in treated hypertensive patients with coronary artery disease with blood pressure less than 130/80 mmHg. The P value was calculated from the log-rank test

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Table 3 Association between baPWV and cardiovascular events during follow-up in patients with blood pressure <130/80 mmHg
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baPWV and clinical outcomes in patients with blood pressure ≥130/80 mmHg

We investigated the association between baPWV and cardiovascular events in treated hypertensive patients with CAD who had blood pressure ≥130/80 mmHg. The cutoff value of baPWV derived from the ROC curve for predicting the composite outcome was 2388 cm/s with an AUC value of 0.52 (95% CI, 0.42–0.61) in patients with blood pressure ≥130/80 mmHg (Supplementary Fig. 3). When we divided 246 patients with blood pressure ≥130/80 mmHg into two groups according to the cutoff value of baPWV of 2388 cm/s, the number of patients with baPWV ≥ 2388 cm/s was too small (n = 7). Therefore, we divided the 246 patients into two groups according to the cutoff value of baPWV of 1731 cm/s derived from the ROC curve for predicting the composite outcome in patients with blood pressure <130/80 mmHg. The clinical characteristics of the patients and clinical events according to the cutoff value of baPWV are summarized in Supplementary Table 7 and Supplementary Table 8. Kaplan–Meier analysis showed that there was no significant difference in the event-free survival rate between patients with baPWV ≥ 1731 cm/s and patients with baPWV < 1731 cm/s (log-rank P = 0.56; Supplementary Fig. 4).

Association between blood pressure, baPWV, and cardiovascular events

There was a significant correlation between systolic blood pressure and baPWV (r = 0.33, P < 0.001). Cox proportional hazard analyses revealed that baPWV ≥ 1731 cm/s was significantly associated with a higher risk for the composite outcome in an unadjusted model in CAD patients with blood pressure <130/80 mmHg (hazard ratio, 2.94; 95% CI, 1.26–6.86; P = 0.01) but not in CAD patients with blood pressure ≥130/80 mmHg (hazard ratio, 1.19; 95% CI, 0.66–2.16; P = 0.56). There was a trend of interaction between blood pressure (<130/80 mmHg) and baPWV (≥1731 cm/s) (P = 0.08).

Discussion

In the present study, we demonstrated that blood pressure <130/80 mmHg was significantly associated with a lower risk of cardiovascular events independent of other conventional risk factors in treated hypertensive patients with a history of CAD. We also demonstrated that baPWV ≥ 1731 cm/s was a significant predictor of a higher incidence of cardiovascular events independent of conventional risk factors in treated hypertensive patients with a history of CAD who had blood pressure <130/80 mmHg. These findings suggest that the newly recommended blood pressure target of <130/80 mmHg for the treatment of hypertensive patients with CAD is appropriate and that baPWV is a useful vascular biomarker for cardiovascular risk assessment in treated hypertensive patients with CAD with well-controlled blood pressure <130/80 mmHg.

Blood pressure-lowering treatment has been shown to significantly reduce cardiovascular morbidity and mortality in patients with hypertension [1,2,3,4]. For the treatment of hypertensive patients with a history of CAD, recent meta-analyses have shown that achievement of blood pressure <130/80 mmHg is associated with greater reductions in cardiovascular events without increases in all-cause death and cardiovascular death [5, 6]. Therefore, in recently updated guidelines, including the 2017 US hypertension guideline, the 2018 European hypertension guideline, and the 2019 Japanese hypertension guideline, the blood pressure target for the treatment of hypertensive patients with a history of CAD has been lowered from 140/90 mmHg to 130/80 mmHg [7,8,9]. In the present study, patients with blood pressure <130/80 mmHg had significantly fewer cardiovascular events than those with blood pressure ≥130/80 mmHg among treated hypertensive patients with CAD. In addition, blood pressure <130/80 mmHg was significantly associated with a lower risk of cardiovascular events independent of other conventional risk factors. These findings support the blood pressure target of <130/80 mmHg recommended in the current major guidelines for the treatment of hypertensive patients with a history of CAD.

Recently, baPWV has been widely used for noninvasive assessment of arterial stiffness in humans. baPWV has been shown to correlate closely with carotid–femoral PWV (cfPWV), the standard criterion for noninvasive assessment of central arterial stiffness [19, 20]. Compared with the measurement of cfPWV requiring specialized training and exposure of the inguinal region during measurement, baPWV measurement is a simple method using a separate oscillometric cuff for each of the four limbs. Therefore, baPWV measurement is more easily applicable than cfPWV measurement to clinical practice. Several lines of evidence have shown that baPWV can be used not only as an index of arterial stiffness but also as a prognostic marker for cardiovascular events [10,11,12,13, 21,22,23]. Recent studies have shown that increased baPWV is significantly associated with an increased risk of cardiovascular events independent of conventional risk factors and confounding factors in patients with hypertension who have no history of CVD [11, 12]. However, there is little information on the association between baPWV and the prognosis of treated hypertensive patients with a history of CAD who had well-controlled blood pressure <130/80 mmHg as recommended in the updated hypertension guidelines. In the present study, baPWV ≥ 1731 cm/s was significantly associated with a higher risk for cardiovascular events in treated hypertensive patients with a history of CAD who had well-controlled blood pressure <130/80 mmHg, suggesting that measurement of baPWV enables cardiovascular risk stratification of treated hypertensive patients with CAD who had well-controlled blood pressure <130/80 mmHg recommended in the current hypertension guidelines [7,8,9].

Structural and functional aspects of arterial stiffness should be taken into account for appropriate interpretation of the results of baPWV measurement. Structural arterial stiffness is considered to be associated with arteriosclerotic change, whereas functional arterial stiffness is affected by systemic hemodynamics, such as blood pressure and heart rate [24, 25]. In the present study, when patients with blood pressure ≥130/80 mmHg were divided into two groups according to the cutoff value of baPWV ≥ 1731 cm/s derived from the ROC curve for predicting the composite outcome in patients with blood pressure <130/80 mmHg, there was no significant difference in event-free survival rate between the two groups, suggesting that the cutoff value of baPWV for cardiovascular risk assessment in CAD patients with well-controlled blood pressure cannot be applied to CAD patients with poorly controlled blood pressure and that the prognostic ability of baPWV is weak in patients with poorly controlled blood pressure. In addition, the AUC value of the ROC curve for predicting the composite outcome was 0.59 with a 95% CI of 0.45–0.72 in CAD patients with well-controlled blood pressure, suggesting that the prognostic ability of baPWV for cardiovascular events is not strong, even in CAD patients with well-controlled blood pressure. Systemic dynamics, especially blood pressure level, and cardiovascular risk assessed by traditional cardiovascular risk factors should be taken into account for appropriate interpretation and application of the results of baPWV measurement. The recommended procedures for the management of hypertensive patients with a history of CAD could be as follows. First, the newly recommended blood pressure target of <130/80 mmHg should be achieved. Second, after achievement of the blood pressure target, measurement of baPWV is recommended to identify individuals with increased arterial stiffness mainly due to arteriosclerotic change who are at high risk for recurrent cardiovascular events. For those patients, individualized intensive management of cardiovascular risk factors should be considered for secondary prevention.

There was a limitation in the present study. Kaplan–Meier analysis can provide appropriate estimates only when characteristics of the compared groups do not differ. A fully adjusted analysis should instead be prioritized in the present study dealing with real-world data. However, it was difficult to perform a fully adjusted analysis due to the relatively small number of primary outcome events in the present study. Therefore, we performed multivariate Cox proportional hazard analyses including only traditional cardiovascular risk factors or variables selected through a stepwise selection procedure as covariates. Further study including a larger number of CAD patients with treated hypertension is needed to perform detailed analysis of the usefulness of baPWV for assessing cardiovascular risk.

In conclusion, in treated hypertensive patients with a history of CAD, blood pressure <130/80 mmHg was significantly associated with a lower risk of cardiovascular events, supporting the newly recommended blood pressure target of <130/80 mmHg for the treatment of hypertensive patients with a history of CAD. In addition, baPWV ≥ 1731 cm/s was significantly associated with a higher risk of cardiovascular events in treated hypertensive patients with CAD who had blood pressure <130/80 mmHg. baPWV may be useful for cardiovascular risk stratification of hypertensive patients with a history of CAD who had well-controlled blood pressure <130/80 mmHg. Further studies are needed to determine whether individualized intensive interventions improve cardiovascular outcomes in treated hypertensive patients with CAD having well-controlled blood pressure who are judged to be at high risk for recurrent cardiovascular events by measurement of baPWV.