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There is scarce evidence on the prognostic impact of ambulatory blood pressure monitoring (ABPM) in patients with coronary heart disease (CHD). We aimed to investigate the risks of all-cause and cardiovascular mortality associated with office and ambulatory blood pressure (BP) in patients with CHD.
Methods
Prospective, observational study with 2679 patients (mean age 67 years, 35% women) with CHD, selected from the Spanish ABPM Registry. Associations between BP indices, as well as BP phenotypes, with all-cause and cardiovascular mortality were assessed by means of Cox-survival models adjusted for clinical confounders and alternative BP measures.
Results
During a median follow-up of 8.7 years, 740 patients (27.6%) died, 331 (12.4%) from cardiovascular causes. Office systolic BP was not associated with mortality, while 24-h (hazard ratio: 1.36; 95% confidence interval: 1.26–1.47), daytime (1.33; 1.23–1.44) and nighttime (1.33; 1.24–1.43) systolic BP were all associated with all-cause mortality, after adjustment for confounders and office BP. Masked hypertension (1.49; 1.10–2.01), sustained hypertension (1.46; 1.19–1.80), isolated daytime hypertension (1.80; 1.21–2.68) and isolated nighttime hypertension (1.33; 1.09–1.63), but not white-coat hypertension, were all associated with an increased risk of mortality compared to reference groups. A blunted nocturnal dipping (1.08; 1.01–1.16, for 1 standard deviation change in systolic night-to-day ratio) was also associated with an increased risk of death. Similar results were obtained for cardiovascular mortality.
Conclusion
ABPM indices are more closely related with the risk of death than office BP in patients with CHD. These results emphasize the use of ABPM for a more accurate BP evaluation in this group of patients.
Ambulatory blood pressure monitoring (ABPM) provides a better assessment of blood pressure (BP) than clinic (or office) measurements in patients with hypertension, but studies in patients with coronary heart disease (CHD) are scarce and with a limited sample size.
This study evaluates mortality (all-cause and cardiovascular) related to office and ambulatory BP in patients with CHD.
What was learned from the study?
Ambulatory systolic BP was more closely related to all-cause and cardiovascular mortality than office systolic BP. In addition, the presence of masked hypertension and a blunted nocturnal BP fall were associated with an increased risk of mortality.
ABPM provides a better risk characterization in patients with CHD and should be widely used in this group of patients.
Digital Features
This article is published with digital features, including a graphical abstract, to facilitate understanding of the article. To view digital features for this article, go to https://doi.org/10.6084/m9.figshare.30210007.
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Introduction
Coronary heart disease (CHD) is the most prevalent manifestation of cardiovascular disease, and represents an important cause of death and disability [1]. Among risk factors for CHD development, hypertension is one of the most important, due to both its high prevalence and its close relation with CHD [2].
Ambulatory blood pressure monitoring (ABPM) provides a better assessment of blood pressure (BP) than clinic (or office) measurements [3‐5]. BP estimates obtained during ABPM, such as 24-h, daytime and nighttime BP better predict cardiovascular events and mortality in patients with hypertension [4‐6]. In addition, other ABPM-derived parameters, such as BP phenotypes [5, 7‐9], nocturnal dip [10, 11], or short-term variability [12, 13] have additional prognostic importance in individuals with hypertension.
ABPM could be especially useful in patients with CHD. However, studies relating ABPM-derived parameters with CHD are scarce, mostly cross-sectional [14] and a few prospective studies with limited sample size [15‐17]. Results of such studies have been relatively inconsistent with respect to the relative impact of daytime or nighttime BP, as well as the effects of nocturnal dipping and BP variability. In most cases, this has been related to low sample sizes, or lack of adjustment for other BP indices.
In this report, we aimed to investigate the risks of all-cause and cardiovascular mortality associated with office and ABPM-derived BP indices, including absolute office, 24-h, daytime and nighttime BP, combined clinic and ABPM phenotypes, isolated daytime and nighttime hypertension, nocturnal dipping and short-term BP variability in a large sample of patients with documented CHD (previous acute coronary syndrome or stable angina) recruited from the Spanish ABPM registry.
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Methods
Study Design
Spanish ABPM Registry characteristics have been previously detailed [5, 8, 9, 11, 13]. Patients included were ≥ 18 years old submitted for ABPM according to circumstances recommended in contemporary guidelines. Recruitment began in March 2004 and ended in December 2014. Permission was obtained to access and use data from the Spanish ABPM Registry. All participants gave informed consent and the study was approved by the corresponding ethics committees. All the analyses were performed in an anonymized database.
BP Measurements
Validated upper-arm cuff oscillometric devices were used for office BP measurement. The standardized procedure included 2 separate readings obtained after a 5-min rest in a sitting position. The average of these 2 measurements was used in the analyses. ABPM was performed using an automated oscillometric device (SpaceLabs 90207, Snoqualmie, Washington, USA). Measurements were taken every 20-min during the day and every 30-min during the night. Pre-established quality criteria included ≥ 70% of BP successful readings during the daytime and nighttime periods, a minimum of 24-h duration, and at least one BP measurement per hour. Daytime and nighttime periods were defined according to the patient self-reported timing of sleep and awakening.
Study Variables
Age, sex, weight, height (with body mass index calculation), main cardiovascular risk factors (smoking, diabetes mellitus, dyslipidemia), and previous cardiovascular disease (coronary heart disease, congestive heart failure, symptomatic peripheral artery disease, or cerebrovascular disease), as well as details on antihypertensive treatment, including drug classes were collected for each patient based on the interviews and physical examination, and from data drawn from clinical records. They were defined and measured in accordance with contemporary European guidelines [18‐20]. For the present analysis, we selected 2679 patients with a previous diagnosis of CHD, including 1291 patients with a diagnosis of myocardial infarction (I21), 1485 patients with a diagnosis of angina (I20) and 97 patients with both diagnoses.
Blood Pressure Phenotypes and Blood Pressure Variability Indices
Blood pressure in the normal range (either normotension or controlled hypertension in treated patients) was considered when office BP was < 140/90 mmHg and 24-h BP was < 130/80 mmHg. White-coat hypertension (or white-coat uncontrolled hypertension in treated patients) was considered when office BP was ≥ 140 and/or 90 mmHg and 24-h BP < 130/80 mmHg. Masked hypertension (or masked uncontrolled hypertension in treated patients) was diagnosed when office BP was < 140/90 mmHg and 24-h BP was ≥ 130 and/or 80 mmHg. Finally, sustained hypertension was considered when both office and 24-h BP were above the aforementioned normal limits.
Isolated daytime hypertension was defined as elevated daytime BP (≥ 135 and/or ≥ 85 mmHg) and normal nighttime BP (< 120/70 mmHg). Isolated nighttime BP was defined as elevated nighttime BP (≥ 120 and/or ≥ 70 mmHg) and normal daytime (< 135/85 mmHg) BP. Combined daytime and nighttime hypertension was defined in the presence of both daytime and nighttime BP elevation.
Night-to-day ratio (NDR) for systolic and diastolic BP was calculated by dividing nighttime and daytime BP. Four different patterns for both systolic and diastolic BP were established: Dipper pattern: NDR < 0.9 and ≥ 0.8; non-dipper pattern: NDR < 1 and ≥ 0.9; extreme dipper pattern: NDR < 0.8 and riser pattern: NDR ≥ 1. Other BP variability indices included standard deviation (SD) for daytime and nighttime BP, 24-h weighted SD (mean of daytime and nighttime SD weighted for the duration of each period [21] and average real variability (ARV) calculated as previously reported [22].
Mortality Data
A computerized search of the vital registry of the Spanish National Institute of Statistics, was used to establish the vital status of each patient, as well as the date and cause of death in those who died during follow-up. Death certificates were consulted to establish the cause of death, determined by a nosologist. Deaths were coded according to the International Statistical Classification of Diseases, Tenth Revision (I00-I99 code for those of cardiovascular origin). Follow-up for each participant was from the date of their recruitment visit in the blood pressure registry to the date of death or December 31, 2019, whichever occurred first.
Statistical Analysis
Data are presented as percentages for categorical variables and as mean ± SD (or median and interquartile range) for continuous variables. Associations between either BP indices or BP categories or phenotypes and all-cause and cardiovascular death were summarized with hazard ratios and their 95% CI for 1 SD changes or for selected categories compared to the reference group. Hazard ratios were calculated by Cox models, adjusted for clinical confounders (age, sex, body mass index, smoking, diabetes, and antihypertensive treatment) and additionally for alternative BP measures.
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The Statistical Package for Social Sciences (SPSS) for Windows version 29.0 software (IBM, Armonk, New York, USA) was used for statistical analysis.
Results
The Spanish ABPM Registry mortality data included a total number of 59,124 patients, from whom 2679 had a previous diagnosis of CHD. Mean age was 67.3 ± 11 years and 939 (35.1%) were women. Table 1 shows general characteristics of the included population.
Table 1
Clinical characteristics of patients with history of coronary heart disease
Parameter
N = 2679
Age, years
67.3 ± 11.0
Sex, women
939 (35.1)
Obesity
1213 (45.3)
Current smokers
280 (10.5)
Diabetes
1008 (37.6)
Treated for hypertension
2366 (88.3)
Blood pressure
Office systolic
149.2 ± 21.4
Office diastolic
81.4 ± 12.4
24-h systolic
130.0 ± 15.1
24-h diastolic
71.5 ± 10.0
Daytime systolic
131.9 ± 15.2
Daytime diastolic
73.7 ± 10.6
Nighttime systolic
124.8 ± 17.9
Nighttime diastolic
65.9 ± 10.3
Blood pressure variability
Systolic NDR
0.95 ± 0.09
Diastolic NDR
0.90 ± 0.10
24-h systolic weighted SD
13.3 ± 3.6
24-h diastolic weighted SD
9.0 ± 2.2
Daytime systolic SD
13.8 ± 4.2
Daytime diastolic SD
9.0 ± 2.7
Nighttime systolic SD
12.3 ± 4.1
Nighttime diastolic SD
9.0 ± 2.2
Systolic ARV
10.6 ± 2.6
Diastolic ARV
7.4 ± 1.9
Data expressed as mean ± standard deviation (SD), or frequency (%). Obesity defined as body mass index > 30 kg/m2
NDR night-to-day ratio, ARV average real variability
During a median follow-up of 8.9 years (interquartile range: 6.7–11.3 years) 740 patients (27.6%) died, 331 (12.4%) from cardiovascular causes, which included 152 ischemic heart disease deaths, 53 stroke deaths, and 45 heart failure deaths.
Relationship Between Office and Ambulatory Blood Pressure Indices and Mortality
Systolic BP showed U-shaped or J-shaped relation with all-cause and cardiovascular mortality (Fig. 1), while the relation with diastolic BP was flat, with the exception of nighttime BP (Fig. 2). In the confounder adjusted model, office BP was not significantly associated with all-cause or cardiovascular mortality (Table 2). In contrast, ambulatory systolic BP, either 24-h, daytime or nighttime, were all associated with all-cause and cardiovascular mortality. Adjustment for office systolic BP did not significantly modify such association. When daytime and nighttime BP were simultaneously adjusted, both indices remained significantly associated with mortality. With respect to ambulatory diastolic BP indices only nighttime diastolic BP showed a significant association with all-cause and cardiovascular mortality after adjustment for clinical confounders and diastolic office BP.
Fig. 1
All-cause (upper panel) and cardiovascular (lower panel) deaths (%) according to systolic blood pressure (SBP) categories, for office, 24-h, daytime and nighttime blood pressure
All-cause (upper panel) and cardiovascular (lower panel) deaths (%) according to diastolic blood pressure (DBP) categories, for office, 24-h, daytime and nighttime blood pressure
Risk estimates (Hazard Ratio for 1-SD increase) of different office and ambulatory blood pressure in relation to all-cause and cardiovascular mortality
Confounder-adjusteda
Additionally adjusted for office or 24-h BP
Additionally adjusted for daytime or nighttime BP
All-cause mortality
Office SBP
1.04 (0.96–1.11)
0.91 (0.84–0.99)
24-h SBP
1.31 (1.22–1.41)
1.36 (1.26–1.47)
Daytime SBP
1.28 (1.20–1.38)
1.33 (1.23–1.44)
1.16 (1.04–1.29)
Nighttime SBP
1.31 (1.22–1.40)
1.33 (1.24–1.43)
1.21 (1.10–1.34)
Office DBP
0.93 (0.86–1.00)
0.92 (0.84–1.00)
24-h DBP
1.00 (0.92–1.08)
1.04 (0.95–1.14)
Daytime DBP
0.97 (0.89–1.05)
1.01 (0.92–1.11)
0.87 (0.76–0.99)
Nighttime DBP
1.07 (0.99–1.16)
1.11 (1.03–1.21)
1.21 (1.08–1.35)
Cardiovascular mortality
Office SBP
1.01 (0.91–1.12)
0.87 (0.77–0.98)
24-h SBP
1.36 (1.23–1.51)
1.44 (1.29–1.61)
Daytime SBP
1.34 (1.21–1.49)
1.43 (1.27–1.60)
1.27 (1.08–1.49)
Nighttime SBP
1.33 (1.20–1.47)
1.36 (1.23–1.51)
1.17 (1.01–1.16)
Office DBP
0.99 (0.88–1.10)
0.94 (0.83–1.07)
24-h DBP
1.09 (0.97–1.24)
1.13 (0.98–1.30)
Daytime DBP
1.08 (0.95–1.23)
1.12 (0.97–1.29)
0.99 (0.82–1.20)
Nighttime DBP
1.13 (1.01–1.27)
1.16 (1.03–1.31)
1.17 (0.99–1.38)
BP blood pressure, SD standard deviation, SBP systolic BP, DBP diastolic BP
aAdjusted for age, sex, body mass index, smoking, diabetes, and treatment for hypertension
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Considering BP phenotypes, white-coat hypertension (elevated office BP but normal 24-h BP) was not associated with an increased risk of all-cause or cardiovascular death, while sustained hypertension (elevated both office and 24-h BP) was associated with an increased risk of all-cause death (HR: 1.46 95% CI: 1.19–1.80) and cardiovascular death (1.45; 1.06–1.96) compared to normal BP. Masked hypertension (normal office, but elevated 24-h BP) was associated with an increased risk in all-cause death (1.49; 1.10–2.01), but the association was non-significant with respect to cardiovascular death (1.36; 0.87–2.12) (Table 3).
Table 3
Hazard ratio of different blood pressure phenotypes in relation to all-cause and cardiovascular mortality
Phenotype
Number of patients
Number of deaths
Confounder-adjusteda
All-cause mortality
BP in the normal range
562 (21%)
118 (21%)
Reference
White-coat hypertension
768 (28.7%)
169 (22%)
0.86 (0.68–1.10)
Masked hypertension
233 (8.7%)
69 (29.6%)
1.49 (1.10–2.01)
Sustained hypertension
1116 (41.7%)
384 (34.4%)
1.46 (1.19–1.80)
Cardiovascular mortality
BP in the normal range
562 (21%)
55 (9.8%)
Reference
White-coat hypertension
768 (28.7%)
69 (9%)
0.76 (0.53–1.08)
Masked hypertension
233 (8.7%)
30 (12.9%)
1.36 (0.87–2.12)
Sustained hypertension
1116 (41.7%)
177 (15.9%)
1.45 (1.06–1.96)
BP blood pressure
aAdjusted for age, sex, body mass index, smoking, diabetes, and treatment for hypertension
Compared to patients with normal daytime and nighttime BP, those having isolated daytime hypertension (elevated daytime and normal nighttime BP), isolated nighttime hypertension (elevated nighttime and normal daytime BP), or combined daytime and nighttime hypertension, had significant increased risk of death (Table 4). Only combined daytime and nighttime hypertension had significantly increased risk of cardiovascular death, compared to normal daytime and nighttime BP, while the risk in groups with isolated either daytime or nighttime hypertension was not statistically significant (wide confidence interval due to low number of patients and cardiovascular deaths).
Table 4
Hazard ratio of phenotypes according to daytime or nighttime blood pressure elevation in relation to all-cause and cardiovascular mortality
Phenotype
Number of patients
Number of deaths
Confounder-adjusteda
All-cause mortality
Daytime and nighttime normal BP
879 (32.8%)
163 (18.5%)
Reference
Isolated daytime hypertension
124 (4.6%)
30 (24.2%)
1.80 (1.21–2.68)
Isolated nighttime hypertension
693 (25.9%)
205 (29.6%)
1.33 (1.08–1.63)
Combined daytime and nighttime hypertension
993 (36.7%)
342 (46.2%)
1.79 (1.48–2.16)
Cardiovascular mortality
Daytime and nighttime normal BP
879 (32.8%)
68 (7.7%)
Reference
Isolated daytime hypertension
124 (4.6%)
13 (10.5%)
1.81 (0.98–3.33)
Isolated nighttime hypertension
693 (25.9%)
87 (12.6%)
1.34 (0.98–1.85)
Combined daytime and nighttime hypertension
993 (36.7%)
331 (12.4%)
2.06 (1.55–2.73)
BP blood pressure
aAdjusted for age, sex, body mass index, smoking, diabetes, and treatment for hypertension
Table 5 shows risks associated with the night-to-day ratio (NDR) of BP, as well as groups defined by nocturnal phenotypes. In models adjusted for clinical confounders and 24-h BP, 1-SD increase in both systolic and diastolic NDR was associated with an increased risk of all-cause death (1.08; 95% CI: 1.01–1.16 for systolic NDR and 1.09; 1.01–1.17, for diastolic NDR. Considering nocturnal phenotypes, and compared with the dipper pattern, only the diastolic riser pattern was associated with a significant risk of death (1.39; 1.13–1.71), while neither the non dipper or the extreme dipper pattern were associated with an increased risk. Neither the NDR, nor any of the nocturnal phenotypes were significantly associated with the risk of cardiovascular death. With respect to other variability estimates (daytime or nighttime SD, 24-h weighted SD, or AVR) only nighttime SBP-SD was significantly associated (1.09; 1.01–1.17) with all-cause mortality in models adjusted for clinical confounders and absolute BP (Table 6).
Table 5
Hazard ratio for systolic and diastolic night-to-day ratios (per 1-standard deviation change) as well as categorical dipping patterns in relation to all-cause and cardiovascular mortality
Number of patients (%)
Number of deaths (%)
Confounder adjusteda
Additionally adjusted for 24-h BP
All-cause mortality
Systolic pattern
NDR
1.11 (1.04–1.19)
1.08 (1.01–1.16)
Dipper
748 (27.9)
154 (20.6)
Reference
Reference
Extreme dipper
106 (4.0%)
14 (13.2)
0.69 (0.40–1.20)
0.71 (0.41–1.23)
Non dipper
1135 (42.4%)
313 (27.6)
1.07 (0.88–1.30)
1.05 (0.86–1.27)
Riser
690 (25.8)
259 (37.5)
1.26 (1.03–1.56)
1.18 (0.96–1.46)
Diastolic pattern
NDR
1.13 (1.05–1.21)
1.09 (1.01–1.17)
Dipper
1038 (38.7)
248 (23.9)
Reference
Reference
Extreme dipper
391 (14.6)
81 (20.7)
0.97 (0.76–1.25)
0.97 (0.75–1.25)
Non dipper
884 (33.0)
266 (30.1)
1.14 (0.96–1.35)
1.14 (0.96–1.35)
Riser
366 (13.7)
145 (39.6%)
1.39 (1.13–1.71)
1.39 (1.13–1.71)
Cardiovascular mortality
Systolic pattern
NDR
1.08 (0.97–1.20)
1.05 (0.95–1.17)
Dipper
748 (27.9)
70 (9.4)
Reference
Reference
Extreme dipper
106 (4.0)
7 (6.6)
0.77 (0.35–1.68)
0.79 (0.36–1.73)
Non dipper
1135 (42.4)
141 (12.4)
1.05 (0.79–1.40)
1.03 (0.77–1.37)
Riser
690 (25.8)
113 (16.4)
1.20 (0.88–1.63)
1.12 (0.82–1.53)
Diastolic pattern
NDR
1.09 (0.98–1.22)
1.04 (0.94–1.17)
Dipper
1038 (38.7)
111 (10.7)
Reference
Reference
Extreme dipper
391 (14.6)
40 (10.2)
1.06 (0.74–1.53)
1.07 (0.75–1.55)
Non dipper
884 (33.0)
117 (13.2)
1.12 (0.87–1.46)
1.12 (0.87–1.45)
Riser
366 (13.7)
63 (17.2)
1.35 (0.99–1.85)
1.35 (0.98–1.84)
NDR night-to-day ratio, BP blood pressure
aAdjusted for age, sex, body mass index, smoking, diabetes, and treatment for hypertension
Table 6
Hazard ratio for systolic and diastolic blood pressure variability parameters (per 1-standard deviation change) in relation to all-cause and cardiovascular mortality
BP variability parameter
All-cause mortality
Cardiovascular mortality
Confounder-adjusteda
Additionally adjusted for absolute BP
Confounder-adjusteda
Additionally adjusted for absolute BP
24-h SBP weighted SD
1.12 (1.04–1.21)
1.02 (0.94–1.10)
1.00 (0.89–1.13)
1.05 (0.93–1.18)
24-h DBP weighted SD
0.98 (0.89–1.06)
0.97 (0.88–1.06)
1.05 (0.93–1.19)
1.02 (0.89–1.16)
Systolic ARV
1.09 (0.99–1.20)
0.99 (0.90–1.09)
1.10 (0.96–1.26)
1.00 (0.86–1.15)
Diastolic ARV
0.94 (0.85–1.03)
0.94 (0.85–1.04)
1.05 (0.92–1.20)
1.04 (0.91–1.19)
Daytime SBP-SD
1.09 (1.01–1.18)
1.01 (0.93–1.10)
1.12 (1.00–1.25)
1.03 (0.91–1.16)
Daytime DBP SD
0.97 (0.90–1.05)
0.97 (0.90–1.06)
1.02 (0.91–1.15)
0.99 (0.88–1.12)
Nighttime SBP-SD
1.13 (1.05–1.22)
1.09 (1.01–1.17)
1.15 (1.03–1.28)
1.10 (0.99–1.24)
Nighttime DBP SD
0.99 (0.92–1.08)
0.99 (0.91–1.07)
1.07 (0.96–1.20)
1.05 (0.94–1.18)
ARV average real variability, BP blood pressure, SD standard deviation, SBP systolic BP, DBP diastolic BP
aAdjusted for age, sex, body mass index, smoking, diabetes, and treatment for hypertension
Discussion
The present study demonstrate that ABPM-derived indices are superior to office BP in predicting all-cause and cardiovascular mortality in patients with documented coronary heart disease. Twenty-four-hour, daytime and nighttime SBP were all significantly associated with all-cause and cardiovascular mortality in models adjusted for clinical confounders and office SBP. The superior impact of ABPM on mortality was also observed by the analysis of BP phenotypes, with increased rates of mortality in subgroups with masked and sustained hypertension, while white-coat hypertension was not significantly associated with an increased risk. In relation to BP variability, NDR was significantly associated with mortality as it was the presence of a riser pattern (nocturnal BP higher than daytime BP). These results are in accordance with previous reports in the general population of patients with hypertension and emphasize the use of ABPM in patients with CHD, in order to better assess the BP-related risk in this population.
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Although ABPM is considered the best accurate method for BP measurement [23], and its role in hypertension diagnosis and management has been extensively investigated [3‐13], studies evaluating its role in patients with CHD are scarce, mostly cross-sectional, or with a limited sample size [14]. First prospective studies [15, 24] use Holter identified transient ischemic episodes as outcome while later reports examined the risk of new myocardial infarction [17], restenosis [25], or a composite endpoint of fatal and non-fatal events [16, 26]. In most cases, sample sizes have been small (< 100 patients) and results included a positive relationship with 24-h, daytime, and nighttime BP elevation, as well as with a non-dipping pattern.
Our results demonstrate the superiority of ABPM-derived BP indices over office BP in the prognosis of patients with CHD. Although both systolic office and ABPM were associated with the risk of death in unadjusted models, after clinical confounders adjustments, office BP was no longer predictive, whilst 24-h, daytime and nighttime SBP significantly associated with all-cause and cardiovascular mortality, and this association was not modified by office SBP adjustment. These results are similar as other previously reported in the general population of patients with hypertension [5], or in patients with hypertension and diabetes [27] or with a previous stroke [28]. It is noteworthy that hazard ratios for both daytime and nighttime SBP were similar and after simultaneous adjustment both indices maintained their association with all-cause and cardiovascular death. Although it has been clearly demonstrated that nighttime BP has a superior prognostic accuracy in relation to both cardiovascular events development and mortality in the general population of patients with hypertension [4, 5], as well as in patients with hypertension and a previous stroke [28], the present results suggest that in patients with CHD both ABPM-derived indices have similar importance in their association with the risk of death.
In the same direction, when patients were separated in groups of isolated daytime or nighttime hypertension, or combined daytime and nighttime hypertension, all the obtained phenotypes have a significant association with all-cause mortality, when compared to patients with normal daytime and nighttime BP (the reference group), also indicating that both daytime and nighttime BP are important in their association with mortality. For cardiovascular mortality, hazard ratios had similar values than for all-cause mortality. However, confidence intervals were wider, lacking statistical significance, possibly due to the low number of cardiovascular deaths in each of these groups. These observations have possible implications indicating that both daytime and nighttime BP should be equally targeted with antihypertensive treatment in patients with CHD.
The analysis of BP phenotypes of white-coat, masked, and sustained hypertension revealed that only sustained and masked hypertension were associated with mortality, while white-coat hypertension was not. These results are aligned with those we have previously reported in the general population of patients with hypertension, also showing a lack of association between white-coat hypertension and risk of mortality [5]. Although this has been controversial in other reports, this is possibly related to the way white-coat hypertension is defined, regarding normal 24-h or normal daytime BP [8]. In the case of masked hypertension, the association was statistically significant with all-cause mortality, but not with cardiovascular mortality. As also commented before, we interpret that the lack of statistical significance is also influenced by the low number of deaths (masked hypertension is the phenotype with the lowest number of patients) and the resulting wide confidence interval.
We have examined the association between BP variability and mortality in this group of patients. Night-to-day ratio, both systolic and diastolic was associated with all cause mortality in models adjusted for clinical confounders and additionally for 24-h BP. Regarding nocturnal phenotypes, only the riser pattern based on diastolic BP was associated with the risk of death. In the case of cardiovascular mortality neither NDR nor any phenotype was associated with an increased risk. Previous observational studies have focused on these nocturnal phenotypes and the risk of cardiovascular events in patients with CHD, with some inconsistent results. While some found increased risk of Holter-identified transient ischemic episodes [15, 24] in non-dippers (combining non dippers and risers in the same group), a more recent report [26] concluded that the impact of a riser pattern was lost when adjusted for absolute values of nocturnal BP. In the general population of patients with hypertension, we have reported that non-dipping was associated with all-cause and cardiovascular death, even in the absence of nocturnal BP elevation. However, nocturnal BP was a more powerful estimate than non-dipping [11]. It is acknowledged that these nocturnal BP phenotypes have a limited reproducibility, and are significantly influenced by the interference of the ABPM procedure with the quality of sleep [3].
The association of other short-term variability parameters, such as SD or ARV with the risk of death was mild and, in most cases became non-significant after adjustment for absolute BP values. Only nighttime systolic BP-SD remained significant but with only a moderate association (9% increase in total mortality for 1 SD change). Whereas we and others have previously reported an association between short-term BP variability and prognosis in patients with hypertension, in all cases such associations were mild compared with the risk driven by absolute BP elevation [13, 29]. In the present report in patients with CHD, short-term BP variability did not seem to provide a significant prognostic effect added to that of absolute BP elevation.
The present study has important limitations. First, the history of CHD was based on the clinical record, limited to a previous diagnosis of an acute coronary event or stable angina. We do not have more information regarding clinical characteristics of the event, type of coronary lesions or revascularization treatments. Second, patients included in the Registry were those with an indication for ABPM, based on guidelines, and it does not necessarily represent the general population of people with CHD. Third, data regarding antihypertensive treatment was available only at baseline, whilst changes done during follow-up were not collected, and fourth, the observational nature of the study precludes any direct inference on the possible benefit of basing treatment on ambulatory BP measurements. Nevertheless, the present study has several strengths, as represents the largest cohort of patients with CHD and ABPM, as well as the long duration of follow-up.
Conclusion
Twenty-four-hour, daytime and nighttime SBP obtained through ABPM were associated with the risk of all-cause and cardiovascular mortality in patients with CHD, while office SBP was not significantly associated. Different hypertension phenotypes, such as masked or sustained hypertension, isolated daytime or nighttime hypertension or a reduced nocturnal dipping were associated with an increased risk of mortality, while white-coat hypertension or an excess in the nocturnal BP decline (extreme dipping pattern) did not carry an increased risk. These results support the use of ABPM for a more accurate evaluation in patients with hypertension and CHD.
Acknowledgements
The authors would like to thank all patients who participated in the Spanish ABPM Registry.
Declarations
Conflict of Interest
Alejandro de la Sierra, Ernest Vinyoles, Manuel Gorostidi, Julian Segura and Luis M. Ruilope have no conflicts of interest in relation to this article.
Ethical Approval
Permission was obtained to access and use data from the Spanish ABPM Registry. All participants gave informed consent and the study was approved by the corresponding ethics committees. All the analyses were performed in an anonymized database.
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
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