Nocturnal Hypertension or Nondipping: Which Is Better Associated With the Cardiovascular Risk Profile?

Transcription

1 Original Article Nocturnal Hypertension or Nondipping: Which Is Better Associated With the Cardiovascular Risk Profile? Alejandro de la Sierra, 1 Manuel Gorostidi, 2 José R. Banegas, 3 Julián Segura, 4 Juan J. de la Cruz, 3 Luis M. Ruilope 4 background Both increased night blood pressure (BP) and nondipping are associated with worse cardiovascular risk and prognosis. However, as they are often related features, their relative importance has been difficult to assess separately. In this study we address separate associations of nocturnal hypertension and nondipping with cardiovascular risk profile in treated and untreated hypertensive patients. methods A total of 37,096 untreated patients and 62,788 patients receiving antihypertensive treatment from the Spanish Ambulatory Blood Pressure Monitoring Registry were included. Each cohort was separated into 4 groups: group 1, night systolic blood pressure (SBP) <120 mm Hg and normal dipping (>10%); group 2, night SBP <120 mm Hg and nondipping ( 10%); group 3, nocturnal hypertension (SBP 120 mm Hg) and normal dipping; and group 4, nocturnal hypertension and nondipping. results The smallest proportion of patients with additional cardiovascular risk factors, organ damage, and history of previous events was observed in Ambulatory blood pressure monitoring (ABPM) has emerged as a valuable tool in determining the BP, as it provides a more accurate assessment with respect to clinic BP. 1 8 ABPM helps to distinguish between patients with both clinical and ambulatory elevated BP from patients with white coat 6,9 and masked hypertension. 6,10 In addition to the mean value of BP obtained during a 24-hour period, both absolute values of BP during the night 1 4,7 9,11 15 and nocturnal dipping 11,16 18 have been reported as important predictors of cardiovascular risk and prognosis. However, both nocturnal hypertension and nondipping are often present together, thus confounding their association with risk and prognosis. In the Spanish Ambulatory Blood Pressure Monitoring Registry, we reported an association between nondipping and the group with both normal night SBP and dipping, whereas those with both nocturnal hypertension and nondipping showed the largest proportion of cardiovascular risk factors and diseases. When groups showing only 1 abnormality were compared, nondipping was associated with female sex, reduced renal function, and previous cardiovascular events, whereas nocturnal hypertension was associated with male sex, smoking, and increased urinary albumin excretion. In treated patients, it was also associated with the presence of diabetes. conclusion Nondipping is related to more advanced disease (reduced renal function and clinical evidence of cardiovascular disease), whereas nocturnal hypertension is associated with albuminuria. The worst cardiovascular risk profile is present in patients exhibiting both nocturnal hypertension and nondipping. Keywords. ambulatory blood pressure monitoring; blood pressure; cardiovascular risk; circadian pattern; hypertension; nocturnal hypertension; nondipping. doi: /ajh/hpt175 cardiovascular risk. 18 Mean values of night SBP in nondippers were mm Hg higher. In another study, based on estimates derived from ABPM, the best predictor of cardiovascular events, after adjusting for baseline risk, in those with high-risk hypertension was night SBP. 19 Here, we looked at the association between both nocturnal hypertension and nondipping, examined separately, and the cardiovascular risk profile. For this purpose, we analyzed both treated and untreated patients from the Spanish ABPM Registry by stratifying them into 4 groups depending on absolute night SBP and nocturnal dipping. This allowed us to specifically address those factors related to nocturnal hypertension in the absence of nondipping and those factors related to nondipping in the absence of nocturnal hypertension. Correspondence: Alejandro de la Sierra (adelasierra@mutuaterrassa.cat). Initially submitted April 29, 2013; date of first revision June 19, 2013; accepted for publication August 21, 2013; online publication September 23, Department of Internal Medicine, Hospital Mutua Terrassa, University of Barcelona, Barcelona, Spain; 2 Department of Nephrology, Hospital Universitario Central de Asturias, Oviedo, Spain; 3 Department of Preventive Medicine and Public Health, Universidad Autónoma de Madrid, Madrid, Spain; and 4 Hypertension Unit, Hospital 12 de Octubre, Madrid, Spain. American Journal of Hypertension, Ltd All rights reserved. For Permissions, please journals.permissions@oup.com 680 American Journal of Hypertension 27(5) May 2014

2 Nocturnal Hypertension Versus Non Dipping METHODS Study design The Spanish ABPM Registry was developed to promote the use of ABPM in clinical practice. Details regarding its characteristics have been reported elswhere. 9,18 21 The study protocol was approved by the institutional review boards from the different autonomous communities of Spain. Patients gave informed consent. For this study, we analyzed the data for 99,884 patients included in the ABPM database (most of Caucasian origin). Patients had either an office BP 140 mm Hg and/or 90 mm Hg obtained from at least 2 measurements and did not receive any antihypertensive agent (untreated group; N = 37,096; 37.1%) or received a documented diagnosis of essential hypertension, independent of office BP, received treatment with at least 1 antihypertensive drug, and were stable for 2 months (treated group; N = 62,788; 62.9%). BP measurements BP was measured at the physician s office with a calibrated mercury sphygmomanometer or a validated oscillometric device after a 5-minute rest in a sitting position. BP values were estimated as the mean of 2 readings. Thereafter, 24-hour ABPM was measured using an automated noninvasive oscillometric device programmed to register BP at 20-minute intervals for a 24-hour period (SpaceLabs 90207). Valid registries had to fulfill a series of preestablished criteria, including 80% of systolic BPs (SBPs) and diastolic BPs (DBPs) successfully recorded during the daytime and nighttime, 24-hour duration, and at least 1 BP measurement taken per hour. Daytime and nighttime periods were defined individually according to each patient s self-reported data of going-to-bed and getting-up times. The cohorts of both untreated and treated patients were divided in 4 groups depending on nocturnal SBP and nocturnal systolic dip: [(daytime SBP nighttime SBP)/daytime SBP] 100. Group 1 consisted of patients with normal night SBP (<120 mm Hg) and normal dipping (>10%), group 2 consisted of patients with normal night SBP and nondipping ( 10%), group 3 consisted of patients with nocturnal hypertension (SBP 120 mm Hg) and normal dipping, and group 4 consisted of patients with both nocturnal hypertension and nondipping. Study variables Variables collected for each patient based on interviews and physical examination at the time of the visit and on data drawn from clinical records were defined and measured in accordance with national guidelines. 22 Variables included age, gender, weight, height, waist circumference, body mass index (BMI), duration of hypertension, known cardiovascular risk factors such as smoking and diabetes mellitus, biochemical values of creatinine and lipid profile, target organ damage including urinary albumin excretion (microalbuminuria defined as 2.5 mg/mmol in males and 3.5 mg/ mmol in females) and electrocardiogram (left ventricular hypertrophy (LVH) defined as a Sokolow Lyon voltage >38 and/or Cornell duration/voltage index >2,440 mm/ms), and clinical cardiovascular disease (coronary artery disease, congestive heart failure, or cerebrovascular disease). Statistical analysis Data are presented as frequencies and percentages for qualitative variables and as mean ± standard deviation (or median (interquartile range)) for quantitative variables. Differences in study variables among the 4 groups were assessed with the Pearson χ 2 test for qualitative variables and the analysis of variance (with log-transformed variables when required) for quantitative data. Comparisons between each pair of groups were then performed (Student t test or χ 2 test), and P values were corrected according to the Bonferroni method (6 comparisons). As categorization of both night SBP and nocturnal dipping is based on arbitrary cutoffs, the association of both parameters, analyzed as continuous variables, with the cardiovascular risk profile was examined through logistic regression analyses. For these analyses, night SBP and nocturnal dipping were entered in regression models in order to test their association with each clinical characteristic (smoking, diabetes, microalbuminuria, reduced estimated glomerular filtration rate (egfr), and previous history of a cardiovascular event). Odds ratios (ORs) for night SBP and nocturnal dipping were calculated and then adjusted for age and gender. SPSS for Windows version 18.0 software (SPSS Inc., Chicago, IL) was used for statistical analysis. RESULTS General characteristics of patients In the cohort of 37,096 untreated patients, 54% were males and mean age 53.2 ± 14.4 years. Office SBP/DPB was ± 17.3/88.5 ± 12.1 mm Hg and 24-hour ABP was ± 13.1/78.5 ± 9.7 mm Hg. Mean BMI was 28.5 ± 4.8 kg/ m 2. Cardiovascular risk factors included diabetes in 12.9% of patients and current smoking in 18.7%. History of cardiovascular clinical conditions included coronary artery disease in 1.7%, stroke in 1.7%, congestive heart failure in 0.5%, and chronic kidney disease in 0.5%. In the cohort of 62,788 treated patients, 52.2% were males and mean age was 61.7 ± 12.8 years. Office SBP/DPB was ± 20.1/86.3 ± 12.2 mm Hg and 24-hour ABP was ± 14.9/75.2 ± 10.4 mm Hg. Approximately 35% of patients were on monotherapy, and 73% took their medication in the morning. Mean BMI was 29.9 ± 4.9 kg/m 2. Cardiovascular risk factors included diabetes in 24.1% of patients and current smoking in 14.9%. History of cardiovascular clinical conditions included coronary artery disease in 7.2%, stroke in 5.2%, congestive heart failure in 2.7%, and chronic kidney disease in 2.6%. Prevalence of nocturnal hypertension and nondipping In the untreated group of patients, 21,909 (59.1%) had nocturnal SBP <120 mm Hg, whereas the remaining 15,187 (40.9%) had nocturnal hypertension (SBP 120 mm Hg). American Journal of Hypertension 27(5) May

3 de la Sierra et al. A normal dipping pattern (nocturnal SBP decline >10%) was observed in 20,590 untreated patients (55.5%), whereas the remaining 16,506 (44.5%) were considered nondippers (nocturnal SBP decline 10%). Mean values of office and ambulatory BP in groups with either normal or abnormal night SBP and nocturnal dipping are depicted in Supplementary Table S1. Nocturnal hypertension was observed in half of the treated patients (31,277, 49.8%), whereas nondipping was present in 35,925 patients (57.2%). Supplementary Table S2 shows mean values of office and ambulatory BP in groups with either normal or abnormal night SBP and nocturnal dipping. Differences among groups of untreated patients classified on the basis of night SBP and dipping Table 1 shows clinical differences in the 4 groups of patients classified as having normal or elevated night SBP and nocturnal dipping. The lowest prevalence of additional cardiovascular risk factors such as age, BMI, hypertension duration, prevalence of type 2 diabetes, and organ damage, such as LVH, microalbuminuria, reduced renal function as determined by an egfr <60 ml/min/1.73 m 2, and history of previous cardiovascular disease, was observed in group 1 (normal night BP and normal dipping), whereas the highest prevalence was seen in group 4 (both nocturnal hypertension and nondipping). Groups 2 and 3 showed intermediate values. In the direct comparison between groups having only 1 abnormality, i.e., group 2 (normal night SBP and nondipping) vs. group 3 (nocturnal hypertension and normal dipping), the former was associated with female sex (54.3% vs. 37.7%), reduced renal function (7.3% vs. 5.0%), and previous history of a cardiovascular event (4.8% vs. 3.1%). In contrast, patients with nocturnal hypertension but with normal dipping exhibited higher prevalence of male sex (62.3% vs. 45.7%), current smoking (22.0% vs. 14.2%), and increased values of urinary albumin excretion and prevalence of microalbuminuria (11.3% vs. 9.3%). To further explore the separate associations of nocturnal hypertension and nondipping with the cardiovascular risk profile, logistic regression models (before and after adjusting for age and gender) were used to test both night SBP and nocturnal dipping with each selected clinical variable (smoking, diabetes, renal function albuminuria, and history of cardiovascular events). Table 2 shows multivariate ORs for such associations. Whereas both night SBP and nocturnal dipping were associated with diabetes and smoking (nocturnal dipping showing an inverse relationship), the association with both reduced renal function and previous history of cardiovascular disease was significant only for nocturnal dipping and the association with microalbuminuria was significant only for night SBP. Differences among groups of treated patients classified on the basis of night SBP and nocturnal dipping Table 3 shows the results for the same analysis that is as depicted in Table 1 performed in the cohort of treated patients. As in the group with untreated hypertension, prevalence of most cardiovascular risk factors, organ damage, 682 American Journal of Hypertension 27(5) May 2014 and previous disease was the lowest in group 1 (normal night SBP and dipping) and the highest in group 4 (nocturnal hypertension and nondipping). In the direct comparison between groups having only 1 of these abnormalities, i.e., group 2 (nondipping with normal night SBP) vs. group 3 (nocturnal hypertension with normal dipping), the former was associated with female sex (52.9% vs. 43.4%), decreased renal function (18.0% vs. 15.4%), and previous history of a cardiovascular event (14.9% vs. 11.9%). In contrast, patients with nocturnal hypertension and normal dipping were more frequently males (56.6% vs. 47.1%), smokers (18.4% vs. 12.1%), diabetics (26.1% vs. 19.6%), and had increased values of urinary albumin excretion and prevalence of microalbuminuria (25.1% vs. 18.7%). Table 4 shows multivariate ORs for night SBP and nocturnal dipping in their association with clinical features. As in the untreated group, after adjusting for age and gender, both parameters showed an association with smoking (nocturnal dipping being inversely associated). Only night SBP was associated with diabetes and microalbuminuria, whereas only nondipping was associated with reduced renal function and previous cardiovascular disease. Discussion The present analysis from the Spanish ABPM Registry shows that the concomitant presence of both nocturnal hypertension and nondipping is associated with the worst cardiovascular risk profile, including traditional cardiovascular risk factors such as age, diabetes, and obesity as well as organ damage, such as left ventricular hypertrophy, microalbuminuria, reduced renal function, and previous history of cardiovascular events. Moreover, in the direct comparison between groups of patients having only 1 of these 2 abnormalities, those with a nondipping pattern but normal night SBP were more frequently female, with reduced renal function or with a previous cardiovascular event. In contrast, nocturnal hypertension without nondipping was associated with male sex, smoking, and asymptomatic target organ damage, especially microalbuminuria. In treated patients, it was also associated with diabetes, such association being nonsignificant in untreated patients. Both nocturnal hypertension 1 4,7 9,11 15 and nondipping 7,13,16 18 have been associated with a worse cardiovascular risk profile and increased all-cause and cardiovascular mortality. Prospective observational studies have, for the most part, concluded that nocturnal BP is a better predictor of a worse prognosis in comparison to 24-hour BP or daytime BP The nature of this finding was related to BP alone (night BP better represents the baseline BP of a patient) or with aspects regarding its measurement (night BP is usually measured while the patient is in the supine position and is subjected to less variability). In a follow-up analysis of highrisk patients included in the Spanish ABPM Registry, we reported that absolute values of nocturnal SBP were the best predictor of future cardiovascular events, after adjusting for baseline risk and other ABPM-derived parameters. 19 Nondipping has also been associated with poor prognosis. From the first report of this term by O Brien and colleagues, 23 several studies have also reported an increased

4 Nocturnal Hypertension Versus Non Dipping Table 1. Clinical features in untreated patients with normal or elevated night systolic blood pressure and normal or abnormal dipping pattern Group 1: Night SBP <120 mm Hg, normal dipping Parameter (N = 15,743) Group 2: Night SBP <120 mm Hg, nondipping (N = 6,166) Group 3: Night SBP 120 mm Hg, normal dipping (N = 4,847) Group 4: Night SBP 120 mm Hg, nondipping (N = 10,340) P value (analysis of variance or χ 2 test) Age, years 49.9 ± ± 14.8 a 53.6 ± 13.6 b 57.8 ± 14.8 d,e,f <0.001 Gender, % males a 62.3 b,c 55.0 d,e,f <0.001 Body mass index, kg/m ± ± 5.0 a 28.6 ± 4.7 b 28.9 ± 4.8 d,e,f <0.001 Abdominal obesity, % a 34.5 b 36.1 d <0.001 Duration of hypertension, years 0 [0 1] 0 [0 2] a 1 [0 3] b 1 [0 3] d,e,f <0.001 Smoker, % a 22.0 c 16.8 d,e,f <0.001 Diabetic, % a 13.9 b 16.8 d,e,f <0.001 Total cholesterol, mmol/l 5.44 ± ± ± ± High-density lipoprotein-cholesterol, mmol/l 1.42 ± ± ± 0.38 b 1.32 ± Triglycerides, mmol/l 1.40 ± ± ± 0.80 b 1.47 ± 0.83 d Creatinine, µmol/l 79.6 ± ± ± ± 27.4 e Estimated glomerular filtration rate <60 ml/min/1.73 m 2, % a 5.0 c 7.2 d,f <0.001 Urinary albumin excretion, mg/mmol 0.36 [ ] 0.43 [ ] 0.49 [ ] c 0.57 [ ] d,e <0.001 Microalbuminuria, % a 11.3 b,c 14.6 d,e,f <0.001 Left ventricular hypertrophy by electrocardiogram, % a 2.1 b 2.6 d <0.001 Previous cardiovascular disease, % a 3.1 c 5.2 d,f <0.001 Values are mean ± standard deviation or median (interquartile range). Abdominal obesity calculated on the basis of waist circumference (>102 cm in men and >88 cm in women). Estimated glomerular filtration rate calculated on the basis of the Modification of Diet on Renal Disease simplified formula. a P < 0.05 comparing group 2 with group 1; b P < 0.05 comparing group 3 with group 1; c P < 0.05 comparing group 3 with group 2; d P < 0.05 comparing group 4 with group 1; e P < 0.05 comparing group 4 with group 2; f P < 0.05 comparing group 4 with group 3. American Journal of Hypertension 27(5) May

5 de la Sierra et al. Table 2. Multivariate odds ratios and 95% confidence intervals (before and after age and sex adjustments) for night systolic blood pressure and nocturnal dipping in their association with selected clinical variables in the group of untreated patients Multivariate OR (unadjusted) Multivariate OR (age and sex adjusted) Variable Night SBP Nocturnal dipping Night SBP Nocturnal dipping Smoking ( ) ( ) ( ) ( ) Diabetes ( ) ( ) ( ) ( ) Reduced renal function a ( ) ( ) ( ) ( ) Microalbuminuria ( ) ( ) ( ) ( ) Previous cardiovascular event ( ) ( ) ( ) ( ) Abbreviations: OR, odds ratio; SBP, systolic blood pressure. a As defined by estimated glomerular filtration rate (Modification of Diet on Renal Disease) <60 ml/min/1.73 m 2. mortality of those with a nondipping or a riser (higher BP during the night than during the day) pattern. 7,13,16,17 In a previous analysis of the Spanish ABPM Registry, we found an association between nondipping and baseline cardiovascular risk and previous organ damage and disease, suggesting that some of these clinical circumstances (older age or advanced disease) were responsible for the blunted nocturnal BP decline. 18 The most important problem when addressing the importance of these 2 ABPM-derived estimates on their association with cardiovascular risk and prognosis is that they are not independent of each other. 24 Patients with nocturnal hypertension are more prone to show a nondipping pattern, and nondippers usually exhibit higher values of night BP than dippers. In a previous report from the Spanish ABPM Registry, 18 nondippers had absolute values of nocturnal SBP mm Hg higher than those with normal dipping. Moreover, among patients who subsequently developed a cardiovascular event, nocturnal SBP was higher and nocturnal dipping blunted in comparison to patients free from cardiovascular events. 19 When these 2 ABPM-derived parameters were analyzed in multivariate regression models, absolute night BP was predictive for both mortality and cardiovascular events, whereas nondipping loses some of its predictive value, especially for nonfatal events. 11,13 In a recent review by Hansen and colleagues, 14 both night BP and nondipping were associated with all-cause mortality and cardiovascular events, although the former was a more powerful predictor. Our results are in agreement with those previously reported, as both nocturnal hypertension and nondipping were associated with most of the cardiovascular risk factors, both analyzed categorically (Tables 1 and 3) and continuously (Tables 2 and 4). A specific objective of this study was to clarify separate associations of these 2 parameters by analyzing patients who had only 1 abnormality. For this reason, we examined separately patients exhibiting nocturnal hypertension and normal dipping and patients with nondipping but normal night SBP. Patients were also divided into cohorts of treated and untreated. In both cohorts, nondipping was associated with female sex, reduced renal function, and history of previous cardiovascular events, whereas nocturnal hypertension was related to male sex, smoking, and increased urinary albumin excretion. Nocturnal hypertension also correlated with the presence of diabetes, but the association was only significant in the group of treated patients (a larger group and a higher prevalence of diabetes). These results reinforce the suggestion previously raised that nondipping is essentially a reflection of more advanced disease, 11,18 and the presence of cardiovascular or renal diseases is the main factor promoting a failure to achieve an appropriate BP reduction during nighttime, possibly through more advanced sympathetic nervous system disturbances. In this view, a recent report has also shown that in patients with nocturnal hypertension, there were no differences between dippers and nondippers in left ventricular mass, carotid intima-media thickness, or urinary albumin excretion. 25 In contrast, nocturnal hypertension, even with a normal dip, was associated with target organ damage, especially microalbuminuria. These findings were also in agreement with a previous report of a close association between albuminuria and nocturnal BP in a group of resistant hypertensive patients. 26 These findings suggest that the level of SBP at rest (night SBP is probably the closer estimate to resting BP) is directly translated to organs, and its elevation is responsible for promoting organ damage (albuminuria in the kidneys). Limitations of our study are derived from its crosssectional nature, thus not allowing us to draw inferences about its prognostic importance. Moreover, clinical characteristics were collected at the same time of ABPM procedure; however, they cannot be considered as baseline, especially in the treated group, as they are also influenced by chronic antihypertensive treatment. Results are also limited to the Caucasian population, as other ethnicities were only marginally represented. In contrast, this is the first time that nocturnal hypertension and nondipping were examined separately by comparing groups exhibiting only 1 of these 2 abnormalities. The study included untreated and treated patients irrespective of ABPM values. Thus, results apply to the hypertensive population as a whole but not to specific categories based on ABPM values (white coat, masked, controlled, or uncontrolled hypertension). In conclusion, we found that nondipping, even in the absence of nocturnal hypertension, is dependent on more advanced disease (renal failure and previous cardiovascular events), whereas smoking, diabetes, and microalbuminuria are associated with nocturnal hypertension, even though it occurs in patients with normal dipping. Coexistence of 684 American Journal of Hypertension 27(5) May 2014

6 Nocturnal Hypertension Versus Non Dipping Table 3. Clinical features in treated patients with normal or elevated night systolic blood pressure and normal or abnormal dipping pattern Group 1: Night SBP <120 mm Hg, normal dipping Parameter (N = 19,643) Group 2: Night SBP <120 mm Hg, nondipping (N = 11,868) Group 3: Night SBP 120, normal dipping (N = 7,220) Group 4: Night SBP 120 mm Hg, nondipping (N = 24,057) P (analysis of variance or χ 2 test) Age, years 57.9 ± ± 12.7 a 61.5 ± 12.5 b 65.1 ± 12.3 d,e,f <0.001 Gender, % males a 56.6 b,c 53.1 e,f <0.001 Body mass index, kg/m ± ± 5.0 a 29.8 ± 4.7 b 30.2 ± 4.9 d,e,f <0.001 Abdominal obesity, % a 46.9 b 51.1 d,e,f <0.001 Duration of hypertension, years 5 [2 10] 5 [2 10] a 5 [2 10] b 7 [3 12] d,e,f <0.001 Smoker, % a 18.4 c 13.4 d,e,f <0.001 Diabetic, % a 26.1 b,c 31.0 d,e,f <0.001 Total cholesterol, mmol/l 5.31 ± ± 1.02 a 5.29 ± ± 1.06 d,f <0.001 High-density lipoprotein-cholesterol, mmol/l 1.38 ± ± ± ± 0.40 d,e <0.001 Triglycerides, mmol/l 1.52 ± ± ± ± Creatinine, µmol/l 84.0 ± ± 35.4 a 86.6 ± 38.0 b 90.2 ± 44.2 d,e,f <0.001 Estimated glomerular filtration rate <60 m/min/1.73 m 2, % a 15.4 b,c 22.1 d,e,f <0.001 Urinary albumin excretion, mg/mmol 0.57 [ ] 0.64 [ ] 0.94 [ ] b,c 1.02 [ ] d,e Microalbuminuria, % b,c 29.1 d,e <0.001 Left ventricular hypertrophy by electrocardiogram, % a 9.3 b 11.8 d,e,f <0.001 Previous cardiovascular disease, % a 11.9 b,c 18.0 d,e,f <0.001 Values are mean ± standard deviation or median (interquartile range). Abdominal obesity calculated on the basis of waist circumference (>102 cm in men and >88 cm in women). Estimated glomerular filtration rate calculated on the basis of the Modification of Diet on Renal Disease simplified formula. a P < 0.05 comparing group 2 with group 1; b P < 0.05 comparing group 3 with group 1; c P < 0.05 comparing group 3 with group 2; d P < 0.05 comparing group 4 with group 1; e P < 0.05 comparing group 4 with group 2; f P < 0.05 comparing group 4 with group 3. American Journal of Hypertension 27(5) May

7 de la Sierra et al. Table 4. Multivariate odds ratios and 95% confidence intervals (before and after age and sex adjustments) for night systolic blood pressure nocturnal dipping in their association with selected clinical variables in the group of treated patients Multivariate OR (unadjusted) Multivariate OR (age and sex adjusted) Variable Night SBP Nocturnal dipping Night SBP Nocturnal dipping Smoking ( ) ( ) ( ) ( ) Diabetes ( ) ( ) ( ) ( ) Reduced renal function a ( ) ( ) ( ) ( ) Microalbuminuria ( ) ( ) ( ) ( ) Previous cardiovascular event ( ) ( ) ( ) ( ) Abbreviations: OR, odds ratio; SBP, systolic blood pressure. a As defined by estimated glomerular filtration rate (Modification of Diet on Renal Disease) <60 ml/min/1.73 m 2. nocturnal hypertension and nondipping is associated with the worst cardiovascular risk profile. SUPPLEMENTARY MATERIAL Supplementary materials are available at American Journal of Hypertension ( Acknowledgments We thank all participants of the Spanish ABPM Registry. Their names are available at DISCLOSURE The Spanish ABPM Registry was initiated and is maintained by an unrestricted grant from Lacer Laboratories, Spain, and the Spanish Society of Hypertension. The investigators received a grant from the Spanish Health Authority (Fondo de Investigación Sanitaria: PI10/01011). References 1. Dolan E, Stanton A, Thijs L, Hinedi K, Atkins N, McClory S, Den Hond E, McCormack P, Staessen JA, O Brien E. Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: the Dublin Outcome Study. Hypertension 2005; 46: Kikuya M, Ohkubo T, Asayama K, Metoki H, Obara T, Saito S, Hashimoto J, Totsune K, Hoshi H, Satoh H, Imai Y. Ambulatory blood pressure and 10-year risk of cardiovascular and noncardiovascular mortality: the Ohasama Study. Hypertension 2005; 45: Sega R, Facchetti R, Bombelli M, Cesana G, Corrao G, Grassi G, Mancia G. Prognostic value of ambulatory and home blood pressures compared with office blood pressure in the general population. Follow-up results from the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study. Circulation 2005; 111: Staessen JA, Thijs L, Fagard R, O Brien ET, Clement D, de Leeuw PW, Mancia G, Nachev C, Palatini P, Parati G, Tuomilehto J, Webster J, for the Systolic Hypertension in Europe Trial Investigators. Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension. JAMA 1999; 282: Hansen TW, Kikuya M, Thijs L, Björklund-Bodegård K, Kuznetsova T, Ohkubo T, Richart T, Torp-Pedersen C, Lind L, Jeppesen J, Ibsen H, Imai Y, Staessen JA, on behalf of the IDACO Investigators. Prognostic superiority of daytime ambulatory over conventional blood pressure in four populations: a meta-analysis of 7030 individuals. J Hypertens 2007; 25: Ohkubo T, Kikuya M, Metoki H, Asayama K, Obara T, Hashimoto J, Totsune K, Hoshi H, Satoh H, Imai Y. Prognosis of masked hypertension and white-coat hypertension detected by 24-h ambulatory blood pressure monitoring 10-year follow-up from the Ohasama study. J Am Coll Cardiol 2005; 46: Verdecchia P, Porcellati C, Schillaci G, Borgioni C, Ciucci A, Battistelli M, Guerrieri M, Gatteschi C, Zampi I, Santucci A, Santucci C, Reboldi G. Ambulatory blood pressure. An independent predictor of prognosis in essential hypertension. Hypertension 1994; 24: Clement DL, De Buyzere ML, De Bacquer DA, de Leeuw PW, Duprez DA, Fagard RH, Gheeraert PJ, Missault LH, Braun JJ, Six RO, Van Der Niepen P, O Brien E, for the Office versus Ambulatory Pressure Study Investigators. Prognostic value of ambulatory blood-pressure recordings in patients with treated hypertension. N Engl J Med 2003; 348: Vinyoles E, Felip A, Pujol E, De la Sierra A, Dura R, Hernandez del Rey R, Sobrino J, Gorostidi M, de la Figuera M, Segura J, Banegas JR, Ruilope LM, on behalf of the Spanish Society of Hypertension ABPM Registry. Clinical characteristics of isolated clinic hypertension. J Hypertens 2008; 26: Bobrie G, Clerson P, Ménard J, Postel-Vinay N, Chatellier G, Plouin PF. Masked hypertension: a systematic review. J Hypertens 2008; 26: Boggia J, Li Y, Thijs L, Hansen TW, Kikuya M, Björklund-Bodegård K, Richart T, Ohkubo T, Kuznetsova T, Torp-pedersen C, Lind L, Ibsen H, Imai Y, Wang J, Sandoya E, O Brien E, Staessen JA, on behalf of the International Database on Ambulatory blood pressure monitoring in relation to Cardiovascular Outcomes (IDACO) Investigators. Prognostic accuracy of day versus night ambulatory blood pressure: a cohort study. Lancet 2007; 370: Ben-Dov IZ, Kark JD, Ben-Ishay D, Mekler J, Ben-Arie L, Bursztyn M. Predictors of all-cause mortality in clinical ambulatory monitoring: unique aspects of blood pressure during sleep. Hypertension 2007; 49: Fagard RH, Celis H, Thijs L, Staessen JA, Clement DL, De Buyzere ML, De Bacquer DA. Daytime and nighttime blood pressure as predictors of death and cause-specific cardiovascular events in hypertension. Hypertension 2008; 51: Hansen TW, Li Y, Boggia J, Thijs L, Richart T, Staessen J. Predictive role of nighttime blood pressure. Hypertension 2011; 57: Fan HQ, Li Y, Thijs L, Hansen TW, Boggia J, Kikuya M, Björklund- Bodegård K, Richart T, Ohkubo T, Jeppesen J, Torp-Pedersen C, Dolan E, Kuznetsova T, Stolarz-Skrzypek K, Tikhonoff V, Malyutina S, Casiglia E, Nikitin Y, Lind L, Sandoya E, Kawecka-Jaszcz K, Imai Y, Ibsen H, O Brien E, Wang J, Staessen JA, on behalf of the International 686 American Journal of Hypertension 27(5) May 2014

8 Nocturnal Hypertension Versus Non Dipping Database on Ambulatory blood pressure monitoring in relation to Cardiovascular Outcomes (IDACO) Investigators. Prognostic value of isolated nocturnal hypertension on ambulatory measurement in 8711 individuals from 10 populations. J Hypertens 2010; 28: Ohkubo T, Hozawa A, Yamaguchi J, Kikuya M, Ohmori K, Michimata M, Matsubara M, Hashimoto J, Hoshi H, Araki T, Tsuji I, Satoh H, Hisamichi S, Imai Y. Prognostic significance of the nocturnal decline in blood pressure in individuals with and without high 24-h blood pressure: the Ohasama study. J Hypertens 2002; 20: Brotman DJ, Davidson MB, Boumitri M, Vidt DG. Impaired diurnal blood pressure variation and all-cause mortality. Am J Hypertens 2008; 21: De la Sierra A, Redon J, Banegas JR, Segura J, Parati G, Gorostidi M, de la Cruz JJ, Sobrino J, Llisterri JL, Alonso J, Vinyoles E, Pallarés V, Sarría A, Aranda P, Ruilope LM. Prevalence and factors associated with circadian blood pressure patterns in hypertensive patients. Hypertension 2009; 53: De la Sierra A, Banegas JR, Segura J, Gorostidi M, Ruilope LM. Ambulatory blood pressure monitoring and development of cardiovascular events in high-risk patients included in the Spanish ABPM Registry. J Hypertens 2012; 30: Banegas JR, Segura J, Sobrino J, Rodríguez-Artalejo F, De la Sierra A, De la Cruz JJ, Gorostidi M, Sarría A, Ruilope LM, for the Spanish Society of Hypertension Ambulatory Blood Pressure Monitoring Registry Investigators. Effectiveness of blood pressure control outside the medical setting. Hypertension 2007; 49: De la Sierra A, Segura J, Banegas JR, Gorostidi M, de la Cruz JJ, Armario P, Oliveras A, Ruilope LM. Clinical features of 8295 patients with resistant hypertension classified on the basis of ambulatory blood pressure monitoring. Hypertension 2011; 57: De la Sierra A, Gorostidi M, Marin R, Redon J, Banegas JR, Armario P, Garcia-Puig J, Zarco J, Llisterri JL, Sanchis C, Abarca B, Palomo V, Gomis R, Otero A, Villar F, Honorato J, Tamargo J, Lobos JM, Macías- Nuñez J, Sarria A, Aranda P, Ruilope LM. Evaluation and management of hypertension in Spain. A consensus guide [Article in Spanish]. Med Clin (Barc) 2008; 131: O Brien E, Sheridan J, O Malley K. Dippers and non-dippers. [Letter]. Lancet 1988; 2: Redon J, Lurbe E. Nocturnal blood pressure versus nondipping pattern. What do they mean? Hypertension 2008; 51: Cuspidi C, Sala C, Valerio C, Negri F, Mancia G. Nocturnal hypertension and organ damage in dippers and nondippers. Am J Hypertens 2012; 25: Oliveras A, Armario P, Martell N, Ruilope LM, De la Sierra A. Urinary albumin excretion is associated with nocturnal systolic blood pressure in resistant hypertensives. Hypertension 2011; 57: American Journal of Hypertension 27(5) May