A. Moya

[OP.3A.06] PROGRESSIVE DISRUPTION OF AMBULATORY BLOOD PRESSURE REGULATION WITH SEVERITY STAGE OF CHRONIC KIDNEY DISEASE: THE HYGIA PROJECT

Objective: Sleep-time hypertension and the non-dipper blood pressure (BP) patterning determined by ambulatory BP monitoring (ABPM) are highly prevalent in chronic kidney disease (CKD), and both factors have been consistently associated with the elevated cardiovascular disease (CVD) risk of such patients. We have assessed the prevalence of these alterations in ambulatory BP regulation as a function of the severity stage of CKD among the participants of the Hygia Project, a research network presently composed of 292 investigators of 40 clinical sites, primarily designed, among other objectives, to evaluate the prognostic value of ABPM to predict CVD risk. Design and method: This cross-sectional investigation involved 7,452 patients with CKD (estimated glomerular filtration rate [eGFR] <60, albuminuria, or both, at least twice within 3 months), 4,325 men/3,127 women, 65.3 ± 13.8 years of age, with BP, according to ABPM criteria, ranging from normotension to sustained hypertension. Ambulatory BP was measured for 48 consecutive hours. Results: There was a highly significant (P < 0.001) progressive increase in the asleep systolic BP (SBP) mean with increasing severity of CKD. The awake SBP mean, however, did not changed consistently throughout the different stages of CKD. Accordingly, the sleep-time relative SBP decline was progressively and significantly (P < 0.001) attenuated towards a more non-dipper BP patterning with diminishing eGFR. Most important, the proportion of patients with the riser BP pattern (asleep SBP mean greater than awake SBP mean) significantly and progressively increased from 5.8% of the participants with stage-1-CKD to a very high 33.7% of the participants with stage-5-CKD. Conclusions: This study, the largest reported so far on CKD patients evaluated by highly-reproducible 48 h ABPM, documents the high prevalence of alteration in sleep-time BP regulation in this condition. Most important, prevalence of the riser BP pattern, associated with highest CVD risk, is also very high, from 20% in stage-3-CKD to 34% in end-stage-renal-disease. Collectively, these findings indicate ABPM should be mandatory for proper CVD risk stratification in CKD, as well as a means to establish the most adequate therapeutic scheme to properly control sleep-time BP and decrease CVD risk.

[OP.4A.06] CARDIOVASCULAR RISK IS BETTER REDUCED BY BEDTIME THAN UPON AWAKENING HYPERTENSION TREATMENT-REGIMEN: THE HYGIA PROJECT

Objective: In hypertension, ingesting blood pressure (BP)-lowering medications at bedtime, compared to upon awakening, is usually associated with significantly improved reduction of sleep-time BP mean, a sensitive prognostic marker of cardiovascular disease (CVD) risk. The Hygia Project, a research network presently composed of 292 investigators of 40 clinical sites, was specifically designed to test the hypothesis that bedtime chronotherapy entailing the entire daily dose of >1 conventional hypertension medications exerts better ambulatory BP control and CVD risk reduction than all such medications ingested upon awakening. Design and method: We conducted a prospective, randomized, open-label, blinded endpoint trial of 15,674 hypertensive patients (8,682 men/6,992 women, 60.4 ± 13.7 years of age) according to ambulatory BP (ABPM) criteria. Participants were randomized to ingest all their prescribed hypertension medications upon awakening (n = 7,848) or the entire daily dose of at least one of them at bedtime (n = 7,826). Among the later, 3,918 participants were ingesting all medications at bedtime and the remaining 3,908 ingested some medications at bedtime and others upon awakening. At inclusion and at every scheduled clinic visit for ABPM (at least annually) during follow-up, BP was assessed for 48 h. The primary CVD-outcome was the composite of CVD death, myocardial infarction, coronary revascularization, heart failure, and stroke. Results: During a median 5.1-year follow-up, we documented 1,154 major CVD events. Patients of the bedtime, compared with the upon-waking, treatment group showed significantly lower hazard ratio of CVD events, adjusted for significant influential characteristics of age, sex, type 2 diabetes, chronic kidney disease, cigarette smoking, HDL-cholesterol, asleep systolic BP (SBP) mean, sleep-time relative SBP decline, and previous CVD event (0.47 [95%CI 0.42–0.54], P < 0.001). CVD risk was further reduced among patients who ingested not just some, but all their BP-lowering medications at bedtime (0.27 [0.21–0.34], P < 0.001, compared with ingestion of all medications upon awakening). Conclusions: In hypertensive patients, ingestion of some (preferably all) BP-lowering medications at bedtime, compared with ingestion of all such medications upon-awakening, results in improved ambulatory BP control (significantly enhanced decrease of asleep BP and increase of sleep-time relative BP decline) and, most importantly, markedly reduced risk of major CVD events.

[PP.16.30] SLEEP-TIME AMBULATORY BLOOD PRESSURE AS REFERENCE STANDARD FOR DIAGNOSIS OF HYPERTENSION IN ADULTS: THE HYGIA PROJECT

Objective: Given the substantial evidence that demonstrates ambulatory blood pressure (BP) monitoring (ABPM) predicts long-term cardiovascular disease (CVD) outcomes independent of office BP measurements (OBPM), several international guidelines now propose ABPM as a requirement to confirm office diagnosis of hypertension. Whether such diagnosis should be based on the awake, asleep, 24 h mean, or other ABPM-derived parameter remains unspecified. The Hygia Project, a research network presently composed of 292 investigators of 40 clinical sites, was primarily designed, among other objectives, to compare prospectively the prognostic value of daytime OBPM versus ABPM measures to predict CVD morbidity and mortality. Design and method: This prospective study involved 18,078 persons, 9,769 men/8,309 women, 59.1 ± 14.3 years of age, with baseline BP, according to ABPM criteria, ranging from normotension to hypertension. At inclusion and at every scheduled clinic visit for ABPM (at least annually) during follow-up, BP was assessed at 20-min intervals from 07:00 to 23:00 h and at 30-min intervals at night for 48 h. During ABPM, participants kept a diary listing the times of going to bed at night and awakening in the morning. The primary CVD-outcome was the composite of CVD death, myocardial infarction, coronary revascularization, heart failure, and stroke. Results: During a median 5.1-year follow-up, we documented 2,311 CVD events, including 1,209 for the primary CVD-outcome. The sleep-time systolic BP (SBP) mean (adjusted for significant influential characteristics of age, sex, type 2 diabetes, chronic kidney disease, cigarette smoking, HDL-cholesterol, hypertension treatment-time, and previous CVD event) was the most significant prognostic marker of CVD-outcome (hazard ratio 1.31 [95%CI 1.25–1.37] per SD elevation, P < 0.001), independent of OBPM (1.03 [0.97–1.09], P = 0.315) and awake SBP mean (1.02 [0.94–1.10], P = 0.682) being normal or elevated. Conclusions: The sleep-time SBP mean, but not daytime OBPM or ABPM-derived awake or 24 h BP means, is the most significant independent prognostic marker of CVD morbidity and mortality. Findings of this prospective ABPM trial, the largest ever reported, indicate: (i) hypertension should be diagnosed solely on the basis of elevated sleep-time SBP; and (ii) ABPM is a clinical necessity to accurately detect abnormal sleep-time SBP and properly assess CVD risk.

1C.05: MORNING SURGE AND SLEEP-TIME BLOOD PRESSURE AS PROGNOSTIC MARKERS OF CARDIOVASCULAR RISK: THE HYGIA PROJECT.

Objective: The extent of blood pressure (BP) surge upon waking has been associated with increased cardiovascular (CVD) risk in some, but not all, studies. Numerous studies, however, have consistently shown the association between elevated sleep-time BP mean and the rising BP pattern with increased CVD risk, leading to a paradox, as patients with sleep-time hypertension or non-dipper/riser BP pattern have attenuated morning BP surge. We evaluated the comparative prognostic value for CVD events of the morning BP surge and sleep-time BP among the participants in the ongoing Hygia Project. Design and method: This study involved 11255 subjects, 6028 men/5227 women, 58.9 ± 14.5 years of age, prospectively evaluated throughout a 4.0-year median follow-up. BP was measured at 20-min intervals from 07:00 to 23:00 h and at 30-min intervals at night for 48 h. During monitoring, subjects maintained a diary listing the times of going to bed and awakening. Results: We documented 1539 total events, including 400 deaths, 176 strokes, 144 myocardial infarctions, 147 coronary revascularizations, and 193 heart failures. A greater prewaking systolic BP surge was associated with significantly lower, not higher, CVD risk in a Cox proportional-hazard model adjusted for the significant influential characteristics of age, sex, diabetes, chronic kidney disease, cigarette smoking, waist perimeter, and history of previous CVD event (hazard ratio [HR] 0.83 [95%CI 0.78–0.88] per each 1-SD increment; P < 0.001). The HR was progressively and significantly higher in the first three than in the last two quintiles of increasing prewaking BP surge. The prognostic value of morning surge markedly decreased after correcting by the asleep BP mean, the single most significant prognostic marked of total CVD events (HR = 1.37 [1.29–1.44], P < 0.001). Conclusions: Our findings document that, when properly analyzed as a continuous variable, a larger morning BP surge is associated with a significantly lower CVD risk, in line with the markedly greater risk associated with decreasing dipping of the BP pattern, and the most highly significant prognostic value of progressively elevated asleep BP, an independent prognostic marker of CVD risk that has also been prospectively validated as a relevant therapeutic target for CVD risk reduction.

PREVALENCE OF AN ALTERED CIRCADIAN BLOOD PRESSURE PATTERN IN HYPERTENSIVE SUBJECTS WITH AND WITHOUT DIABETES: THE HYGIA PROJECT: PP.17.113

Objectives: A non-dipper blood pressure (BP) pattern is associated with elevated risk of target organ damage, particularly to the heart, brain, and kidney. A blunted nocturnal decline in BP is frequent in hypertensive patients with diabetes mellitus (DM). The actual prevalence of a non-dipping or even a riser pattern in DM is, however, highly variable among different studies. We studied the impact of DM on the circadian BP pattern in hypertensive subjects participating in the Hygia Project, designed to evaluate prospectively cardiovascular risk by ambulatory BP monitoring (ABPM) in primary care centers of Northwest Spain. Methods: We evaluated 4028 subjects (2198 men), 60.7 ± 14.2 years of age. Among the subjects, 3391 were hypertensive, and among these 902 had type 2 DM. Hypertension was defined as an awake mean >135/85 mmHg for systolic/diastolic BP or an asleep mean >120/70 mmHg. BP was measured every 20-min from 07:00 to 23:00 h and evry 30-min at night for 48 h. Results: Among hypertensive subjects without DM, the prevalence of extreme-dipper, dipper, non-dipper and riser BP patterns were 4.3, 39.5, 44.0 and 12.2%, respectively. The prevalence of non-dipping and rising were significantly higher in DM (46.8 and 22.0%, respectively; P < 0.001). The significantly elevated nocturnal BP among patients with DM lead to a high 21.8% prevalence on patients with masked hypertension (here defined as clinic BP <140/90 mmHg with ABPM above any of the thresholds provided above), while isolated office hypertension was documented in a lower 12.3% of DM-patients. Conclusions: This cross-sectional study corroborates the high prevalence of an altered circadian BP pattern in DM. Most important, almost one quarter of patients with DM had a rising BP pattern, associated with a very high cardiovascular risk. The elevated asleep BP mean in DM leads to a high prevalence of misdiagnosis of hypertension when identification of the condition is based on clinic BP determination. These results support ABPM as a requirement for proper cardiovascular risk assessment among patients with DM.