Masahiro Kikuya

Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis.

BACKGROUND Substantial controversy surrounds the use of estimated glomerular filtration rate (eGFR) and albuminuria to define chronic kidney disease and assign its stages. We undertook a meta-analysis to assess the independent and combined associations of eGFR and albuminuria with mortality. METHODS In this collaborative meta-analysis of general population cohorts, we pooled standardised data for all-cause and cardiovascular mortality from studies containing at least 1000 participants and baseline information about eGFR and urine albumin concentrations. Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause and cardiovascular mortality associated with eGFR and albuminuria, adjusted for potential confounders. FINDINGS The analysis included 105,872 participants (730,577 person-years) from 14 studies with urine albumin-to-creatinine ratio (ACR) measurements and 1,128,310 participants (4,732,110 person-years) from seven studies with urine protein dipstick measurements. In studies with ACR measurements, risk of mortality was unrelated to eGFR between 75 mL/min/1.73 m(2) and 105 mL/min/1.73 m(2) and increased at lower eGFRs. Compared with eGFR 95 mL/min/1.73 m(2), adjusted HRs for all-cause mortality were 1.18 (95% CI 1.05-1.32) for eGFR 60 mL/min/1.73 m(2), 1.57 (1.39-1.78) for 45 mL/min/1.73 m(2), and 3.14 (2.39-4.13) for 15 mL/min/1.73 m(2). ACR was associated with risk of mortality linearly on the log-log scale without threshold effects. Compared with ACR 0.6 mg/mmol, adjusted HRs for all-cause mortality were 1.20 (1.15-1.26) for ACR 1.1 mg/mmol, 1.63 (1.50-1.77) for 3.4 mg/mmol, and 2.22 (1.97-2.51) for 33.9 mg/mmol. eGFR and ACR were multiplicatively associated with risk of mortality without evidence of interaction. Similar findings were recorded for cardiovascular mortality and in studies with dipstick measurements. INTERPRETATION eGFR less than 60 mL/min/1.73 m(2) and ACR 1.1 mg/mmol (10 mg/g) or more are independent predictors of mortality risk in the general population. This study provides quantitative data for use of both kidney measures for risk assessment and definition and staging of chronic kidney disease. FUNDING Kidney Disease: Improving Global Outcomes (KDIGO), US National Kidney Foundation, and Dutch Kidney Foundation.Background A comprehensive evaluation of the independent and combined associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality is required for assessment of the impact of kidney function on risk in the general population, with implications for improving the definition and staging of chronic kidney disease (CKD).

Prognostic significance of the nocturnal decline in blood pressure in individuals with and without high 24-h blood pressure: the Ohasama study.

Objective To examine the relationship between the normal nocturnal decline in blood pressure and the risk of cardiovascular mortality in individuals with and without high 24-h blood pressure values. Methods We obtained 24-h ambulatory blood pressure readings from 1542 residents of Ohasama, Japan, who were aged 40 years or more and were representative of the Japanese general population. We then followed up their survival for a mean of 9.2 years. The relationship was analysed using a Cox proportional hazards model adjusted for possible confounding factors. Results There was a linear relationship between the nocturnal decline in blood pressure and cardiovascular mortality. On average, each 5% decrease in the decline in nocturnal systolic/diastolic blood pressure was associated with an approximately 20% greater risk of cardiovascular mortality. There were no significant interactions for the risk between 24-h systolic/diastolic blood pressure values and continuous values for the nocturnal decline in blood pressure (P for interaction > 0.6). Even when 24-h blood pressure values were within the normal range (< 135/80 mmHg, average 118/69 mmHg), diminished nocturnal decreases in systolic/diastolic blood pressure were associated with an increased risk of cardiovascular mortality. Conclusions This is the first study to demonstrate that a diminished nocturnal decline in blood pressure is a risk factor for cardiovascular mortality, independent of the overall blood pressure load during a 24-h period, in the general population.

Home blood pressure measurement has a stronger predictive power for mortality than does screening blood pressure measurement: a population-based observation in Ohasama, Japan.

Objective To compare the predictive powers of self-measurement of blood pressure at home (home blood pressure measurement) and casual (screening) blood pressure measurement for mortality. Design A prospective cohort study. Subjects and methods We obtained home and screening blood pressure measurements for 1789 subjects aged ≥ 40 years who were followed up for a mean of 6.6 years. The prognostic significance of blood pressure for mortality was determined by the Cox proportional hazards regression model adjusted for age, sex, smoking status, past history of cardiovascular disease, and the use of antihypertensive medication. Results When the home blood pressure values and the screening blood pressure values were simultaneously incorporated into the Cox model as continuous variables, only the average of multiple (taken more than three times) home systolic blood pressure values was significantly and strongly related to the cardiovascular mortality risk. The average of the two initial home blood pressure values was also better related to the mortality risk than were the screening blood pressure values. Conclusions Home blood pressure measurement had a stronger predictive power for mortality than did screening blood pressure measurement for a general population. This appears to be the first study in which the prognostic significances of home and screening blood pressure measurements have been compared.

Prognostic accuracy of day versus night ambulatory blood pressure: a cohort study.

BACKGROUND Few studies have formally compared the predictive value of the blood pressure at night over and beyond the daytime value. We investigated the prognostic significance of the ambulatory blood pressure during night and day and of the night-to-day blood pressure ratio. METHODS We did 24-h blood pressure monitoring in 7458 people (mean age 56.8 years [SD 13.9]) enrolled in prospective population studies in Denmark, Belgium, Japan, Sweden, Uruguay, and China. We calculated multivariate-adjusted hazard ratios for daytime and night-time blood pressure and the systolic night-to-day ratio, while adjusting for cohort and cardiovascular risk factors. FINDINGS Median follow-up was 9.6 years (5th to 95th percentile 2.5-13.7). Adjusted for daytime blood pressure, night-time blood pressure predicted total (n=983; p<0.0001), cardiovascular (n=387; p<0.01), and non-cardiovascular (n=560; p<0.001) mortality. Conversely, adjusted for night-time blood pressure, daytime blood pressure predicted only non-cardiovascular mortality (p<0.05), with lower blood pressure levels being associated with increased risk. Both daytime and night-time blood pressure consistently predicted all cardiovascular events (n=943; p<0.05) and stroke (n=420; p<0.01). Adjusted for night-time blood pressure, daytime blood pressure lost prognostic significance only for cardiac events (n=525; p> or =0.07). Adjusted for the 24-h blood pressure, night-to-day ratio predicted mortality, but not fatal combined with non-fatal events. Antihypertensive drug treatment removed the significant association between cardiovascular events and the daytime blood pressure. Participants with systolic night-to-day ratio value of 1 or more were older, at higher risk of death, and died at an older age than those whose night-to-day ratio was normal (> or =0.80 to <0.90). INTERPRETATION In contrast to commonly held views, daytime blood pressure adjusted for night-time blood pressure predicts fatal combined with non-fatal cardiovascular events, except in treated patients, in whom antihypertensive drugs might reduce blood pressure during the day, but not at night. The increased mortality in patients with higher night-time than daytime blood pressure probably indicates reverse causality. Our findings support recording the ambulatory blood pressure during the whole day.

Prognostic significance of blood pressure and heart rate variabilities: the Ohasama study

To investigate the association between cardiovascular mortality and short-term variabilities in blood pressure and heart rate, we performed a long-term prospective study of ambulatory blood pressure monitoring in Ohasama, Japan, starting in 1987. We obtained ambulatory blood pressure and heart rate in 1542 subjects ≥40 years of age. Blood pressure and heart rate variabilities were estimated as a standard deviation measured every 30 minutes by ambulatory monitoring. There were 67 cardiovascular deaths during the follow-up period (mean=8.5 years). The Cox proportional hazards model, adjusted for possible confounding factors, demonstrated a significant increase in cardiovascular mortality, with an increase in daytime systolic ambulatory blood pressure variability. A similar trend was observed in daytime diastolic and nighttime ambulatory blood pressures. Cardiovascular mortality rate increased linearly, with a decrease in daytime heart rate variability. Subjects in whom the daytime systolic ambulatory blood pressure variability was larger than third quintile and the daytime heart rate variability was lower than the mean−SD were at extremely high risk of cardiovascular mortality. The blood pressure and heart rate variabilities obtained every 30 minutes by ambulatory blood pressure monitoring were independent predictors for cardiovascular mortality in the general population.

Ambulatory Blood Pressure and 10-Year Risk of Cardiovascular and Noncardiovascular Mortality: The Ohasama Study

The objective of this study was to elucidate the long-term prognostic significance of ambulatory blood pressure. Ambulatory and casual blood pressure values were obtained from 1332 subjects (872 women and 460 men) aged ≥40 years from the general population of a rural Japanese community. Survival was then followed for 14 370 patient years and analyzed by a Cox hazard model adjusted for possible confounding factors. There were 72 cardiovascular deaths during the 10.8-year follow-up. The relationship between 24-hour systolic blood pressure and the cardiovascular mortality risk was U-shaped in the first 5 years, then changed to J-shaped over the rest of the 10.8-year follow-up. After censoring the first 2 years of data, the risk flattened until it again increased for the fifth quintile of 24-hour systolic blood pressure for the 10.8-year follow-up period. For 24-hour diastolic blood pressure, the J-shaped relationship remained unchanged, regardless of follow-up duration and censoring. Ambulatory systolic blood pressure values consistently showed stronger predictive power for cardiovascular mortality risk than did casual systolic blood pressure in the 10.8-year follow-up data, whereas such relationships became more marked after censoring the first 2 years. When nighttime and daytime systolic blood pressure values were simultaneously included in the same Cox model, only nighttime blood pressure significantly predicted the cardiovascular mortality risk for the 10.8-year follow-up data. We conclude that the relationship between ambulatory systolic blood pressure and cardiovascular mortality is not U-shaped or J-shaped, and that nighttime blood pressure has better prognostic value than daytime blood pressure.

Prognostic Significance for Stroke of a Morning Pressor Surge and a Nocturnal Blood Pressure Decline: The Ohasama Study

There is continuing controversy over whether the pattern of circadian blood pressure (BP) variation that includes a nocturnal decline in BP and a morning pressor surge has prognostic significance for stroke risk. In this study, we followed the incidence of stroke in 1430 subjects aged ≥40 years in Ohasama, Japan, for an average of 10.4 years. The association between stroke risk and the pattern of circadian BP variation was analyzed with a Cox proportional hazards model after adjustment for possible confounding factors. There was no significant association between total stroke risk and the nocturnal decline in BP (percentage decline from diurnal level) or between total stroke risk and the morning pressor surge. The cerebral infarction risk was significantly higher in subjects with a <10% nocturnal decline in BP as compared with subjects who had a ≥10% nocturnal decline in BP (P=0.04). The morning pressor surge was not associated with a risk of cerebral infarction. On the other hand, an increased risk of cerebral hemorrhage was observed in subjects with a large morning pressor surge (≥25 mm Hg; P=0.04). Intracerebral hemorrhage was also observed more frequently in extreme dippers (those with a ≥20% nocturnal decline in BP) than dippers (those with a 10% to 19% decline; P=0.02). A disturbed nocturnal decline in BP is associated with cerebral infarction, whereas a large morning pressor surge and a large nocturnal decline in BP, which are analogous to a large diurnal increase in BP, are both associated with cerebral hemorrhage.

Prognostic superiority of daytime ambulatory over conventional blood pressure in four populations: a meta-analysis of 7030 individuals

Objective To investigate the multivariate-adjusted predictive value of systolic and diastolic blood pressures on conventional (CBP) and daytime (10–20 h) ambulatory (ABP) measurement. Methods We randomly recruited 7030 subjects (mean age 56.2 years; 44.8% women) from populations in Belgium, Denmark, Japan and Sweden. We constructed the International Database on Ambulatory blood pressure and Cardiovascular Outcomes. Results During follow-up (median = 9.5 years), 932 subjects died. Neither CBP nor ABP predicted total mortality, of which 60.9% was due to noncardiovascular causes. The incidence of fatal combined with nonfatal cardiovascular events amounted to 863 (228 deaths, 326 strokes and 309 cardiac events). In multivariate-adjusted continuous analyses, both CBP and ABP predicted cardiovascular, cerebrovascular, cardiac and coronary events. However, in fully-adjusted models, including both CBP and ABP, CBP lost its predictive value (P ≥ 0.052), whereas systolic and diastolic ABP retained their prognostic significance (P ≤ 0.007) with the exception of diastolic ABP as predictor of cardiac and coronary events (P ≥ 0.21). In adjusted categorical analyses, normotension was the referent group (CBP < 140/90 mmHg and ABP < 135/85 mmHg). Adjusted hazard ratios for all cardiovascular events were 1.22 [95% confidence interval (CI) = 0.96–1.53; P = 0.09] for white-coat hypertension (≥ 140/90 and < 135/85 mmHg); 1.62 (95% CI = 1.35–1.96; P < 0.0001) for masked hypertension (< 140/90 and ≥ 135/85 mmHg); and 1.80 (95% CI = 1.59–2.03; P < 0.0001) for sustained hypertension (≥ 140/90 and ≥ 135/85 mmHg). Conclusions ABP is superior to CBP in predicting cardiovascular events, but not total and noncardiovascular mortality. Cardiovascular risk gradually increases from normotension over white-coat and masked hypertension to sustained hypertension.

Prognostic Value of Reading-to-Reading Blood Pressure Variability Over 24 Hours in 8938 Subjects From 11 Populations

In previous studies, of which several were underpowered, the relation between cardiovascular outcome and blood pressure (BP) variability was inconsistent. We followed health outcomes in 8938 subjects (mean age: 53.0 years; 46.8% women) randomly recruited from 11 populations. At baseline, we assessed BP variability from the SD and average real variability in 24-hour ambulatory BP recordings. We computed standardized hazard ratios (HRs) while stratifying by cohort and adjusting for 24-hour BP and other risk factors. Over 11.3 years (median), 1242 deaths (487 cardiovascular) occurred, and 1049, 577, 421, and 457 participants experienced a fatal or nonfatal cardiovascular, cardiac, or coronary event or a stroke. Higher diastolic average real variability in 24-hour ambulatory BP recordings predicted (P≤0.03) total (HR: 1.14) and cardiovascular (HR: 1.21) mortality and all types of fatal combined with nonfatal end points (HR: ≥1.07) with the exception of cardiac and coronary events (HR: ≤1.02; P≥0.58). Higher systolic average real variability in 24-hour ambulatory BP recordings predicted (P<0.05) total (HR: 1.11) and cardiovascular (HR: 1.16) mortality and all fatal combined with nonfatal end points (HR: ≥1.07), with the exception of cardiac and coronary events (HR: ≤1.03; P≥0.54). SD predicted only total and cardiovascular mortality. While accounting for the 24-hour BP level, average real variability in 24-hour ambulatory BP recordings added <1% to the prediction of a cardiovascular event. Sensitivity analyses considering ethnicity, sex, age, previous cardiovascular disease, antihypertensive treatment, number of BP readings per recording, or the night:day BP ratio were confirmatory. In conclusion, in a large population cohort, which provided sufficient statistical power, BP variability assessed from 24-hour ambulatory recordings did not contribute much to risk stratification over and beyond 24-hour BP.

Day-by-Day Variability of Blood Pressure and Heart Rate at Home as a Novel Predictor of Prognosis: The Ohasama Study

Day-by-day blood pressure and heart rate variability defined as within-subject SDs of home measurements can be calculated from long-term self-measurement. We investigated the prognostic value of day-by-day variability in 2455 Ohasama, Japan, residents (baseline age: 35 to 96 years; 60.4% women). Home blood pressure and heart rate were measured once every morning for 26 days (median). A total of 462 deaths occurred over a median of 11.9 years, composing 168 cardiovascular deaths (stroke: n=83; cardiac: n=85) and 294 noncardiovascular deaths. Using Cox regression, we computed hazard ratios while adjusting for baseline characteristics, including blood pressure and heart rate level, sex, age, obesity, current smoking and drinking habits, history of cardiovascular disease, diabetes mellitus, hyperlipidemia, and treatment with antihypertensive drugs. An increase in systolic blood pressure variability of +1 between-subject SD was associated with increased hazard ratios for cardiovascular (1.27; P=0.002) and stroke mortality (1.41; P=0.0009) but not for cardiac mortality (1.13; P=0.26). Conversely, heart rate variability was associated with cardiovascular (1.24; P=0.002) and cardiac mortality (1.30; P=0.003) but not stroke mortality (1.17; P=0.12). Similar findings were observed for diastolic blood pressure variability. Additional adjustment of heart rate variability for systolic blood pressure variability and vice versa produced confirmatory results. Coefficient of variation, defined as within-subject SD divided by level of blood pressure or heart rate, displayed similar prognostic value. In conclusion, day-by-day blood pressure variability and heart rate variability by self-measurement at home make up a simple method of providing useful clinical information for assessing cardiovascular risk.