Epidemiology/Population. Home Blood Pressure and Cardiovascular Outcomes in Patients During Antihypertensive Therapy

Epidemiology/Population Home Blood Pressure and Cardiovascular Outcomes in Patients During Antihypertensive Therapy Primary Results of HONEST, a Large-Scale Prospective, Real-World Observational Study Kazuomi Kario, Ikuo Saito, Toshio Kushiro, Satoshi Teramukai, Yusuke Ishikawa, Yoshihiro Mori, Fumiaki Kobayashi, Kazuyuki Shimada Abstract This study aimed to investigate the relationship between on-treatment morning home blood pressure (HBP) and incidence of cardiovascular events using data from the Home Blood Pressure Measurement With Olmesartan Naive Patients to Establish Standard Target Blood Pressure (HONEST) study, a prospective observational study of 21 591 outpatients with essential hypertension (mean age, 64.9 years; women, 50.6%) enrolled between 2009 and 2010 at clinics and hospitals in Japan. They received olmesartan-based treatment throughout. The primary end point was major cardiovascular events. After a mean follow-up period of 2.02 years, cardiovascular events occurred in 280 patients (incidence, 6.46/1000 patient-years). The risk for the primary end point was significantly higher in patients with ontreatment morning HBP 145 to <155 mm Hg (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.12 2.99) and 155 mm Hg (HR, 5.03; 95% CI, 3.05 8.31) than <125 mm Hg and with on-treatment clinic blood pressure 150 to <160 mm Hg (HR, 1.69; 95% CI, 1.10 2.60) and 160 mm Hg (HR, 4.38; 95% CI, 2.84 6.75) than <130 mm Hg. Morning HBP associated with minimum risk was 124 mm Hg by spline regression analysis. Cardiovascular risk was increased in patients with morning HBP 145 mm Hg and clinic blood pressure <130 mm Hg (HR, 2.47; 95% CI, 1.20 5.08) compared with morning HBP <125 mm Hg and clinic blood pressure <130 mm Hg. In conclusion, it is essential to control morning HBP to <145 mm Hg, even in patients with controlled clinic blood pressure. Clinical Trial Registration URL: http://www.umin.ac.jp/ctr/index.htm. UMIN Clinical Trials Registry, trial No. UMIN000002567. (Hypertension. 2014;64:989-996.) Online Data Supplement Key Words: antihypertensive agents blood pressure monitoring, ambulatory cardiovascular diseases hypertension masked hypertension observational study Home blood pressure (HBP) monitoring has several benefits. Compared with clinic BP (CBP), HBP measurements provide a more accurate prognosis for survival. 1 3 HBP monitoring enables the identification of patients with masked hypertension, the diagnosis of which is not possible when only CBP is measured, and carries a cardiovascular risk at least equal to that of uncontrolled hypertension. 4,5 Cardiovascular events tend to occur in the morning, along with a peak in ambulatory BP, 6 and of clinic, 24-hour, awake, sleep, evening, preawake, and morning BP, morning systolic BP (SBP) is the strongest independent predictor for stroke. 7 Therefore, antihypertensive treatment for morning hypertension is likely to offer greater benefit in preventing cardiovascular events. Received July 14, 2014; first decision July 27, 2014; revision accepted August 1, 2014. From the Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, Shimotsuke, Japan (K.K.); Keio University, Yokohama, Japan (I.S.); The Life Planning Center Foundation, Tokyo, Japan (T.K.); Department of Biostatistics, Graduate School of Medical Science Kyoto Prefectural University of Medicine, Kyoto, Japan (S.T.); Daiichi Sankyo Co, Ltd, Tokyo, Japan (Y.I., Y.M., F.K.); and Shin-Oyama City Hospital, Oyama, Japan (K.S.). The main study results featured in this article were presented at the Joint Meeting of the 24th European Meeting on Hypertension and Cardiovascular Protection and the 25th Scientific Meeting of International Society of Hypertension, Athens, Greece, June 13 16, 2014. The subanalysis results were presented at the 34th Annual Scientific Meeting of the Japanese Society of Hypertension, Utsunomiya, Japan, October 20 22, 2011; the 35th Annual Scientific Meeting of the Japanese Society of Hypertension, Nagoya, Japan, September 20 22, 2012; the 36th Annual Scientific Meeting of the Japanese Society of Hypertension, Osaka, Japan, October 24 26, 2013; the 2nd Annual Scientific Forum of Clinical Hypertension of the Japanese Society of Hypertension, Tokyo, Japan, May 25 26, 2013; the 77th Annual Scientific Meeting of the Japanese Circulation Society, Yokohama, Japan, March 15 17, 2013; the 24th Scientific Meeting of the International Society of Hypertension, Sydney, Australia, September 30 October 4, 2012. The report summarizing the study protocol was published in Saito et al (Hypertens Res. 2013;36:177 182). The reports of subanalyses were published in Kario et al (J Hum Hypertens. 2013;27:721 728), Kario et al (J Clin Hypertens. 2013;15:555 561), Yaginuma et al (J Clin Ther Med. 2013;29:665 679 [in Japanese]), and Kario et al (J Clin Hypertens. 2014;16:442 450). The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/hypertensionaha. 114.04262/-/DC1. Correspondence to Kazuomi Kario, Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. E-mail kkario@jichi.ac.jp 2014 American Heart Association, Inc. Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.114.04262 989

990 Hypertension November 2014 Previous studies that investigated the relationship between HBP and incidence of cardiovascular events mainly involved the general population. 1 3,8 In a study that involved patients receiving antihypertensive treatment, baseline BP was used as a marker. 4 The relationship between on-treatment BP and incidence of cardiovascular events is more of a concern for clinical physicians; however, few studies have used on-treatment HBP as a marker. 9,10 The Home Blood Pressure Measurement With Olmesartan Naive Patients to Establish Standard Target Blood Pressure (HONEST) study is a large-scale prospective observational study involving >20 000 patients receiving olmesartan-based antihypertensive treatment for 2 years; time from start of treatment to first occurrence of major cardiovascular events is the primary end point. 11 In the present analysis, we used HBP and CBP data from patients receiving antihypertensive treatment to determine their relationship with the incidence of cardiovascular events, which was a primary objective of the HONEST study. Methods Study Design The aims and protocol of the HONEST study have already been reported. 11 HONEST is a large-scale prospective observational study with a 2-year follow-up period and is registered at the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/index.htm) with the unique trial number UMIN000002567. The study protocol was approved by the Ethical Committee of Daiichi Sankyo Co, Ltd, and the review boards of the participating institutions, at their discretion. The study conforms with the pharmaceutical affairs laws of Japan and was approved by the Ministry of Health, Labour and Welfare of Japan before commencement. It was performed in registered medical institutions, in compliance with Good Post-marketing Study Practice in Japan and internal regulations for clinical studies at each institution. Patients Olmesartan-naive outpatients with essential hypertension (physician reported, no BP range) had recorded their morning HBP on 2 days in the 28 days before taking olmesartan. After providing written informed consent and being prescribed olmesartan, patients were registered. The selection of CBP and HBP targets was at the discretion of individual physicians. No restrictions were placed on prior antihypertensive drug treatment, with the exception of prior use of olmesartan, or on the use of combination antihypertensive drug treatment during the study. The data collected included patient characteristics (eg, disease history and complications), CBP and HBP, clinical laboratory test values, and incidence of cardiovascular events and adverse events during the study period. In the present analysis, we did not cross-check the data obtained from participating institutions against medical records. HBP Measurements Patients who already had an electric device for measuring HBP based on the cuff-oscillometric principle were registered. At the time of obtaining informed consent, patients were asked to measure their HBP twice in the morning and twice at bedtime according to the guidelines of the Japanese Society of Hypertension (JSH 2009). 12 During the follow-up period, HBP was measured at 1 week, 4 weeks, 16 weeks, 6 months, 12 months, 18 months, and 24 months. In principle, patients reported their HBP measured twice in the morning and twice at bedtime on 2 different days for each measurement point. We calculated the average of the 2 HBP measurements at each time. Then, for each measurement point, we used the average of the HBP over 2 days. In analyses of the relationship with the incidence of cardiovascular events, the averaged BP during the follow-up period (excluding baseline BP) was used. For patients who had cardiovascular events, the average of BP values obtained until the first occurrence of such events was used for the analysis. The average of morning and evening (Av-ME) HBP values was calculated using morning and evening HBP measured on the same day. CBP Measurement The HONEST study was done in the setting of daily medical practice, so CBP and pulse rate were measured according to the usual methods of each institution; no recommendations or training were provided with respect to the measurement of CBP. During the follow-up period, CBP was measured at 4 weeks, 16 weeks, 6 months, 12 months, 18 months, and 24 months. For each measurement point, 1 measurement was reported. Analyses of the relationship with the incidence of cardiovascular events were done using the same method used for HBP. Evaluation of Cardiovascular Events Evaluation of events was done under blinded conditions by 3 Event Review Committees (for cerebrovascular, cardiovascular, and other events) consisting of specialists (Table S1 in the online-only Data Supplement) and in accordance with event definitions (Table S2 and Figure S1). The primary end point was time from start of treatment to first occurrence of a major cardiovascular event, that is, cerebral infarction, intracerebral hemorrhage, subarachnoid hemorrhage, unclassified stroke, myocardial infarction, coronary revascularization procedures for angina pectoris, or sudden death. Statistical Analysis The analysis population comprised eligible patients who received olmesartan at least once during the treatment period. The cumulative event rate was estimated using the Kaplan Meier method. The Cox proportional hazards model was used to investigate the relationship between on-treatment BP and incidence of events as categorical variables, with the covariates of cardiovascular risk factors. Multivariateadjusted generalized additive models with a spline function of 3 degrees of freedom were used to investigate potential nonlinear relationships between incidence of events and on-treatment BP as continuous variables. These models were used to estimate the BP associated with minimum risk. All statistical tests were 2 sided, using a significance level of 0.05. SAS release 9.2 software (SAS Institute, Cary, NC) was used for all statistical analyses. Results Study Profile A total of 22 373 patients throughout Japan were registered between October 1, 2009, and September 30, 2010. Case report forms were not collected from 75 of these patients, for the reasons of participating medical institutions. Of the 22298 patients whose case report forms were collected, data from 21591 were included in the analysis after excluding 351 patients who did not visit hospital after the start of treatment, 258 patients who withdrew their consent to participate in the study and refused the use of data obtained until then, and 98 patients for whom violations of the inclusion criteria were found during the follow-up period. The baseline characteristics of the 21 591 patients are presented in Table 1. The mean follow-up period was 2.02±0.50 years, and the median and maximum follow-up periods were 2.08 and 3.4 years, respectively. During the follow-up period, 425 patients withdrew consent (but agreed to the use of data obtained until then) and 190 patients died. Of the patients

Kario et al Medicated HBP and Cardiovascular Outcomes 991 AQ2 Table 1. Baseline Characteristics of Patients in the Home Blood Pressure Measurement With Olmesartan Naive Patients to Establish Standard Target Blood Pressure (HONEST) Study Patient Characteristics No. of Patients (%) or Mean±SD (n=21 591) 72.4±20.2 Women 10 921 (51) Age, y 64.9±11.9 Body mass index, kg/m 2 24.3±3.7 Disease history Cerebral or cardiovascular disease 2269 (11) Cerebrovascular disease 1432 (7) Cardiovascular disease 981 (5) Complications Dyslipidemia 9626 (45) Diabetes mellitus 4426 (21) Chronic kidney disease 4346 (20) Cardiac disease 2019 (9) Current smokers 2654 (12) Regular alcohol drinkers 3473 (16) Previously used antihypertensive drugs 10 872 (50) Calcium channel blocker 7783 (36) Angiotensin II receptor blocker 4581 (21) β-blocker 1380 (6) Diuretic 1260 (6) Angiotensin-converting enzyme inhibitor 785 (4) α-blocker 470 (2) Other 97 (0) Drugs used at study entry Lipid-lowering drugs 6127 (28) Antidiabetic drugs 2985 (14) Anticoagulant or antiplatelet drugs 2685 (12) Lipid Total cholesterol, mg/dl 202.5±35.9 Low-density lipoprotein cholesterol, mg/dl 118.7±31.0 High-density lipoprotein cholesterol, mg/dl 58.5±15.7 Triglycerides, mg/dl 133.3±86.4 Fasting plasma glucose, mg/dl 106.0±29.8 HbA1c (NGSP), % 6.19±1.09 Creatinine, mg/dl 0.79±0.31 Estimated glomerular filtration rate, ml/min/1.73 m 2 HbA1c indicates hemoglobin A1c; NGSP, National Glycohemoglobin Standardization Program. who agreed to continue to participate in the study, contact was lost with 1950 (9.0%), and their follow-up period was <21 months. The administration of antihypertensive drugs is shown in Table S3. Changes in BP Figure S2 shows changes in morning HBP and CBP throughout the follow-up period. The values at baseline and after 24 months, as well as the average of these values during follow-up for morning HBP, CBP, evening HBP, and Av-ME HBP, are shown in Table S4. During follow-up, mean morning home SBP (HSBP), clinic SBP (CSBP), evening HSBP, and Av-ME HSBP were 135.2±10.8, 135.2±11.5, 130.0±11.2, and 132.8±10.1 mm Hg, respectively. Number and Incidence of Cardiovascular Events Table 2 shows the number and incidence of cardiovascular events. Details of individual cardiovascular events are shown in Table S5. The primary end point occurred in 280 patients (incidence, 6.46/1000 patient-years). The Kaplan Meier curves in Figure S3 show the cumulative incidence of the primary end point. Excluding data from patients with a history of cardiovascular disease and using the composite end point (cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction), the incidence was 3.62/1000 patient-years. Relationship Between BP and Cardiovascular Events During Follow-Up Figure 1 shows the relationship between morning HSBP, CSBP, evening HSBP, and Av-ME HSBP during the followup period and the primary end point. Hazard ratios (HRs) for the primary end point increased significantly at the following cutoff values: morning HSBP 145 to <155 mm Hg (HR, 1.83; 95% confidence interval Table 2. Cardiovascular Events Cardiovascular Events During Follow-Up No. of Events Incidence, Events/1000 Patient-Years (95% CI) Primary end point 280 6.46 (5.75 7.27) Secondary end point 336 7.76 (6.98 8.64) Stroke events* 127 2.92 (2.46 3.48) Atherothrombotic cerebral infarction 43 0.99 (0.73 1.33) Lacunar infarction 40 0.92 (0.67 1.25) Cerebral hemorrhage 17 0.39 (0.24 0.63) Unclassified cerebral infarction 13 0.30 (0.17 0.51) Subarachnoid hemorrhage 8 0.18 (0.09 0.37) Cardiogenic cerebral infarction 4 0.09 (0.03 0.24) Unclassified stroke 3 0.07 (0.02 0.21) Cardiac events 167 3.85 (3.30 4.48) Coronary revascularization procedure 77 1.77 (1.42 2.21) for angina pectoris* Myocardial infarction* 45 1.03 (0.77 1.38) Hospitalization for heart failure 36 0.83 (0.60 1.15) Hospitalization for angina pectoris 13 0.30 (0.17 0.51) All death 190 4.36 (3.78 5.02) Cardiovascular death 46 1.05 (0.79 1.41) Sudden death* 35 0.80 (0.58 1.12) Aortic dissection 5 0.11 (0.05 0.28) Arteriosclerosis obliterans 12 0.28 (0.16 0.48) CI indicates confidence interval. *Events comprising the primary end point. The secondary end point comprised the primary end point, hospitalization for heart failure and angina pectoris, aortic dissection, and arteriosclerosis obliterans. Cardiovascular death comprised fatal stroke, fatal myocardial infarction, and sudden death.

992 Hypertension November 2014 Figure 1. Relationship between the primary end point and mean morning home systolic blood pressure (SBP; A), clinic SBP (B), evening home SBP (C), and averaged morning and evening home SBP (D) during the follow-up period. The Cox proportional hazards model was used, adjusting for sex, age, family history of cardiovascular disease, dyslipidemia, diabetes mellitus, chronic kidney disease, history of cardiovascular disease, and smoking status. Vertical lines indicate 95% confidence interval. Number of events per 1000 patients-years. [CI], 1.12 2.99), CSBP 150 to <160 mm Hg (HR, 1.69; 95% CI, 1.10 2.60), evening HSBP 145 to <155 mm Hg (HR, 1.63; 95% CI, 1.01 2.61), and Av-ME HSBP 145 to <155 mm Hg (HR, 2.36; 95% CI, 1.44 3.85). In addition, for morning HSBP, Cox proportional hazards model analysis using the value immediately before the event as a time-dependent covariate was also done. The results were not essentially different from those of the analysis using mean BP during the follow-up period (data not shown). BP Associated With Minimum Risk by Spline Regression Figure 2 shows spline regression analysis generated to help determine the relationship between continuous morning HSBP, CSBP, evening HSBP, and Av-ME HSBP (the average of values during the follow-up period) and relative risk of the primary end point. Minimum risks of morning HSBP, CSBP, evening HSBP, and Av-ME HSBP were 124, 131, 124, and 124 mm Hg, respectively.

Kario et al Medicated HBP and Cardiovascular Outcomes 993 AQ2 Figure 2. Relationship between systolic blood pressure (SBP) during the follow-up period and relative risk (odds ratio) of the primary end point, with 3 degrees of freedom by spline regression analysis, adjusting for sex, age, family history of cardiovascular disease, dyslipidemia, diabetes mellitus, chronic kidney disease, history of cardiovascular disease, and smoking status. The risk at BP during the follow-up period (mean morning home SBP, clinic SBP, evening home SBP, and averaged morning and evening SBP were 135.2, 135.2, 130.0, and 132.8 mm Hg, respectively) was defined as relative risk 1. The solid line indicates morning home SBP (A), clinic SBP (B), evening home SBP (C), and averaged morning and evening home SBP (D), and the dotted line indicates the 95% confidence interval (CI). The morning home SBP, clinic SBP, evening home SBP, and averaged morning and evening home SBP associated with minimum cardiovascular risk were 124, 131, 124, and 124 mm Hg, respectively, and the values at which the lower limit of 95% CI exceeded relative risk 1 were 144, 148, 141, and 142 mm Hg, respectively. Incidence of Cardiovascular Events by Category of Morning HSBP and CSBP Using morning HSBP 125 and 145 mm Hg and CSBP 130 and 150 mm Hg as cutoff values, HRs for the incidence of cardiovascular events in each SBP were calculated (Figure 3). The patients with morning HSBP <125 mm Hg and CSBP <130 mm Hg were defined as a reference. HR was highest in the patients with morning HSBP 145 mm Hg and CSBP 150 mm Hg (HR, 3.92; 95% CI, 2.22 6.92), followed by the patients with morning HSBP 145 mm Hg and CSBP <130 mm Hg (HR, 2.47; 95% CI, 1.20 5.08). Analysis using evening HSBP and Av-ME HSBP showed essentially the same results (data not shown). The characteristics of patients with morning HSBP 145 mm Hg, stratified by CSBP 130 and 150 mm Hg, and their use of antihypertensive drugs at the end of the study are summarized in Table S6. In the patients with morning HSBP 145 mm Hg and CSBP <130 mm Hg, the mean age and proportion of history of cardiovascular disease, previous antihypertensive agents, and number of antihypertensive agents used at end of study were higher than in other patients (except number of antihypertensive agents P<0.001, number of antihypertensive agents P=0.008 and P=0.004). And the mean of body mass index was lower (P=0.003 and P<0.001). Discussion This report features the main results of the HONEST study that involved >20 000 hypertensive patients and provides several new findings about HBP in a real-world setting. First, we found that on-treatment morning HSBP 145 mm Hg is associated with a significant increase in cardiovascular risk for 2 years. Second, morning HSBP associated with minimum risk was 124 mm Hg. Finally, the risk of cardiovascular events is high in patients with masked hypertension and uncontrolled morning HSBP, although their CSBP is not increased. Based on this evidence, it is essential to control morning HSBP to <145 mm Hg as a first step, even in patients with controlled CSBP. These real-world findings emphasize the importance of HBP monitoring in clinical practice. Morning HBP Based on the previous study showing that morning SBP is the strongest indicator of cardiovascular events, 7 we used SBP in this study. The threshold value of morning HBP 145 mm Hg determined through the Cox proportional hazards model in the present study is higher than the value used in the diagnostic criteria for morning HBP (135 mm Hg). However, the threshold BP higher than the diagnostic criteria for morning HBP was also determined in a previous observational study. 10 Moreover, no interventional study has been conducted to determine the threshold BP value for increased cardiovascular risk. 9 Because the HONEST study is not an interventional study, we cannot define <145 mm Hg as the BP target; however, we can at least suggest that cardiovascular risk increases above that value, based on the results of our study, which followed up patients for 2 years. This interpretation is further supported by the value for the lower limit of 95% CI exceeding the relative risk of 1, as determined by spline regression analysis for continuous variables. In addition, the finding that morning HBP 124 mm Hg is associated with minimum risk, as determined by spline

994 Hypertension November 2014 Figure 3. Relationship between the primary end point and systolic blood pressure (SBP) divided into 9 categories. The Cox proportional hazards model was used, adjusting for sex, age, family history of cardiovascular disease, dyslipidemia, diabetes mellitus, chronic kidney disease, history of cardiovascular disease, and smoking status. Morning home SBP <125 mm Hg and clinic SBP <130 mm Hg were used as a reference. regression analysis, also suggests that further lowering of BP may be beneficial. Comparison With HBP Reported in Previous Studies The Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure (HOMED-BP) study is similar to the present study in that patients receiving antihypertensive therapy were enrolled to determine the relationship between on-treatment HBP during the follow-up period and the incidence of cardiovascular events (cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction). 9 In this study, 2 groups with different BP targets were compared, and the incidence of cardiovascular events was 2.93 and 3.00/1000 patient-years. We found that morning HSBP (HONEST, 131.5 mm Hg versus HOMED-BP, 130 and 129 mm Hg) and CSBP (HONEST, 132.6 mm Hg versus HOMED-BP, 130 and 129 mm Hg) at last visit are similar. However, there was a large difference in the percentage of patients with a history of cardiovascular disease (HONEST, 11% versus HOMED-BP, 3%). After excluding data from patients with a history of cardiovascular disease and using the same composite end point as in HOMED-BP, the incidence of cardiovascular events in patients in the HONEST study was similar to the results of the HOMED-BP study. There are some other studies that investigated the relationship between HBP and cardiovascular events. Those reporting the incidence of cardiovascular events are as follows: the Finnish home BP monitoring (Finn-HOME) study 3 involving 2081 individuals from a general population reported the incidence of cardiovascular events (cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, percutaneous coronary intervention, or coronary artery bypass graft surgery) to be 11.5/1000 person-years and the Self measurement of blood pressure at Home in the Elderly: Assessment and Follow-up (SHEAF) study 4 involving 4939 hypertensive patients being treated reported the incidence of cardiovascular mortality of 5.6/1000 patient-years. These prospective HBP studies found the consistent result that baseline HBP is superior to CBP for predicting cardiovascular events. 3,4 Compared with those previous studies, the present study involved a large number of patients (>20 000 patients) and followed them both for HBP and CBP throughout 2 years, strengthening the clinical value of HBP during antihypertensive treatment. Morning Versus Evening and Av-ME Among morning HSBP, evening HSBP, and Av-ME HSBP, morning HSBP showed the greatest discrepancy between mean SBP during follow-up and the SBP associated with minimum risk, as determined by spline regression analysis. And with the Cox proportional hazards model, the ratio of patients with SBP 145 mm Hg was highest in morning HSBP. Those findings indicate insufficient control of morning HSBP compared with other types of SBP in real-world clinical practice. Circadian changes in BP, such as morning surge, 13 may underlie uncontrolled morning HSBP, so strict monitoring of morning HSBP is recommended. Masked Hypertension The results of the present study show that the incidence of cardiovascular events increases as morning HSBP and CSBP increase; however, cardiovascular risk is also increased in patients whose HSBP is 145 mm Hg but whose CSBP is

Kario et al Medicated HBP and Cardiovascular Outcomes 995 AQ2 <130 mm Hg. The patients with severe masked hypertension were generally older and more likely to have lower body mass index and a history of cardiovascular disease. In a study of an untreated Finnish adult population, older age, greater body mass index, current smoking, excessive alcohol consumption, and left ventricular hypertrophy were reported to be independent determinants of masked hypertension. 14 More than 60% of these patients had been receiving antihypertensive treatment at the time of study entry, and they were receiving more antihypertensive drugs at study completion. Because of these background factors, it is difficult to control BP throughout 24 hours, and therefore, these patients had high out-of-clinic BP; this may have contributed to the high incidence of cardiovascular events in these patients. The results of previous studies have shown that masked hypertension is associated with higher cardiovascular risk as with sustained hypertension. 4,5,15,16 This is consistent with the findings of the present study, which used on-treatment BP as an indicator. Therefore, we strongly recommend measuring and monitoring HBP in real-world clinical practice so as to identify masked hypertension, which can be described as a pitfall in the treatment of hypertension. Study Limitations The findings of the present study are limited by the study design that intended to reflect real-world clinical practice; patients were not blinded to treatment, and there was no control group. Therefore, we do not intend to determine a target BP based on the results of the present study. Randomized studies would be needed. There are additional limitations in terms of patient selection, types of home devices used, and BP measurement technique. The present study included patients who already had cuff-oscillometric HBP-measuring devices. No specific types of device were used to measure HBP. HBP-measuring devices available in Japan have been validated and approved by the Ministry of Health, Labour and Welfare of Japan and are in accordance with US (Association for the Advancement of Medical Instrumentation) 17 or European standards. 18 As done in the most of the previous studies, 1 5,8,10 home BP measurements were recorded by patients and reported to their physician, so the possibility of biased reporting by patients and physicians cannot be excluded completely. However, we consider their influence to be limited because of the nature of the study design that used both HBP and CBP with a large sample size. In the present study, participating physicians were not advised by which types of BP measurement they adjust the treatment. However, JSH 2009, published in the year the study started, emphasized the importance of HBP. 12 Moreover, the study protocol stated that the aim was to evaluate BP using HBP as an indicator, the participating physicians were thought to be aware of the importance of HBP. Finally, the mean follow-up period of the present study was relatively short (2.02 years), the risk of cardiovascular events at the morning HSBP 135 to <145 mm Hg may increase significantly during longer follow-up with a higher number of cardiovascular events. However, because the present study involved a large number of patients, aggregated data for the events per patient-year were similar to or greater than those reported in previous studies. Perspectives This analysis of the HONEST study involving >20 000 hypertensive patients produced several new findings about HBP in a real-world setting. First, we found that on-treatment morning HSBP 145 mm Hg is associated with a significant increase in cardiovascular risk for 2 years. Second, morning HSBP associated with minimum risk was 124 mm Hg. Finally, the risk of cardiovascular events is high in patients with masked hypertension and uncontrolled morning HSBP, although their CSBP is not increased. Based on this evidence, it is essential to control morning HSBP to <145 mm Hg as a first step, even in patients with controlled CSBP. These real-world findings emphasize the importance of HBP monitoring in clinical practice. Acknowledgments We gratefully acknowledge the numerous study investigators, fellows, nurses, and research coordinators at each of the study sites, who have participated in the HONEST study. The Appendix in the online-only Data Supplement shows a list of physicians who participated in the study. We also gratefully acknowledge their contribution to the study. Sources of Funding The study was supported by funding from Daiichi Sankyo Co, Ltd (Tokyo, Japan). Statistical analyses were done by EPS Corporation (Tokyo, Japan) under the direction of the sponsor and the authors. Medical editorial assistance was provided by Nature Japan KK (Macmillan Medical Communications, Tokyo, Japan) and funded by Daiichi Sankyo Co, Ltd. Disclosures K. Kario reported having received honoraria (significant) from Daiichi Sankyo, Mochida Pharmaceutical, and Takeda Pharmaceutical and research grants (significant) from Teijin Pharma, Novartis Pharma, and Takeda Pharmaceutical. I. Saito reported having received honoraria (modest) from Daiichi Sankyo, Takeda Pharmaceutical, Pfizer, Kyowa Hakko Kirin, Novartis Pharma, MSD, Sumitomo Dainippon Pharma, and Astellas and is a consultant/advisory board member of Daiichi Sankyo. T. Kushiro reported having received honoraria (modest) from Daiichi Sankyo, Takeda Pharmaceutical, and Sumitomo Dainippon Pharma, research grants (significant) from Sumitomo Dainippon Pharma, and is a consultant/advisory board member of Kyorin Pharmaceutical and Daiichi Sankyo. S. Teramukai reported having received honoraria (modest) and research grant (modest) from Daiichi Sankyo and is a consultant/advisory board member of Daiichi Sankyo. Y. Ishikawa, Y. Mori, and F. Kobayashi are employees of Daiichi Sankyo. K. Shimada reported having received honoraria (significant) from Daiichi Sankyo, Sumitomo Dainippon Pharma, honoraria (modest) from Takeda Pharmaceutical, MSD, Shionogi, and Toa Eiyo, and is a consultant/advisory board member of Omron. References 1. Ohkubo T, Imai Y, Tsuji I, Nagai K, Kato J, Kikuchi N, Nishiyama A, Aihara A, Sekino M, Kikuya M, Ito S, Satoh H, Hisamichi S. Home blood pressure measurement has a stronger predictive power for mortality than does screening blood pressure measurement: a population-based observation in Ohasama, Japan. J Hypertens. 1998;16:971 975. 2. 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;111:1777 1783. 3. Niiranen TJ, Hänninen MR, Johansson J, Reunanen A, Jula AM. Homemeasured blood pressure is a stronger predictor of cardiovascular risk than office blood pressure: the Finn-Home study. Hypertension. 2010;55:1346 1351. 4. Bobrie G, Chatellier G, Genes N, Clerson P, Vaur L, Vaisse B, Menard J, Mallion JM. Cardiovascular prognosis of masked hypertension detected

996 Hypertension November 2014 by blood pressure self-measurement in elderly treated hypertensive patients. JAMA. 2004;291:1342 1349. 5. Hara A, Ohkubo T, Kondo T, et al. Detection of silent cerebrovascular lesions in individuals with masked and white-coat hypertension by home blood pressure measurement: the Ohasama study. J Hypertens. 2009;27:1049 1055. 6. Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation. 1989;79:733 743. 7. Kario K, Ishikawa J, Pickering TG, Hoshide S, Eguchi K, Morinari M, Hoshide Y, Kuroda T, Shimada K. Morning hypertension: the strongest independent risk factor for stroke in elderly hypertensive patients. Hypertens Res. 2006;29:581 587. 8. Stergiou GS, Nasothimiou EG, Kalogeropoulos PG, Pantazis N, Baibas NM. The optimal home blood pressure monitoring schedule based on the Didima outcome study. J Hum Hypertens. 2010;24:158 164. 9. Asayama K, Ohkubo T, Metoki H, Obara T, Inoue R, Kikuya M, Thijs L, Staessen JA, Imai Y; Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure (HOMED-BP). Cardiovascular outcomes in the first trial of antihypertensive therapy guided by self-measured home blood pressure. Hypertens Res. 2012;35:1102 1110. 10. Shimada K, Fujita T, Ito S, Naritomi H, Ogihara T, Shimamoto K, Tanaka H, Yoshiike N. The importance of home blood pressure measurement for preventing stroke and cardiovascular disease in hypertensive patients: a sub-analysis of the Japan Hypertension Evaluation with Angiotensin II Antagonist Losartan Therapy (J-HEALTH) study, a prospective nationwide observational study. Hypertens Res. 2008;31:1903 1911. 11. Saito I, Kario K, Kushiro T, Teramukai S, Zenimura N, Hiramatsu K, Kobayashi F, Shimada K. Rationale, study design, baseline characteristics and blood pressure at 16 weeks in the HONEST Study. Hypertens Res. 2013;36:177 182. 12. Ogihara T, Kikuchi K, Matsuoka H, et al; Japanese Society of Hypertension Committee. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2009). Hypertens Res. 2009;32:3 107. 13. Kario K, Pickering TG, Umeda Y, Hoshide S, Hoshide Y, Morinari M, Murata M, Kuroda T, Schwartz JE, Shimada K. Morning surge in blood pressure as a predictor of silent and clinical cerebrovascular disease in elderly hypertensives: a prospective study. Circulation. 2003;107:1401 1406. 14. Hänninen MR, Niiranen TJ, Puukka PJ, Mattila AK, Jula AM. Determinants of masked hypertension in the general population: the Finn- Home study. J Hypertens. 2011;29:1880 1888. 15. Björklund K, Lind L, Zethelius B, Andrén B, Lithell H. Isolated ambulatory hypertension predicts cardiovascular morbidity in elderly men. Circulation. 2003;107:1297 1302. 16. Pierdomenico SD, Lapenna D, Bucci A, Di Tommaso R, Di Mascio R, Manente BM, Caldarella MP, Neri M, Cuccurullo F, Mezzetti A. Cardiovascular outcome in treated hypertensive patients with responder, masked, false resistant, and true resistant hypertension. Am J Hypertens. 2005;18:1422 1428. 17. Association for the Advancement of Medical Instrumentation. American National Standard. Electronic or Automated Sphygmomanometers. ANSI/ AAMI SP10 1992. Arlington, VA: Association for the Advancement of Medical Instrumentation;1993:40. 18. European Committee for Standardization. Non-invasive Sphygmomanometers. Part 3. Supplementary Requirements for Electromechanical Blood Pressure Measuring Systems. British Standard BS EN 1060 3: 1997. European Standard EN 1060-3 1997. Brussels, Belgium: European Committee for Standardization; 1997. What Is New? This analysis of the Home Blood Pressure Measurement With Olmesartan Naive Patients to Establish Standard Target Blood Pressure (HONEST) study involving >20 000 hypertensive patients produced several new findings about home blood pressure in a real-world setting. First, we found that on-treatment morning home systolic blood pressure 145 mm Hg is associated with a significant increase in cardiovascular risk for 2 years. Second, morning home systolic blood pressure associated with minimum risk was 124 mm Hg. Finally, the risk of cardiovascular events is high in patients with masked hypertension and uncontrolled morning home systolic blood pressure, although their clinic systolic blood pressure is not increased. Novelty and Significance What Is Relevant? These real-world findings emphasize the importance of home blood pressure monitoring in clinical practice. Summary Based on this evidence, it is essential to control morning home systolic blood pressure to <145 mm Hg as a first step, even in patients with controlled clinic systolic blood pressure.