The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2019)

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CHAIRPERSON

Satoshi UMEMURA (Yokohama Rosai Hospital)

EXECUTIVE COMMITTEE

Satoshi UMEMURA (Yokohama Rosai Hospital)

Shigeyuki SAITOH (Sapporo Medical University)

Sadayoshi ITO (Tohoku University)

Yusuke OHYA (University of the Ryukyus)

Hiromi RAKUGI (Osaka University)

Nobuhito HIRAWA (Yokohama City University Medical Center)

WRITING COMMITTEE

Kei ASAYAMA (Teikyo University)

Shuji ARIMA (Kindai University)

Hisatomi ARIMA (Fukuoka University)

Shunya IKEDA (International University of Health and Welfare)

Toshihiko ISHIMITSU (Dokkyo Medical University)

Sadayoshi ITO (Tohoku University)

Masaaki ITO (Mie University)

Yoshio IWASHIMA (Dokkyo Medical University)

Satoshi UMEMURA (Yokohama Rosai Hospital)

Shinichiro UEDA (University of the Ryukyus)

Yoshinari UEHARA (Fukuoka University)

Hidenori URATA (Fukuoka University Chikushi Hospital)

Takayoshi OHKUBO (Teikyo University)

Takafumi OKURA (Ehime University)

Yusuke OHYA (University of the Ryukyus)

Hisashi KAI (Kurume University Medical Center)

Naoki KASHIHARA (Kawasaki Medical School)

Kei KAMIDE (Osaka University)

Yuhei KAWANO (Teikyo University Fukuoka)

Yoshihiko KANNO (Tokyo Medical University)

Toru KIKUCHI (Saitama Medical University)

Takanari KITAZONO (Kyushu University)

Kazuo KITAMURA (University of Miyazaki)

Masataka KUDO (Tohoku University)

Hiroo KUMAGAI (National Defense Medical College)

Katsuhiko KOHARA (Ehime University)

Shigeyuki SAITOH (Sapporo Medical University)

Hirotaka SHIBATA (Oita University)

Tatsuo SHIMOSAWA (International University of Health and Welfare)

Hiromichi SUZUKI (Musashino Tokushukai Hospital)

Shori TAKAHASHI (Itabashi Chuo Medical Center)

Kouichi TAMURA (Yokohama City University Graduate School of Medicine)

Takuya TSUCHIHASHI (Steel Memorial Yawata Hospital)

Yasuaki DOHI (Nagoya Gakuin University)

Hirofumi TOMIYAMA (Tokyo Medical University)

Satoko NAKAMURA (Kansai University of Welfare Sciences)

Yoshitaka HIROOKA (Takagi Hospital / International University of Health and Welfare)

Satoshi HOSHIDE (Jichi Medical University)

Takeshi HORIO (Ishikiriseiki Hospital)

Hideo MATSUURA (Saiseikai Kure Hospital)

Kiyoshi MATSUMURA (Kitakyushu Wakasugi Hospital)

Katsuyuki MIURA (Shiga University of Medical Science)

Masashi MUKOYAMA (Kumamoto University)

Hiromi RAKUGI (Osaka University)

LIAISON MEMBERS

Satoaki MATOBA (Kyoto Prefectural University of Medicine)

Yoshihiko NISHIO (Kagoshima University)

Seiji UMEMOTO (Hiroshima University Hospital)

Shintaro MAKINO (Juntendo University)

Masatoshi KOGA (National Cerebral and Cardiovascular Center Hospital)

Shinichiro UEDA (University of the Ryukyus)

Miho NAGAI (Tokyo Medical University)

Hidetomo NAKAMOTO (Saitama Medical University Hospital)

Masaaki MIYAKAWA (Miyakawa Internal Medicine & Pediatrics)

Takeshi ISHIDA (Saitama Citizens Medical Center)

Mitsuaki ISOBE (Sakakibara Heart Institute)

Kenichiro KITAMURA (University of Yamanashi)

Ichiro HISATOME (Tottori University)

Akiyo TANABE (Center Hospital of the National Center for Global Health and Medicine)

Atsuo ITAKURA (Juntendo University)

Hiroaki MASUZAKI (University of the Ryukyus)

Masahiro AKISHITA (University of Tokyo)

Shinya ITO (The Hospital for Sick Children / University of Toronto)

Eishu NANGO (Tokyo-Kita Medical Center)

Hiroshi ONO (Sakanoue Family Clinic)

Osamu ITO (Tohoku Medical and Pharmaceutical University)

Yoshikazu NAKAMURA (Center for Community Medicine Jichi Medical University)

DOCUMENT REVIEWERS

Isao ABE (Japan Seamen’s Relief Association Moji Ekisaikai Hospital)

Mikio ARITA (Sumiya Social Medical Corporation)

Naohiko ANZAI (Chiba University)

Katsuyuki ANDO (Kitamura Memorial Clinic)

Shinichi ANDO (Kyushu University Hospital)

Kazumoto IIJIMA (Kobe University)

Tomoaki ISHIGAMI (Yokohama City University)

Atsuhiro ICHIHARA (Tokyo Women’s Medical University Hospital)

Hiroshi ITOH (Keio University)

Yutaka IMAI (Tohoku Institute for Management of Blood Pressure)

Hiroshi IWAO (Shitennoji University)

Yoshio UEHARA (Kyoritsu Women’s University)

Makoto UCHIYAMA (Uonuma Kikan Hospital)

Seiji UMEMOTO (Hiroshima University Hospital)

Nobuyuki URA (Sapporo Nishimaruyama Hospital)

Kazuo EGUCHI (Hanyu General Hospital)

Mitsuru OISHI (Kagoshima University)

Ichiro OHKUBO (City of Yokohama, Health and Social Welfare Bureau, Institute for Health)

Tomonori OKAMURA (Keio University)

Shigehiro KATAYAMA (Saitama Medical University Kawagoe Clinic)

Tomohiro KATSUYA (Katsuya Clinic)

Norihiro KATO (National Center for Global Health and Medicine)

Kazuomi KARIO (Jichi Medical University)

Takuya KISHI (International University of Health and Welfare)

Kazuo KITAGAWA (Tokyo Women’s Medical University Hospital)

Yasuki KIHARA (Hiroshima University)

Kazumi KIMURA (Nippon Medical School)

Kenjiro KIMURA (Tokyo Takanawa Hospital)

Genjiro KIMURA (Asahi Rosai Hospital)

Miho KUSAKA (Kusaka Clinic)

Toshio KUSHIRO (Hinohara Memorial Clinic)

Masahiro KOHZUKI (Tohoku University)

Masakazu KOHNO (Hattori Memorial Hospital)

Yoshihiro KOKUBO (National Cerebral and Cardiovascular Center)

Atsuo GOTO (Japanese Red Cross Medical Center)

Shuzo KOBAYASHI (Shonan Kamakura General Hospital)

Ikuo SAITO (Japanese Bankers Association Clinic)

Yasushi SAKATA (Osaka University)

Masataka SATA (Tokushima University)

Atsuhisa SATO (International University of Health and Welfare Mita Hospital)

Fumitoshi SATOH (Tohoku University)

Hiroshi SATONAKA (Dokkyo Medical University)

Kazuyuki SHIMADA (Shin-Oyama City Hospital)

Yoshikatsu SUZUKI (Aichi Medical University)

Masayoshi SOMA (Kyoundo Hospital)

Hakuo TAKAHASHI (Medical Corporation Yukio Board Biwako Central Hospital)

Yoshiyu TAKEDA (Innovative Clinical Research Center, Kanazawa University)

Yoshiyuki TOYA (Yokohama City University)

Kazunori TOYODA (National Cerebral and Cardiovascular Center)

Daisuke NAGATA (Jichi Medical University)

Ichiei NARITA (Niigata University)

Akira NISHIYAMA (Kagawa University)

Toshiharu NINOMIYA (Kyushu University)

Koichi NODE (Saga University)

Naoyuki HASEBE (Asahikawa Medical College)

Kaori HAYASHI (Keio University)

Koichi HAYASHI (Tokyo Dental College Ichikawa General Hospital)

Jitsuo HIGAKI (Minamimatsuyama Hospital)

Yasunobu HIRATA (Tokyo Teishin Hospital)

Nobuhito HIRAWA (Yokohama City University Medical Center)

Noboru FUKUDA (Nihon University Itabashi Hospital)

Koji MAEMURA (Nagasaki University Hospital)

Shinichiro MIURA (Fukuoka University Hospital)

Tetsuji MIURA (Sapporo Medical University)

Kazutoshi MIYASHITA (Keio University)

Atsuko MURASHIMA (National Center for Child Health and Development)

Toyoaki MUROHARA (Nagoya University)

Masaki MOGI (Ehime University)

Shinichi MOMOMURA (Jichi Medical University Saitama Medical Center)

Shigeto MORIMOTO (Kanazawa Medical University Hospital)

Akira YAMASHINA (Tokyo Medical University Medical Education Promotion Center)

Koichi YAMAMOTO (Osaka University)

Kotaro YOKOTE (Chiba University)

Michihiro YOSHIMURA (Jikei University)

SYSTEMATIC REVIEW GROUP

Yuki IMAIZUMI (Jichi Medical University)

Yuko OTA (Kyushu Dental University Hospital)

Toshio OTSUBO (Japanese Red Cross Fukuoka Hospital)

Hirofumi ONISHI (Sapporo Medical University)

Ryuji OKAMOTO (Mie University)

Sayoko OGURA (Nihon University)

Hiromichi WAKUI (Yokohama City University)

Joji KATO (University of Miyazaki)

Hiroaki KAWANO (Nagasaki University)

Takuya KISHI (International University of Health and Welfare)

Toshihito KITA (University of Miyazaki Hospital)

Eita KUMAGAI (Kurume University)

Kenichi GOTO (Kyushu University Hospital)

Kentaro KOHAGURA (University of the Ryukyus Hospital)

Sanae SAKA (Yokohama City University Medical Center)

Atsushi SAKIMA (University of the Ryukyus)

Minoru SATOH (Kawasaki Medical School Hospital)

Michihiro SATOH (Tohoku Medical and Pharmaceutical University)

Hiroshi SATONAKA (Dokkyo Medical University)

Yuhei SHIGA (Fukuoka University Hospital)

Rei SHIBATA (Nagoya University)

Makoto SUGIHARA (Fukuoka University)

Jun SUZUKI (Ehime University Hospital)

Yoichi TAKAMI (Osaka University)

Yukako TATSUMI (Teikyo University)

Norifumi NISHIDA (Kurume University)

Yoshisuke HARUNA (Kawasaki Medical School Hospital)

Michio FUKUDA (Nagoya University Hospital)

Eitaro FUJII (Mie University)

Takeshi FUJIWARA (Jichi Medical University)

Akira FUJIYOSHI (Shiga University of Medical Science)

Akira FUJIWARA (Yokohama City University)

Toshiki MAEDA (Fukuoka University)

Chisa MATSUMOTO (Tokyo Medical University)

Tatsuya MARUHASHI (Hiroshima University Hospital)

Eikan MISHIMA (Tohoku University)

Kenichi MIYOSHI (Ehime University)

Norihito MONIWA (Sapporo Medical University Hospital)

Ryo MORIMOTO (Tohoku University)

Keisuke YATSU (Minna no Naika Clinic Ningyocho-Suitengu)

Koichi YAMAMOTO (Osaka University)

Yuichi YOSHIDA (Oita University)

Makoto WATANABE (National Cerebral and Cardiovascular Center)

SYSTEMATIC REVIEW SUPPORT GROUP

Hisatomi ARIMA (Fukuoka University)

Yasuto SATO (Tokyo Women’s Medical University Hospital)

Takeo NAKAYAMA (Kyoto University)

Masahiro YOSHIDA (International University of Health and Welfare)

ASSESSMENT MEMBERS

Internal

Tsutomu IMAIZUMI (Fukuoka Sanno Hospital)

Hirotsugu UESHIMA (Shiga University of Medical Science)

Tanenao ETO (University of Miyazaki)

Toshio OGIHARA (Morinomiya University of Medical Sciences)

Kenjiro KIKUCHI (Asahikawa Medical University)

Takao SARUTA (Keio University)

Kazuyuki SHIMADA (Shin-Oyama City Hospital)

Kazuaki SHIMAMOTO (Japan Health Care College)

Shuichi TAKISHITA (Okinawa College of Rehabilitation and Welfare)

Kunio HIWADA (Ehime University)

Koshiro FUKIYAMA (Japan Seamen’s Relief Association Moji Ekisaikai Hospital)

Toshiro FUJITA (University of Tokyo)

Hiroaki MATSUOKA (Utsunomiya Central Hospital)

Yoshio YAZAKI (International University of Health and Welfare)

External

Yoshimichi SAI (Japan Pharmaceutical Association)

Yutaka HATORI (Japan Medical Association)

Masaaki MIYAKAWA (Kanagawa Physicians Association)

Ikuko YAMAGUCHI (Consumer Organization for Medicine & Law)

Satomi YAMADA (Japanese Nursing Association)

SECRETARY GENERAL

Nobuhito HIRAWA (Yokohama City University Medical Center)

Introduction

The Japanese Society of Hypertension (JSH) revised the Guidelines for the Management of Hypertension 2014 (JSH 2014), and published the JSH 2019. In the development of the JSH 2019, in addition to the use of the textbook description method based on the conventional guideline development strategies, clinical questions (CQs) concerning hypertension management were determined according to “Minds Manual for Guideline Development. Ver. 2.0 (2016.03.15)” established by the Medical Information Network Distribution Service (Minds) in Japan, systematic reviews (SRs) of CQs were performed to clarify evidence at present, and recommendations were formulated. In the “Introduction section”, the methods used to develop the JSH 2019 are introduced.

1. Objective of the JSH 2019, subjects for management using JSH 2019, and JSH 2019 users

Hypertension is a major cause of strokes (such as cerebral infarction, cerebral hemorrhage, and subarachnoid hemorrhage), heart diseases (such as coronary artery disease, cardiac hypertrophy, and heart failure), kidney diseases (such as nephrosclerosis), and macrovascular diseases. Therefore, the primary objective of the JSH 2019 is to present standard management strategies and evidence to all medical workers to provide appropriate treatment to patients with hypertension most frequently encountered by clinicians/practitioners in daily practice for the prevention of the onset/progression of hypertension complications in the brain/heart/kidney by blood pressure control. The JSH 2019 is one of data for reference while medical workers, such as attending physicians, determine therapeutic strategies by their communication with patients. It neither restricts the attending physician’s right to determine prescriptions nor presents criteria for medical disputes or lawsuits. Since therapeutic strategies are individually determined based on the patient’s background and complications, the attending physician who determines therapeutic strategies that differ from those in the JSH 2019 should give an adequate explanation to patients and also describe the reason for the determination of the strategies in the medical chart.

The subjects for blood pressure control using JSH 2019 consist of patients with hypertension (≥ 140/90 mmHg), people with an elevated blood pressure (130–139/80–89 mmHg), and all people with a blood pressure ≥ 120/80 mmHg in whom the cardiovascular risk increases with the blood pressure.

The JSH 2019 users include “all medical workers who examine, manage, and treat hypertensive patients, health ∙ administrative personnel, and medical workers in the clinical setting.” Hypertension is the most common lifestyle-related disease and difficult to treat by hypertension specialists alone. Indeed, hypertension is managed by many clinicians/practitioners. Considering such circumstances, the JSH 2019 was developed for the use of mainly clinicians/practitioners. It is also expected to be used by pharmacists who are engaged in treatment with physicians. Blood pressure control is also important for specific health checkups/health guidance, and has been increasingly performed in health promotion projects by municipalities. Therefore, the JSH 2019 is also used by team medicine members, such as health nurses, nurses, and registered dieticians, for hypertension management and health administrative personnel. In addition, “The Certified Hypertension & Cardiovascular Disease Prevention Educator System” was established in 2015. This license is given jointly by the JSH, Japanese Society of Cardiovascular Disease Prevention, and Japan Atherosclerosis Society for the prevention of cardiovascular diseases to health nurses, nurses, pharmacists, registered dietitians, physical therapists, clinical psychologists, medical psychologists, clinical technologists, and health fitness programmers who have an ability to give appropriate instructions for the improvement and prevention of lifestyle-related diseases, such as hypertension, and the management of other risk factors. The JSH 2019 is also expected to be used by people in these types of occupation.

2. Constitution of the guideline development committee

At the Board of Directors of the JSH in December 2016, the guideline development chairperson (Satoshi Umemura) was selected. Under the chairperson, the basic guideline development strategies were determined. For adjustments in general contents, an executive committee consisting of 6 members including the president and vice-president of the society was organized. The secretary general (Nobuhito Hirawa) was nominated by the chairperson and accepted by the board of directors.

The guideline development committee included: (1) executive members, (2) writing members, (3) SR members, and (4) document reviewers. In addition, SR support members, liaison members, assessment members, and advisory members were also appointed.

For the selection of writing members, the guideline development chairperson devised a plan, referring to councilors’ opinions, and determined writing members based on the principle that “the guidelines for hypertension management are the official guidelines of the JSH and developed on the responsibility of the entire society.” and in accordance with “the Guidance on Eligibility Criteria for Participation in Clinical Practice Guideline Formulation” of the Japanese Association of Medical Science. There were 44 writing members. Due to the introduction of the CQ-SR method in the JSH 2019, SR members were recommended by the writing members, and 43 members were selected. Four SR support members were appointed. A total of 74 document reviewers were appointed for individual writing items consisting of the councilors of the JSH and special-field members recommended on a questionnaire survey. There were 2–5 document reviewers per writing item. In addition, 22 liaison members were appointed on the recommendation of 22 affiliated societies. In addition, 14 assessment members were selected from honorary members of the JSH while 5 advisory members were selected on the recommendation of such as the patient group, Japan Medical Association, and the Japan Pharmaceutical Association. The assessment members had been closely involved in the guideline formulation (JSH 2000, 2004, 2009, 2014). After the production of the final draft, we asked “Minds” to evaluate JSH2019 hypertension guideline according to the Appraisal of Guidelines for Research & Evaluation II (AGREE II).

3. Guideline development strategies and procedure

The basic principle for the development of the JSH 2019 was to establish highly transparent evidence-based consensus guidelines for clinicians/practitioners, considering the conflict of interest (COI). In addition, the JSH 2019 was developed basically according to “Minds Manual for Guideline Development. Ver. 2.0 (2016.03.15)”.

The JSH 2019 uses two description methods i.e., the conventional textbook description method and recommendations formulated after SRs of clinical questions (CQs) in 17 items. In textbook description, there was not enough evidence for SRs, but 9 items about which clinicians/practitioners clinically have questions were also presented as questions (Qs), and these Qs were answered. SRs were performed mainly by several young physicians. Data on CQs in the literature were collected, and all selected items were evaluated according to the outcome as well as study design. The results were compiled (body of evidence), evaluated, and integrated. The outcomes of interventions include expected effects (benefit) and adverse events (harm). Considering their balance, “recommendations” were formulated using the Delphi method (the summarizing of opinions after repeated rounds of voting by e-mail).

Papers on many SRs will be prepared and published in Hypertens Res. Thus, see these papers for the details of SRs. SRs not published as papers and related data (such as charts) can be seen on the website of the JSH.

The development process of the JSH 2019 is as follows.

  • December 25, 2016

    Executive committee meeting (guideline preparation committee meeting)

  • April 14, 2017

    1 st executive committee meeting

    Determination of guideline development strategies and each committee

  • May 12–13, 2017

    2 nd executive committee meeting, 1 st guideline development committee meeting

    Confirmation and determination of guideline development strategies, committee composition, the table of contents, and CQs

  • May 14, 2017

    Study meeting about the SR method

  • August 19, October 19–22, and December 23, 2017

    3 rd and 4 th executive committee meetings and 2 nd –4 th guideline development committee meetings

    Evaluation of SRs and recommendations for each CQ, and parts described by a conventional method

  • February-May, 2018

    Opinion exchange concerning each CQ among all writing members by e-mail

  • February 12, March 24, and April 14, 2018

    5 th –7 th executive (expanded) committee meetings

    Evaluation of the risk score assessment method, reference values in the management of hypertension, and the blood pressure goal

  • April-June, 2018

    Opinion exchange by e-mail among writing members and document reviewers for each chapter

  • May 19–20, 2018

    8 th executive (expanded) committee meeting, 5 th guideline development committee meeting

    After evaluation of CQs, formulation of recommendations by the Delphi’s method on e-mail

  • July 15–16, 2018

    6 th guideline development committee meeting

    Manuscript evaluation and revision

  • September 13–16, 2018

    9 th executive (expanded) committee meeting

  • September-December, 2018

    Proofreading of the first and revised manuscripts by writing members

    Reviews by liaison members, assessment members, and advisory members and their opinion exchange

  • January, 2019

    Collection of public comments, revision based on public comments, and completion of the final draft

  • April, 2019

    Publication

4. Establishment of the evidence level and recommendation grade

Based on “Minds Handbook for Clinical Practice Guideline Development 2014” and “Minds Manual for Guideline Development. Ver. 2.0 (2016.03.15)”, the evidence level and recommendation grade for CQs were determined.

Evidence level

  1. A

    Strong: strong confidence

  2. B

    Moderate: moderate confidence

  3. C

    Weak: limited confidence

  4. D

    Very weak: negligible confidence

Recommendation grade

  1. 1.

    Strong recommendation (proposal)

  2. 2.

    Weak recommendation (proposal)

No recommendation: no definite recommendation

(Some recommendation contents are difficult to shown using the above definition words. For such recommendations, expressions in accordance with the context are used.)

5. Confirmation and disclosure of COI

Based on “the Guidance on Eligibility Criteria for Participation in Clinical Practice Guideline Formulation” of the Japanese Association of Medical Science, COIs during the previous 3-year period (2016–2018) were disclosed using the form of the above guidance on the website of the JSH according to each committee (writing, document review and SR committees).

Chapter 1. Epidemiology of hypertension

POINT 1

  1. 1.

    Cardiovascular disease/chronic kidney disease (CKD) morbidity and mortality risks increase with blood pressure elevation above blood pressure levels of 120/80 mmHg.

  2. 2.

    The annual number of cardiovascular deaths due to hypertension in Japan is estimated to be 100000, accounting for the largest portion of all cardiovascular deaths. About 50% of cardiovascular disease deaths are estimated to be due to blood pressure> 120/80 mmHg.

  3. 3.

    Among blood pressure parameters, systolic blood pressure (SBP) more strongly predicts the cardiovascular disease risk. In the presence of other risk factors, this risk increases further.

  4. 4.

    The number of hypertensives in Japan is estimated to be 43 million, including 31 million poorly controlled hypertensives. It is estimated that of these 31 million hypretensives, 14 million are unaware of hypertension, 4.5 million are left untreated despite disease awareness and 12.5 million are poorly controlled despite drug therapy.

  5. 5.

    The mean salt intake among the Japanese remains high. Reducing salt intake is important for lowering the blood pressure levels of the Japanese. Furthermore, the prevalence of obesity-related hypertension has increased.

  6. 6.

    In Health Japan 21 (II), a 4-mmHg decrease in the average SBP level of the Japanese within 10 years is targeted by promoting strategies for diet/physical activities/alcohol consumption. If this is achieved, the annual number of deaths from stroke will decrease by approximately10,000 and that of deaths from coronary artery disease will decrease by approximately 5000.

1. Association between hypertension and various diseases

1) Hypertension-related increase in the risk for stroke/heart disease

Hypertension is the most important risk factor for cardiovascular diseases (stroke and heart disease). In the 1960s, Japan was one of the countries with the highest mortality rate due to stroke. The mortality rate due to stroke has markedly decreased during the past 50 years, and the mortality rate from all heart diseases, including heart failure, has become higher than that due to stroke. However, the mortality/morbidity rates due to stroke are still higher than those due to acute myocardial infarction [1, 2]. The age-adjusted mortality rate due to stroke in Japan was about three times higher than that due to acute myocardial infarction [1, 2]. Several epidemiological studies have also reported that the morbidity rate from stroke was about three to four times higher than that from acute myocardial infarction [3,4,5]. With respect to the subtype of stroke, the morbidity rate from cerebral infarction was two to four times higher than that from intracerebral hemorrhage [3, 5, 6]. On the other hand, the morbidity rate from myocardial infarction has slightly increased primarily in urban areas [4, 7]. In the Suita Study, the morbidity rate from stroke was about two times higher than that from acute myocardial infarction, showing a reduction in the difference [8, 9].

There is a continuous, positive association between blood pressure level and risk for cardiovascular diseases [6, 10,11,12,13,14,15,16]. In a project to pool data from major cohort studies in Japan, EPOCH-JAPAN, a meta-analysis of 10 cohort studies (total: approximately 70,000 persons) showed that the association between blood pressure level and cardiovascular mortality risk was almost logarithmically linear in middle-aged (40–64 years) and early-phase older (65–74 years) people. The slope was stronger in younger people, and the risk was lowest in those with blood pressure levels of <120/80 mmHg (Figure 1-1) [10]. In late-phase older people (75–89 years), the cardiovascular mortality risk also increased with blood pressure level. An analysis excluding deaths during the first 3 years of follow-up to eliminate the reverse causation (a phenomenon that blood pressure decreases before death and the death rate looks higher at lower blood pressure levels) indicated a significant increase in the risk from blood pressure levels of 130/85 mmHg or higher. This association has been similarly observed when reviewing mortality due to all subtypes of stroke, cerebral infarction, intracerebral hemorrhage or coronary artery disease [10, 11, 17]. In particular, the association with mortality due to cerebral hemorrhage is stronger. Furthermore, the EPOCH-JAPAN revealed a significant association also between blood pressure level and mortality due to heart failure [10, 17].

Fig. 1-1
figure1

Hazard ratio and population-attributable fraction (PAF) for cardiovascular disease mortality according to blood pressure categories (prepared from Ref. [10])

The results of cohort studies investigating morbidity as an outcome in Japan also showed a similar association [6, 12, 13, 18]. The associations between blood pressure level and stroke/coronary artery disease morbidity risks were continuous. The risks were the lowest in blood pressure levels of <120/80 mmHg. In the Hisayama Study, the risk for lacunar infarction, a subtype of cerebral infarction, was shown to be high at blood pressure levels of 130/85 mmHg or higher [13]. The Suita Study revealed an association between SBP and the risk for new onset atrial fibrillation [19]. The Framingham Study in the United States demonstrated a continuous association between SBP and onset of heart failure [20].

Recent cohort studies have indicated the population-attributable fraction, which reflects the proportion of excess cardiovascular disease mortality/morbidity related to blood pressure level exceeding 120/80 mmHg [6, 10,11,12,13, 18]. According to EPOCH-JAPAN, blood pressure level exceeding 120/80 mmHg explained 50% of all cardiovascular disease deaths, 52% of stroke deaths and 59% of deaths from coronary artery disease. The number of excess deaths from grade I hypertension was the largest [10]. Also according to the 24-year follow-up data of NIPPON DATA 80, 43% of deaths from cardiovascular diseases (81% in middle-aged men) was attributable to blood pressure levels above 120/80 mmHg [11]. The Circulatory Risk in Communities Study (CIRCS) indicated that the portion of excess stroke morbidity from grade I hypertension has been increasing and that from grade III hypertension has been decreasing [6]. Therefore, lifestyle modification in persons with elevated blood pressure or grade I hypertension and strategies to prevent the development of hypertension are further important.

2) Hypertension and other conditions such as kidney disease/total mortality

Hypertension increases the risk for reduced estimated glomerular filtration rate (eGFR), CKD and end-stage kidney disease (ESKD) [21,22,23,24]. A cohort study in Okinawa showed that the future risk of ESKD increased by approximately 30% per 10-mmHg increase in SBP [21]. The Hisayama Study indicated that hypertension, especially mid-life hypertension, increased the risk of vascular dementia in later life (Figure 1-2a) [25]. Another study reported that middle-age hypertension increased the risk of reduction in future activities of daily living (ADL) (Figure 1-2b) [26].

Fig. 1-2
figure2

Hazard ratio of each blood pressure level for vascular dementia (a) and reduced ADL (b). (prepared from Refs. [25, 26])

Hypertension also increases the total mortality risk by various diseases described above. A meta-analysis involving 13 cohorts in Japan (total: 180000 persons; EPOCH-JAPAN) revealed that the total mortality risk increased with the blood pressure in both men and women aged 40–89 years [27]. It was estimated that blood pressure level exceeding 120/80 mmHg is responsible for approximately 20% of all-cause deaths. An estimation on the basis of the results of previous epidemiological studies showed that hypertension is the most important factor of cardiovascular death in Japan, and the annual number of deaths due to hypertension was estimated to be 100000 (Figure 1-3) [28]. According to NIPPON DATA 80, the average hypertension-related shortening of life expectancy was 2–3 years in men and women aged 40–49 [29], but the actual shortening of average life expectancy is estimated to be greater than this if we consider that this figure was not adjusted for the influence from antihypertensive therapy during the follow-up period.

Fig. 1-3
figure3

Number of cardiovascular deaths attributable to various risk factors in Japan (prepared from Ref. 28)

3) Accumulation of risk factors, metabolic syndrome and risk for cardiovascular diseases

When other established risk factors accumulate in the presence of hypertension, the risk for cardiovascular diseases increases further [30,31,32,33,34]. Many cohort studies in Japan and their meta-analyses have revealed an increase in cardiovascular disease risk with the accumulation of smoking, diabetes, hypercholesterolemia or CKD in the presence of hypertension.

Metabolic syndrome is also a condition involving elevation of blood pressure as a factor. Many cohort studies in Japan have reported a metabolic syndrome-related increase in the risk for cardiovascular diseases. Cardiovascular disease morbidity and mortality risks increased 1.5- to 2.4-fold [35,36,37]. On the other hand, several cohort studies investigating cardiovascular disease morbidity/mortality as an end point [38,39,40,41,42,43] and the integrated analysis of 10 cohort studies including these cohorts [44] have suggested that the accumulation of metabolic risk factors is important regardless of the presence or absence of obesity. Because hypertensive patients in Japan are often free of obesity, the contribution to the population risk for cardiovascular diseases is higher with hypertension not associated with obesity than with hypertension associated with obesity [44, 45]. Thus, antihypertensive measures are important not only in obese individuals but also in non-obese individuals.

4) Various blood pressure parameters and cardiovascular disease risk

Large-scale meta-analyses have been carried out in Japan to identify blood pressure parameters closely associated with the risk for cardiovascular diseases among various parameters of blood pressure (including SBP, diastolic blood pressure [DBP] and pulse pressure) [46,47,48]. The analyses have shown that SBP most strongly predicts the future risk. In a meta-analysis involving 16 cohorts in Japan (the Japan Arteriosclerosis Longitudinal Study: JALS), SBP was the strongest predictor of stroke morbidity risk in both the middle-aged group and the older group. The prediction ability was less strong with DBP and further less strong with pulse pressure [46].

In most studies investigating the association between blood pressure and risk for cardiovascular diseases, blood pressure measured in the clinic or during health checkup was used. However, the cardiovascular disease risk-prediction ability of blood pressure measured at home and ambulatory 24-h blood pressure has been reported to be stronger than that of office blood pressure [49,50,51,52,53,54]. It has also been reported that the visit-to-visit variability in office blood pressure and the day-to-day variability in home blood pressure increase the risk for death, cardiovascular diseases, CKD and dementia [55,56,57].

2. Current status of blood pressure among the nation and its changes over time

According to the National Health and Nutrition Survey 2016, the prevalence of hypertension (SBP ≥140 mmHg or DBP ≥90 mmHg or use of antihypertensive medication) is 60% for men aged 40–74, 41% for women in the same age range, 74% for men aged 75 and over and 77% for women in the same age range [58].

According to the analysis conducted by the State about changes over time in the prevalence, treatment rate and control rate of hypertension during the 36-year period (1980–2016) on the basis of the National Surveys of Circulatory Disorders and the National Health and Nutrition Surveys, the prevalence of hypertension increased with age, exceeding 50% among men aged 50 and over and women aged 60 and over (Figure 1-4a) [59]. Although the prevalence of hypertension has been tending to decrease with age among women, there is no evident tendency of reduction among men aged 50 and over. As aging of the population further intensifies, the number of patients with hypertension can further increase in Japan.

Fig. 1-4
figure4

Annual changes in hypertension prevalence, treatment rate and control rate by sex and age group (1980–2016) (Source: Ref. [59])

The hypertension treatment rate (percentage of individuals receiving antihypertensive medication among hypertensives) has been rising during the past 36 years, exceeding 50% among men and women aged 60–69 and exceeding 60% among men and women aged 70–79 (Figure 1-4b) [59].

The hypertension control rate (percentage of individuals with blood pressure less than 140/90 mmHg among antihypertensive drug users) has been rising during the past 36 years, but remaining only about 40% among men and about 45% among women (Figure 1-4c) [59]. This rate is 55–60% according to some reports, but it is still not very high [60].

The average SBP, which tends to increase with age in both men and women, has decreased markedly in each age group over the past approximately 6 decades in Japan (Figure 1-5a) [59]. The age-adjusted stroke mortality in Japan reached a peak in the 1960s and then fell sharply (1965: 361 for men and 244 for women, 2016: 36 for men and 20 for women [per 100000 population]) [61], resulting in a world top-level average life expectancy which owes much to the reduction in average blood pressure among the Japanese people. A similar tendency has been demonstrated also in other epidemiological studies in Japan [4, 62]. A reduction in average blood pressure among the entire nation in Japan seems to be attributable to progress and spread of antihypertensive drug therapy and changes in the nation’s lifestyle and living environments (e.g., salt intake reduction). However, the DBP among men aged 30–59 does not show an evident reduction but is showing a movement requiring close attention (Figure 1-5b) [59].

Fig. 1-5
figure5

Annual changes in average blood pressure by sex and age group (1961–2016) (Source: Ref. [59])

According to the NIPPON DATA2010, 33% of hypertensives were unaware of hypertension [63]. On the basis of these findings, the number of hypertensives in Japan is estimated to be 43 million as of 2017. Of these individuals, 31 million are estimated to be poorly controlled (140/90 mmHg or higher), 14 million of these 31 million individuals are estimated to be unaware of hypertension, 4.5 million are estimated to remain untreated despite awareness of the disease and 12.5 million are estimated to be poorly controlled despite ongoing treatment (Figure 1-6). Measures to reduce the number of poorly controlled hypertensive patients are needed.

Fig. 1-6
figure6

Estimated number of hypertensives, hypertensives receiving antihypertensive drug therapy and poorly controlled hypertensives in Japan (2017)

3. Characteristics of hypertension in the Japanese

1) High salt intake

An excessive intake of salt was one of the possible causes for the high prevalence of hypertension and stroke in the past in Japan. A high salt intake increases blood pressure. Numerous observational or interventional studies have demonstrated that blood pressure was high in groups with a high salt intake, and that blood pressure decreased following reduced salt intake [64,65,66].

Few studies have strictly evaluated salt intake using 24-h urine collection in the general population. In the survey conducted in the Tohoku District in the 1950 s, the salt intake estimated by 24-h urine collection was as high as 25 g/day [67]. The mean salt intake of men and women was 12.3 and 10.9 g per day, respectively, according to the INTERMAP Study, in which salt intake was measured in men and women aged 40–59 years in four districts of Japan between 1996 and 1999 [68]. The salt intake evaluated by the weighing method in the National Health and Nutrition Survey has also been tending to decrease gradually, and the National Health and Nutrition Survey in 2016 showed that the mean daily salt intake per person was 9.9 g (men: 10.8 g, women: 9.2 g) [58]. In the Dietary Reference Intake in Japanese (2015), the dietary goal of salt intake to be achieved in adult men and women in the next 5 years is <8.0 and <7.0 g per day, respectively [69]. Health Japan 21 (II) (2012) targeted a reduction in the average salt intake of the Japanese to 8.0 g before 2022 [70]. In the World Health Organization guidelines on sodium intake, which were published in 2012, it is recommended that salt intake should be reduced to <5 g per day in adults [71]. The current status in Japan is still far from this recommendation, indicating the need of further actions to promote salt reduction among the nation for prevention of hypertension.

2) Increases in the prevalence of obesity and metabolic syndrome

Obesity is less common in Japan than in other developed countries. However, mean body mass index (BMI, kg/m2), which is an index of obesity, has been increasing annually in men; the proportion of obesity (BMI ≥25 kg/m2) in men aged 20 and over was 31% [58], having increased by about twofold during the past 30 years [72, 73], according to the National Health and Nutrition Survey in 2016. On the other hand, there was no overall increase in the proportion of obesity in women aged 20 and over during the past 30 years, being 21% in 2016.

Regarding the characteristics of hypertensive Japanese, lean hypertensives with a high salt intake accounted for a high percentage in the past, but the number of obese hypertensives has recently increased, particularly among men. According to the analysis of changes over time during 3 decades from 1980 to 2010 shown in NIPPON DATA, the proportion of hypertensive men in whom obesity contributed to hypertension increased gradually over time [73]. This would reflect an increase in the prevalence of metabolic syndrome in Japan. The National Health and Nutrition Survey in 2016 showed that metabolic syndrome was strongly suspected in more than 30% of men aged over 60 years [58].

In the United States, the prevalence of obesity has markedly increased since 1990, and those with a BMI of 30 kg/m2 or more account for more than 30% of the population [74]. In Japan, the percentage is 3 to 4%. However, it may increase with the westernization of lifestyle in the future. Strategies to prevent obesity must be promoted.

4. Public health measures against hypertension

As shown by many epidemiological studies, more than half of high blood pressure-related excessive cardiovascular disease mortality/morbidity events occurred in people with mildly high blood pressure (grade I hypertension or lower) [6, 10,11,12,13,14, 18]. To reduce excess cardiovascular disease mortality/morbidity, high-risk strategies involving hypertensives alone are insufficient. Population strategies to lower the blood pressure distribution of the entire Japanese population are necessary (Figure 1-7) [75, 76]. The ‘National Health-Promotion Project in the 21st Century’ (Health Japan 21 (II)), which was announced by the Minister of Health, Labour and Welfare in 2012, targets a decrease in average SBP in Japan by 4 mmHg (men: 138 → 134 mmHg, women: 133 → 129 mmHg) within 10 years (before 2022) [70]. The goal is to lower the blood pressure distribution of the entire nation.

Fig. 1-7
figure7

Population strategy to shift the distribution of SBP in the Japanese to a lower level

The establishment of target values for cardiovascular diseases in Health Japan 21 (II) is presented in Figure 1-8. A 2.3 mmHg decrease in SBP is targeted by nutritional/dietary strategies such as reducing salt intake (to 8 g per day), increasing vegetable/fruit intake (to 350 g per day) and decreasing the number of obese people. A 1.5-mmHg decrease is targeted by physical activity/exercise strategies (approximately 1500 step increase in the number of steps). A 0.12-mmHg decrease is targeted by alcohol strategies (decreasing the number of heavy drinkers). A 0.17-mmHg decrease is targeted by strategies regarding antihypertensive therapy (increasing the compliance rate by 10%). Overall, a 4-mmHg decrease in SBP is targeted [70].

Fig. 1-8
figure8

Target establishment for cardiovascular diseases in Health Japan 21 (II) (Source: Ref. [70])

In Health Japan 21 (II), the cardiovascular disease-reducing effects of target achievement were estimated using the EPOCH-JAPAN database [70]. Overall, the project targets to decrease age-adjusted mortality for stroke (cerebrovascular disease) in men and women by 15.7 and 8.3%, respectively, and that for coronary artery disease (ischemic heart disease) by 13.7 and 10.4%, respectively, as shown in Figure 1-8. To achieve these goals, the role of blood pressure reduction is important. In brief, only a 4-mmHg decrease in average SBP in the Japanese is estimated to reduce age-adjusted mortality from stroke in men and women by 8.9 and 5.8%, respectively (the total number of deaths from stroke will decrease by approximately 10 000 per year), and that for coronary artery disease by 5.4 and 7.2%, respectively (the total number of deaths from coronary artery disease will decrease by approximately 5000 per year).

Population strategies to achieve the above targets include environmental approaches from various aspects, such as mass media-mediated public education, obligations regarding the labeling of salt content by food manufacturers, menu improvement/promotion of nutrition labeling in school lunch/food-service industries, spread of home blood pressure measurement, and utilization of IoT [64, 77, 78]. All health/medical specialists, including physicians, nurses, public health nurses, registered dieticians, pharmacists, school nurses and school dieticians must instruct all persons including hypertension-free individuals to improve their diet (salt reduction/maintenance of optimal body weight), increase physical activities and maintain moderate alcohol consumption in health care/medical practice.

It is necessary to promote high-risk strategies in parallel with population strategies. The Specific Health Checkups and Specific Health Guidance, started in 2008, serve as an essential element of such strategies [79]. Health insurers should take actions to facilitate detection of hypertensives by improvement in the health screening coverage, to improve the health guidance implementation rate and to reduce untreated hypertensives, treatment-discontinued hypertensive patients and poorly controlled hypertensive patients (for prevention of severe course of the disease). For this purpose, in 2015 the “Data Health Plan” involving planning and evaluation by each health insurer by analysis of health insurance claims/health screening data was started [80].

Comprehensive measures, combining the population strategies with the high-risk strategies as mentioned above, need to be taken to achieve the goals of reduction in the cardiovascular disease morbidity/mortality, optimization of healthcare expenditure and extending the healthy life expectancy of the nation (Figure 1-9) [81].

Fig. 1-9
figure9

Open issues related to hypertension and a roadmap for longer healthy life expectancy in Japan (modified from Ref. 81)

Chapter 2. Measurement and clinical evaluation of blood pressure

POINT 2a Blood pressure measurement/assessment

  1. 1.

    Office blood pressure should be measured by placing the forearm on a support table and maintaining the arm-cuff position at the heart level during rest in a seated position. The measurement must be performed two or more times at intervals of 1–2 min, and the mean value of two measurements that provides stable values (difference in the values: <5 mmHg) should be used. Diagnosis of hypertension should be based on office blood pressures measured on at least two different occasions.

  2. 2.

    Office blood pressure is measured by the auscultation method, which is the standard procedure, but the use of an automatic sphygmomanometer of the upper arm type is also permitted.

  3. 3.

    Home blood pressure measurement and 24-h ambulatory blood pressure (ABP) monitoring (ABPM) are useful for the diagnosis of hypertension, white coat hypertension and masked hypertension, as well as for evaluating the drug effect and its duration.

  4. 4.

    Home blood pressure should be measured with upper-arm devices. As a rule, it must be determined twice, and the mean value should be used as a blood pressure value on the occasion. When the measurement is performed only once per occasion, its value should be used as a level on the occasion. For the diagnosis of hypertension and the evaluation of responses to antihypertensive drugs, the mean of morning and evening blood pressure readings for 7 days (at least 5 days) should be used.

  5. 5.

    Criteria for hypertension differ among office blood pressure, 24-h ABP and home blood pressure. An office blood pressure of >140/90 mmHg, a home blood pressure of >135/85 mmHg and a mean 24-h ABP of >130/80 mmHg are regarded as indicators of hypertension.

  6. 6.

    When there is a discrepancy of diagnosis between office blood pressure and home blood pressure, a home blood pressure-based diagnosis should have priority.

  7. 7.

    Every blood pressure measurement should use a sphygmomanometer having undergone periodical inspection, taking into consideration its durability and past frequency of use. In addition, aneroid sphygmomanometers require immediate disposition and exchange when deterioration is suspected because errors are theoretically more likely to result in this type of sphygmomanometer following exposure to shock or changes over time.

  8. 8.

    Manufacture and export/import of mercury sphyngmomanometers will be prohibited from 2021 on. Their maintenance will also become difficult. Thus, mercury sphyngmomanometers should not be used.

1. Blood pressure measurement

1) Office blood pressure measurement

Correct measurement of blood pressure is necessary for the diagnosis of hypertension. In a clinical setting (for example, an outpatient office), blood pressure is measured by the auscultation method or by using an automatic sphygmomanometer verified as to precision by an acknowledged evaluation method. Although a mercury sphygmomanometer has conventionally been used for standard blood pressure measurement by the auscultation method, manufacture and export/import of devices containing mercury (including mercury sphygmomanometers) are prohibited, for a reason of environmental pollution with mercury, from January 1, 2021 under the Minamata Convention on Mercury [82] having come into effect in 2017 and having been ratified also by Japan. It is therefore anticipated that precision control of mercury sphygmomanometers will be difficult also in Japan. As a substitute for mercury sphygmomanometers, it is recommended to use an electronically generated pressure column (quasi-mercury) sphygmomanometer (using an electronic analog column instead of a mercury column) or an aneroid sphygmomanometer for the auscultation method or to use an automatic upper-arm sphygmomanometer (see Q1).

Table 2-1 shows the standard procedure for blood pressure measurement at the outpatient office. Office blood pressure measurement, in strict accordance with the procedure shown in Table 2-1, is known to more accurately reflect the true blood pressure compared with measurements obtained by disregarding this procedure, and is found to have a clinical value at least comparable to that of ABPM or home blood pressure measurement [83, 84]. However, blood pressure is rarely measured in accordance with such guidelines in a screening or clinical setting. In addition, the accuracy of measurement is often disregarded or ignored [85, 86].

Table 2-1 Measurement of the office blood pressure

In sphygmomanometry by the auscultation method, however, there are problems of terminal digit preference, that is, the tendency for the reading of the first digit of the mercury column height to converge at 0 (e.g., 110 mmHg, 120 mmHg), auscultation gap and examiner’s hearing loss [87, 88]. At present, office blood pressure measurement is usually taken with an automatic sphygmomanometer. The Guidelines on Hypertension included in the Canadian Educational Program 2015 recommend the use of an automatic sphygmomanometer for office blood pressure measurement in view of the fact that the accuracy of measurement by the auscultation has not been ensured [89]. Office blood pressure measurement by the auscultation method should be carried out by a well-trained examiner by the method shown in Table 2-1 adequately. If this is difficult, the use of an automatic sphygmomanometer is recommended. In terms of the accuracy of automatic sphygmomanometers, there is no significant problem when a device made by a Japanese manufacturer is used. The results of accuracy test of automatic sphygmomanometers are given in the website of the Japanese Society of Hypertension (JSH) [90].

An automatic rolling-type sphygmomanometer is used in the waiting room of the office, and the blood pressure value obtained is often adopted as an office blood pressure level. In particular, for self-measurement with the automatic rolling-type sphygmomanometer by patients, blood pressure must be measured under thorough guidance and management regarding the following points: an arm cuff should not be placed on the elbow; the arm-cuff should be maintained at the heart level; and extremely anterior tilting should be avoided.

In recent years, automated office blood pressure (AOBP) has begun to be used in Western countries. AOBP is measured many times with an automatic office sphygmomanometer while leaving the patient alone in quiet environments. AOBP has been shown to be more accurate than the manually measured blood pressure and to allow elimination of the white coat effect [91]. The results of SPRINT indicate that antihypertensive treatment with a goal set at lowering the systolic blood pressure (SBP) (measured as AOBP) to less than 120 mmHg reduced the incidence of cardiovascular events and the total mortality [92, 93]. However, because of the hurdles, such as difficulty in securing the space and the need of patient guidance, AOBP has been seldom adopted in Japan and few evaluations/analyses have been conducted concerning clinical feasibility and usefulness of AOBP measurement or the relationship between home blood pressure and AOBP.

For blood pressure measurement in adults using the auscultation method, cuffs with rubber bags 13 cm wide and 22–24 cm long are usually used. Internationally, however, cuffs with a width of ≥40% of the brachial girth and a length sufficient to cover at least 80% of the brachial girth are recommended [94].

Office blood pressure measurement requires periodical inspection of the sphygmomanometer and use of the sphygmomanometer taking into account its durability and frequency of use. In addition, aneroid sphygmomanometers require immediate disposition and exchange when deterioration is suspected because errors are theoretically more likely to result in this type of sphygmomanometer following exposure to shock or changes over time.

A problem encountered in blood pressure measurement is the presence of false hypertension related to incomplete compression of the brachial artery by an increase in arterial stiffness. The presence of incomplete compression of the brachial artery by an increase in arterial stiffness can be predicted, based on Osler’s sign (case in which the brachial or radial artery is still palpable at the periphery of the cuff even when pulsation has been stopped by sufficient inflation) [95].

If pulses of the lower-limb arteries (femoral, popliteal and dorsalis pedis arteries) are weak or not palpable, blood pressure is measured in the leg to exclude peripheral artery disease. For the measurement of blood pressure in the leg, an arm cuff is applied to the lower leg, and auscultation is performed using the dorsalis pedis or posterior tibial artery, or the cuff is applied to the thigh (using a cuff with a rubber bag that is 20% wider than the femoral diameter—that is, 15–18 cm), and auscultation is performed using the popliteal artery. Currently, lower-limb blood pressure measurement at the lower leg by the cuff-oscillometric method and ankle-brachial pressure index (ABI) measurement during brachial-ankle pulse wave velocity (baPWV) measurement are commonly used.

In patients with arrhythmia (premature beats), SBP is overestimated and diastolic blood pressure (DBP) is underestimated by the auscultation method [96]. Therefore, the effects of arrhythmia must be excluded by repeating the measurement three or more times and adopting their average. In patients with atrial fibrillation, accurate sphygmomanometry is often difficult, but proportionate values of SBP and DBP can be obtained by the cuff-oscillometric method unless the patients have bradycardia [97]. In this case, the measurement must also be repeated three or more times and adopting their average [98].

In pregnant women, Korotkoff sounds (vascular murmurs) are occasionally heard at 0 mmHg. In this case, the blood pressure at the starting point of the fourth Korotkoff sound (muffling of the sound) is regarded as the diastolic pressure.

There is as yet no highly accurate or consistent method for performing indirect sphygmomanometry during exercise. In addition, there are no sufficient grounds for the evaluation of blood pressure during exercise for the general diagnosis of hypertension [96].

As blood pressure can be extremely variable, it occasionally shows marked increases even under routine measuring conditions. Therefore, a diagnosis of hypertension should be made on the basis of blood pressure measurements taken on two or more different occasions.

2) Out-of-office blood pressure measurement

Self-measurement of blood pressure at home (home blood pressure measurement) and ABPM are methods for blood pressure measurement in an out-of-office setting. Home and ABPs are often considered to have clinical values comparable to, or greater than, that of office blood pressure. These blood pressure measurements also have value as blood pressure information differing in nature (Table 2-2) [99].

Table 2-2 Characteristics of each type of blood pressure measurement

(1) Home blood pressure measurement

Home blood pressure measurement is useful for improving the treatment adherence of patients and for preventing an excessive or insufficient antihypertensive effect of drugs. Measurement before taking a drug is particularly useful for assessing the duration of the drug effect (morning/evening ratio or evening/monitoring ratio) [100]. Home blood pressure measurement is also useful for the diagnosis of white coat hypertension, morning hypertension or masked hypertension and for making a diagnosis of resistant hypertension and deciding the therapeutic strategy [101]. As home blood pressure can be frequently measured over a long period, it is also useful for the evaluation of blood pressure variability over an extended period such as seasonal variations of blood pressure [102]. Home blood pressure measurement is widely prevalent in Japan [103,104,105]. An upper-arm-cuff device based on the cuff-oscillometric principle that has been confirmed in a population including hypertensive patients to yield differences within 5 mmHg compared with those of the auscultation method is used for home blood pressure measurement. According to the conditions presented in Table 2-3, the measurement is performed [99].

Table 2-3 Methods, conditions, and evaluation of home blood pressure measurement

The clinical significance of home blood pressure increases by standardized measurement, as indicated for office blood pressure. On the other hand, guidance on conditions for home blood pressure measurement varies among clinicians in clinical practice; it should be standardized [106, 107]. In clinical practice, each clinician must guide the home blood pressure measurement method based on the measurement conditions described in the guidelines.

There is no definite rationale for judging which value is appropriate for use in clinical evaluation of home blood pressure (see Q2). These guidelines, as the JSH 2014 Guidelines [108], recommend measuring blood pressure twice as a rule on each occasion and adopting their mean as the blood pressure value at a given occasion. When blood pressure measurement is performed only once, the value obtained should be used as a blood pressure level on the occasion. If subjects spontaneously measure blood pressure three times, the mean of three measured values may be used as a blood pressure level on the occasion. Adherence to measurement decreases if too many measurements are requested on each occasion [109]. Therefore, four or more measurements per occasion should not be recommended. Concerning records, all values measured on one occasion should be recorded in a recording sheet, as previously described. This is aimed at avoiding “selection (report) bias, i.e., a tendency for the examiner to select and report a value he/she prefer from the different values of measurement.

To evaluate hypertension, normal blood pressure and the effects of antihypertensive drugs based on home blood pressure, the mean of the morning values and that of the evening values measured 7 days (at least 5 days) should be used.

The wrist-cuff device for blood pressure measurement is easy to use, but often provides inaccurate measurements because of the difficulty in correcting the difference in hydrostatic pressure between the heart level and wrist level, and because of the difficulty in completely compressing arteries due to anatomical issues with the wrist [110]. At present, therefore, a blood-pressure-measuring device with an upper-arm cuff is used for home blood pressure measurement [99]. However, for obese individuals with quite thick and short brachium, the use of a wrist-cuff device should also be considered because compression of the brachium is sometimes difficult. The accuracy of upper-arm-cuff devices for home blood pressure measurement using the cuff-oscillometric method is generally acceptable if they are the products of Japanese companies. The results of tests of the accuracy of various home blood pressure-measuring devices are provided in the website of the JSH [90]. Finger-cuff devices for blood pressure measurement are known to be inaccurate and are not recommended in the guidelines in Western countries [111, 112], although no such device for home use is available in Japan.

Since the Ohasama Study first demonstrated home blood pressure as a more reliable predictor of outcome compared with office blood pressure [50, 113], clinical data regarding the relationship between home blood pressure and the incidence of cardiovascular diseases or prognosis have been obtained [114,115,116,117,118,119,120]. Such favorable properties of home blood pressure are associated with the reproducibility of the mean of home blood pressure levels [121, 122].

(2) ABPM

If an automatic device based on the cuff-oscillometric method [123,124,125] is used for noninvasive measurement of blood pressure at intervals of 15–30 min over 24 h ABPM, blood pressure information can be collected in a nonclinical setting such as a 24-h blood pressure profile or blood pressure information during specific periods (24 h, in the daytime, nighttime and early morning). In Japan, guidelines on ABPM has been published by the Japanese Circulation Society (“Guidelines for the clinical use of 24 h ambulatory blood pressure monitoring (ABPM) (JCS 2010)”) [126].

Usually, blood pressure is high during waking hours and low during sleep. It has also been shown that the 24-h average of ABP is correlated more closely with the severity of hypertensive target organ damage than office blood pressure, and that it is closely associated with the regression of target organ damage mediated by antihypertensive medication [127, 128, 832]. Moreover, ABPM allows more accurate prediction of the incidence of cardiovascular diseases than office blood pressure in the general population, older population and in hypertensive patients [49, 52, 129,130,131,132,133].

ABPM is particularly useful for the diagnosis of white coat hypertension. It is indicated for the diagnosis of white coat hypertension, poorly controlled hypertension and resistant hypertension. The indications for ABPM are presented in Table 2-4. However, the reproducibility of the mean values of 24-h, daytime (waking hour) and nighttime (sleep) blood pressures on ABPM, as well as that of diurnal variations in blood pressure, is not always favorable, depending on activity and sleep conditions during the day. A single session of ABPM does not accurately reflect personal blood pressure information [134].

Table 2-4 Indications for ABPM

2. Diagnosis of hypertension

1) Classification of office blood pressure levels

Among most international guidelines, including those in Japan, it is common to regard patients with office blood pressure levels of 140/90 mmHg or more as having hypertension.

In the Hisayama Study in Japan, the cumulative mortality rate due to cardiovascular diseases was lowest when the SBP and DBP were <120 and <80 mmHg, respectively, and the risks of cardiovascular diseases increased significantly when the SBP was ≥140 mmHg compared with <120 mmHg, and when the DBP was ≥90 mmHg compared with <80 mmHg, including in older individuals [135, 136]. Moreover, according to the Tanno/Sobetsu Study, an 18-year prospective epidemiological study in Hokkaido, Japan, a SBP of ≥140 mmHg and a DBP of ≥90 mmHg were considered significant risk factors for cardiovascular and total mortality [137]. Similarly, in NIPPON DATA80, a significant increase in the mortality rate due to cardiovascular diseases was observed at a blood pressure of ≥140/90 mmHg [15]. In addition, according to the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines for Treatment of Hypertension, a blood pressure of ≥130/80 mmHg was defined as hypertension on the basis of the meta-analysis results of the data from observational studies of the association between blood pressure level and cardiovascular diseases and from randomized controlled trials (RCTs) designed to evaluate the effects of improved lifestyles and drug therapy [111]. However, the RCTs as the rationale for such definition included few Japanese trials. Therefore, in these guidelines, a blood pressure of ≥140/90 mmHg is adopted as the criterion for grade I or higher hypertension (Table 2-5).

Table 2-5 Classification of blood pressure levels in adults

In JSH2014, individuals with an office blood pressure of <140/90 mmHg were regarded as showing a normal-range blood pressure. In addition, the normal blood pressure was subclassified into three groups: high-normal, normal and optimal blood pressure. However, the results of observational studies in Europe and the United States [138] and studies in Japan [139, 140] have shown that the incidences of cardiovascular diseases in individuals with a blood pressure of 120–129/80–84 mmHg and those with a blood pressure of 130–139/85–89 mmHg are higher (in the ascending order) than in those with a blood pressure of <120/80 mmHg. Furthermore, it has been shown that in the former two groups (120–139/80–89 mmHg), the chances of developing hypertension are higher than in the third group [141]. Therefore, it does not seem appropriate to regard an office blood pressure of ≥120/80 mmHg as a normal blood pressure. An office blood pressure of <120/80 mmHg is therefore expressed as normal in these guidelines (Table 2-5). The subclasses “normal blood pressure” and “high normal blood pressure” employed in JSH2014 are classified and expressed as “high normal blood pressure” and “elevated blood pressure,” respectively, in these guidelines. For consistency with the goal of antihypertensive measures in these guidelines (see Chapter 3 Table 3-3), the DBP range or these two classes is set at <80 mmHg and 80–89 mmHg, respectively (Table 2-5).

Blood pressure classification using the office blood pressure data should be based on at least two blood pressure measurements, taken on separate occasions in the absence of antihypertensive treatment. On each occasion, blood pressure should be measured many times at intervals of 1–2 min and the mean of two stable values (difference less than 5 mmHg) should be adopted as the blood pressure value at a given occasion.

2) Classification based on out-of-office blood pressure measurement

(1) Classification based on home blood pressure

In many international guidelines, including Japanese guidelines, 135/85 mmHg (Tables 2-5, 2-6) has been adopted as a criterion for hypertension on the basis of the results of meta-analysis of the data from 6470 individuals followed for a median period of 8.3 years (International Database of Home blood pressure in relation to Cardiovascular Outcome: IDHOCO) involving cross-sectional/follow-up studies in USA/Europe and Japan as well as Ohasama Study and Tsurugatani Study in Japan [112, 142,143,144,145]. Also in these guidelines, a home blood pressure of ≥135/85 mmHg was adopted as a criterion for hypertension, as is the case with JSH2014. Furthermore, since the diagnosis of hypertension on the basis of home blood pressure is more popular in Japan, these guidelines classify home blood pressure into normal, high normal and elevated blood pressures, similar to the classification of office blood pressure, on the basis of the data on untreated inhabitants collected in IDHOCO [143] and Ohasama Study [146] (Table 2-5). As described in the preceding section, classification of home blood pressure uses the mean of morning blood pressure and that of evening blood pressure each measured for 7 days (at least 5 days) (see Q2). Each of these categories of blood pressure is adopted in case in which the mean of home blood pressure in the morning or the mean of home blood pressure in the evening or both satisfy the criteria.

Table 2-6 Criteria for hypertension in different measurement methods

(2) Classification based on ABPM

Many international guidelines, including those in Japan, propose to make a diagnosis of hypertension if the 24-h blood pressure measured by ABPM is ≥130/80 mmHg, the daytime blood pressure is ≥135/85 mmHg and the nighttime blood pressure is ≥120/70 mmHg on the basis of the results from cross-sectional/follow-up surveys in USA/Europe and Japan as well as their meta-analysis [126, 134, 144, 145, 147]. Also in these guidelines, similar to JSH2014, a diagnosis of hypertension is made if the mean of 24-h blood pressure is ≥130/80 mmHg, the mean of daytime blood pressure is 135/85 mmHg and the mean of nighttime blood pressure is ≥120/70 mmHg, regardless of where blood pressure is measured (Table 2-6).

3) Classification by systolic and diagnostic blood pressures

For both the classification based on office blood pressure and the classification based on out-of-office blood pressure, SBP and DBP are mutually independent risk factors, and if they belong to different blood pressure categories the individual is classified by the higher category.

The frequency of isolated systolic hypertension increases in older people because SBP increases, whereas DBP often decreases due to a reduced compliance of the large elastic arteries caused by atherosclerosis. Several studies, including the cohort studies in USA/Europe [148,149,150], Hisayama Study and Ohasama Study [136, 151], showed that isolated systolic hypertension was an important risk factor for cerebral or myocardial infarction in older people. Isolated systolic hypertension in older persons is classified into the burned-out type, caused by an aging-related decrease in DBP in cases of essential hypertension, and the de novo type, caused by a novel increase of SBP in old age.

4) Blood pressure measurement and procedures for hypertension diagnosis

Currently, in Japan, 77% of hypertensive patients have a sphygmomanometer for taking home blood pressure measurement. Reportedly, 40% of non-hypertensive individuals possess a home sphygmomanometer [103]. In Japan, approximately 40 000 000 home sphygmomanometers may be in use, corresponding to 1 sphygmomanometer per household [104]. This value is consistent with that reported from the National Health and Nutrition Survey of Japan in 2010 [105]. On the other hand, in Japan, 72% of adult men and 63% of adult women undergo a health checkup in some form or other [152]. Therefore, individuals without a history of hypertension consult a medical facility if hypertension is shown by a health checkup or self-measurement of blood pressure/home blood pressure.

In medical facilities, office blood pressure is measured. Simultaneously, the home blood pressure measured by patients is reported to the facility, or patients begin to measure home blood pressure before the start of treatment as per physicians’ recommendations (Figure 2-1). As criteria for the diagnosis of hypertension based on home blood pressure have been established, a diagnosis of hypertension is made based on patients’ office and home blood pressure levels. In this case, when there is a discrepancy of decision between the two methods, a home blood pressure-based diagnosis of hypertension has priority, because the prognostic value of home blood pressure, that is, its clinical value, is higher than that of office blood pressure. Furthermore, blood pressure measurement in an out-of-office setting has already had priority over office blood pressure for the diagnosis and treatment of white coat or masked hypertension.

Fig. 2-1
figure10

Blood pressure measurement and procedure for hypertension diagnosis

The JSH2014 and 2019 Guidelines differ from those in Europe and the United States in that the clinical availability, feasibility and diagnostic value of home blood pressure are highly appraised. However, ACC/AHA2017 guidelines [111] recommend that home blood pressure measurement is first conducted to evaluate the white coat effect during treatment and to identity poorly controlled masked hypertension and ABPM is then conducted for confirmation. These guidelines proposed a procedure similar to the JSH in that priority is given to diagnosis on the basis of home blood pressure.

In Japan, 40 000 000 home sphygmomanometers are in use, whereas only tens of thousands of ABPM devices are being used [104]. Actually, the clinical application of ABPM is not easy [153]. ABPM devices are expensive, and the mental/physical stress of individuals wearing them is great. In addition, there are manpower- and cost-related problems relating to the medical staff. These factors support the importance of home blood pressure measurement emphasized in the guidelines. However, ABPM has certain merits, and, if necessary, it is clinically important to perform ABPM. In these guidelines, it is recommended that ABPM should be performed, if possible, as a complementary measure for hypertension diagnosis by home/office blood pressure measurement.

POINT 2b

[White coat hypertension]

  1. 1.

    White coat hypertension is defined as cases in which the office blood pressure is ≥140 mmHg and/or 90 mmHg and the home blood pressure is <135 mmHg/85 mmHg or the 24-h mean blood pressure (measured by ABPM) is <130 mmHg/80 mmHg.

  2. 2.

    White coat hypertension is seen in 15–30% of hypertensive patients, and this percentage is higher among older persons.

  3. 3.

    Patients with white coat hypertension require careful follow-up because their risk for composite of cardiovascular events in the future is higher than in non-hypertensive individuals (individuals with normal, high normal or elevated blood pressures) (see CQ2).

[Masked hypertension]

  1. 1.

    Masked hypertension is defined as cases in which the mean office blood pressure is <140 mmHg/90 mmHg and the home blood pressure is ≥135 mmHg and/or 85 mmHg or the 24-h mean blood pressure (measured by ABPM) is ≥130 mmHg and/or 80 mmHg.

  2. 2.

    Masked hypertension includes morning hypertension (early morning blood pressure ≥135/85 mmHg), nighttime hypertension (nighttime blood pressure ≥120/70 mmHg) and daytime hypertension (daytime blood pressure ≥135/85 mmHg).

  3. 3.

    Masked hypertension is seen in 10–15% of the non-hypertensive population and in 9–23% of hypertensive patients whose office blood pressure is controlled to less than 140/90 mmHg by antihypertensive therapy.

  4. 4.

    The cardiovascular risk of untreated masked hypertension is comparable to that of sustained hypertension and may be viewed as hypertension.

[Diurnal variation of blood pressure]

  1. 1.

    During management of hypertension, care should be taken also of diurnal variation patterns of blood pressure (non-dipper, riser, dipper), nighttime blood pressure, early morning blood pressure and blood pressure at workplace.

3. Hypertension based on home blood pressure and ABPM

The office blood pressure level is not always consistent with the non-office, daily blood pressure level measured using a home sphygmomanometer or on ABPM. A rise in blood pressure related to stress in a clinical setting is called the white coat phenomenon. The intensity of the white coat phenomenon (white coat effect) is calculated by subtracting the out-of-office blood pressure level from the office blood pressure level. For the diagnosis of hypertension, the condition can be classified into four types based on office and out-of-office blood pressure levels: non-hypertensive, white coat hypertension, masked hypertension and sustained hypertension. Diagnostic procedures are presented in Figure 2-2 [154]. Although white coat hypertension and masked hypertension are diagnosed on the basis of home blood pressure or ABPM according to their definition, there is a report that the combination of home blood pressure and ABPM allows identification of white coat hypertension or masked hypertension with favorable or poor prognosis [155]. It is therefore ideal to use both of them.

Fig. 2-2
figure11

Conditions classified as masked hypertension and its factors

1) White coat hypertension

White coat hypertension is a condition in which the blood pressure level measured in a clinical setting is at a hypertensive level but that measured in a nonclinical setting is in the non-hypertensive range (Figure 2-2) [154]. This term should be essentially used in untreated patients. White coat hypertension accounts for 15–30% of patients, with an office blood pressure of 140/90 mmHg or more, diagnosed with hypertension. The frequency increases in older persons [154]. There are many reports demonstrating that when comparing white coat hypertension with sustained hypertension, in which the blood pressure level in a nonclinical setting is also high, organ damage is mild, and the cardiovascular prognosis is also favorable [129, 154, 156]. However, this is still controversial. During preparation of these guidelines, this issue was discussed as CQ. As a result, a conclusion that this requires careful follow-up was reached, because patients with white-coat hypertension have a higher risk for cardiovascular diseases events in the future when compared with non-hypertensive individuals (see CQ2 for details). If the office blood pressure is in the range of hypertension and the out-of-office blood pressure is in the non-hypertensive range in hypertensive patients receiving treatment, the condition is described as “hypertension accompanied by white coat phenomenon or white coat effect.” Similar to the diagnosis of hypertension, evaluation should first be made using the home blood pressure and, as needed, ABPM is conducted for confirmation, to judge whether hypertension associated with the white coat effect is present.

2) Masked hypertension

Masked hypertension is a condition in which the blood pressure level measured in a clinical setting is in the non-hypertensive range, but that measured in a nonclinical setting is at a hypertensive level (Figure 2-2) [154, 157]. This term is usually used in patients taking no antihypertensive drug, but these guidelines apply the term to both untreated patients and patients diagnosed as having hypertension (including patients receiving treatment). Masked hypertension in patients receiving treatment is described as masked hypertension under treatment. In Europe and the United States, it is called “masked uncontrolled hypertension.” [147, 158] Masked hypertension is defined on the basis of office and ouf-of-office blood pressure levels, but the condition varies. Morning hypertension, daytime hypertension and nighttime hypertension comprise masked hypertension, and hours during which the blood pressure level in a nonclinical setting increases differ. Masked hypertension is observed in 10–15% of the non-hypertensive general population and in 9–23% of hypertensive patients undergoing antihypertensive therapy in whom office blood pressure level is controlled at <140/90 mmHg [157]. The risks of organ damage and cardiovascular events in patients with masked hypertension are significantly higher than in non-hypertensive individuals or patients with white coat hypertension, being similar to those in patients with sustained hypertension. According to previous clinical studies, in patients with masked hypertension, metabolic abnormalities are more frequent than in non-hypertensive individuals, and hypertensive organ damage progresses regardless of the presence or absence of treatment for hypertension [111, 159]. In follow-up studies of untreated subjects [160], community residents [51, 161] and hypertensive patients receiving treatment [162,163,164], the relative risk for cardiovascular diseases in patients with masked hypertension was similar to that in patients with sustained hypertension [157]. Table 2-7 shows the high risk groups for masked hypertension. In these subjects, it is important to measure home and ABP levels regardless of the office blood pressure level. In some cases, the type of hypertension diagnosed differs between home blood pressure measurement and ABPM [155, 165], and it is necessary to check blood pressure with ABPM, as needed, in addition to home blood pressure measurement. For patients with masked hypertension receiving treatment, checking for overlooked secondary hypertension and elucidation of the cause (e.g., daily habits which require improvement) are also important, in addiction to reinforcement of treatment.

Table 2-7 High risk groups for masked hypertension

3) Morning hypertension

Patients with an office blood pressure of <140/90 mmHg and a mean home blood pressure measured early in the morning of 135/85 mmHg or more are regarded as having morning hypertension. Morning hypertension is classified into two types: non-dipper/riser and morning surge types. Both of these types may become risk factors for organ damage and cardiovascular events [166,167,168]. A mild morning surge is a physiological phenomenon, but an excessive morning surge becomes a risk factor. In contrast, the risk increases in a group with the disappearance of morning surge according to a study. The disappearance of morning surge is associated with the riser type, in which the nighttime blood pressure increases, and autonomic neuropathy such as orthostatic hypotension. Factors affecting morning hypertension are shown in Figure 2-2 [168, 169]. Morning hypertension is significantly associated with the risk for all cardiovascular diseases involving brain, heart, kidneys and other organs and causes organ damage more severe than that caused by the hypertension defined on the basis of office blood pressure, thus increasing the future risk for stroke [170, 171] and the need of daily life care during late senility [115]. Early morning blood pressure can be measured with a home sphygmomanometer, but morning hypertension characterized by specifically higher early morning blood pressure than the blood pressure at other times of the day (e.g. cases in which the bedtime blood pressure is in the non-hypertensive range and early morning blood pressure is at a hypertension level or cases in which early morning blood pressure is higher by 15 mmHg or more than the bedtime blood pressure) is a risk factor independent of mean morning or evening blood pressure [115, 170,171,172]. In hypertensive patients receiving treatment with antihypertensive drugs, a clinically significant problem is that the hypotensive effect of medication is lowest early in the morning (immediately before intake of the drug) even when the clinical blood pressure has been controlled well.

4) Nighttime hypertension

Patients with a mean nighttime blood pressure level measured by ABPM or using a home sphygmomanometer of 120/70 mmHg or more are regarded as having nighttime hypertension. For nighttime blood pressure measurement, ABPM is used, but a home sphygmomanometer can also be used for this purpose at present [173,174,175,176]. The nighttime blood pressure measured using a home sphygmomanometer is associated with organ damage, as described for that measured by ABPM [175]. When a high nighttime blood pressure level persists after waking, it is detected as ‘morning hypertension’ on home blood pressure measurement. The rate of change in nighttime blood pressure is smaller than that in daytime blood pressure. An increase in mean value is more strongly associated with an increase in the risk for cardiovascular diseases and a reduction in cognitive/physical functions [177, 178]. In addition, in patients in whom the nighttime blood pressure level alone is high despite normal-range home blood pressure levels measured early in the morning/at bedtime, vascular disorder is also advanced and the risk for cardiovascular diseases is high [179].

5) Daytime hypertension (hypertension in the presence of stress)

Patients in whom the mean value of blood pressure during stress-exposed daytime hours at the workplace or at home is 135/85 mmHg or more, with favorable reproducibility, despite normal-range office/home blood pressure levels, are regarded as having daytime hypertension. Mental/physical stress influences ABP (Figure 2-2). Workplace hypertension, in which the blood pressure measured on a health checkup or in a clinical setting is normal but that measured at the workplace in the presence of stress is high, is common among obese individuals and among those with a family history of hypertension.

6) Abnormal diurnal variations of blood pressure

When the circadian rhythm of blood pressure is normal, the nighttime blood pressure decreases by 10–20% of the daytime level on waking. This normal pattern is termed a dipper. A pattern in which there is only a slight decrease in nighttime blood pressure (rate of decrease in nighttime blood pressure: 0–10%) is defined as a non-dipper, and a pattern in which there is an increase in blood pressure at night is defined as a riser. In non-dippers and risers, the risks of brain/heart/kidney damage and cardiovascular mortality are high [180,181,182]. When sleep time is shortened in risers, the risk for cardiovascular diseases synergistically increases [183]. In addition, non-dippers in whom there is only a slight decrease in nighttime pulse also become a risk factor for cardiovascular events, independent of blood pressure non-dippers. When both blood pressure and pulse rate show a non-dipper pattern, the risk increases markedly [184]. In addition, even when office and 24-h blood pressure levels are in the non-hypertensive range, the cardiac load or risk of cardiovascular mortality increases in patients with nighttime hypertension or non-dippers/risers [179, 182]. The factors responsible for nighttime hypertension are shown in Figure 2-2.

On the other hand, a pattern in which the nighttime blood pressure level decreases excessively (20% or more of the mean daytime blood pressure) is defined as an extreme-dipper [180, 181]. It remains controversial whether the risk of an extreme-dipper is related to an excessive decrease in nighttime blood pressure or a morning surge in blood pressure/an increase in daytime blood pressure. In older hypertensive patients with an extreme dipper pattern, asymptomatic brain disease is advanced [180, 185], and the risk of stroke is also high [129]. According to several studies, extreme dippers show a reduction in cognitive function and cerebral blood flow, as well as an increase in pulse wave velocity (PWV) [186,187,188,189]. Among young individuals with a normal 24-h blood pressure level, the risk of coronary calcium deposition in non-dippers/risers and extreme dippers is more than four times higher than that in dippers [190]. These results suggest that the impaired circadian rhythm of blood pressure/heart rate becomes a risk factor for organ damage and cardiovascular events, independent of the blood pressure level, or a predisposing factor.

In individuals working on night shifts (shift workers), blood pressure reduction is less likely to occur because the sympathetic activity does not decrease sufficiently during daytime sleep compared with nighttime sleep, often resulting in non-dipper type abnormal variations of blood pressure.

4. Blood pressure variability

Blood pressure variability can be assessed by frequently measurement of blood pressure. Blood pressure variability includes a beat-to-beat variation, respiration-/autonomic output-related changes in a relatively short interval, and seasonal or yearly changes. In clinical practice, short-term diurnal changes can be assessed by measurement at intervals of 10–30 min with 24-h ABPM, morning-evening differences and day-by-day variability by home blood pressure measurement, and visit-to-visit variability by office blood pressure measurement. Long-term home blood pressure measurement data reflect seasonal/annual changes as well. White coat hypertension, masked hypertension, nighttime hypertension, morning hypertension and morning surge are also classified as a phenotype of blood pressure variability.

Significant association of visit-to-visit blood pressure variability with cardiovascular disease outcomes [191,192,193] and prognostic significance of diurnal and day-by-day blood pressure variability measured at home and with ABPM, respectively [194,195,196,197], have been reported. However, when blood pressure variability is evaluated with considering the impact of blood pressure level, the prognostic ability of blood pressure variability for cardiovascular complications is not very high and does not exceed the importance of blood pressure level (see Q3 “Blood pressure variability evaluation method”) [198,199,200,201]. Whereas, recent epidemiological studies have demonstrated the usefulness of day-by-day home blood pressure variability in the prediction of onset/progression of dementia [57, 202]. Furthermore, usefulness of seasonal variations of long-term home blood pressure measurement for the adjustment of prescribed drug dose and the prediction of cardiovascular outcome has been reported [203].

Blood pressure variability is affected largely by the setting for measurement. Of blood pressure variabilities, nighttime blood pressure dipping (vs daytime) and masked hypertension (out-of-office measurement vs office measurement) have been definitely shown to have high clinical significance (see the preceding section), whereas visit-to-visit and day-by-day blood pressure variability show no change [201, 204] or only limited change [205, 206] in response to antihypertensive drug therapy. Such blood pressure variabilities are therefore difficult to treat as an intervention-possible risk factor and currently serve only as a risk marker.

5. Pulse rate

According to the general population-based cohort studies in Japan, the mean pulse rate is 74/min for women and 70/min for men, with the age-related differences remaining in the range of approximately ±5/min [207]. Accumulating evidence suggests that an increase in pulse rate is associated with cardiovascular morbidity and total mortality [208,209,210]. The Ohasama Study demonstrated an increase in cardiovascular mortality when the pulse rate by home morning blood pressure measurement exceeds 70/min [211]. The prognostic ability of pulse rate measured by 24-h ABPM is lower than that of pulse rate by office blood pressure measurement [212], but the pulse rate measured by nighttime ABPM has recently been shown significant predictive power for cardiovascular morbidity and total mortality [213]. It has also been reported that a decrease in pulse rate by drug treatment can improve the prognosis for cardiovascular diseases [214, 215]. However, there is no established evidence regarding an optimal pulse rate and an improvement of prognosis in individuals by controlling pulse rate. The definition of tachycardia at rest also varies among reports from intervention studies and observational studies, with the lower limit set from 79 to 84/min with insufficient rationale (e.g., at upper interquartile point or arbitrary defined threshold) [210]. In the current guidelines, therefore, the optimal pulse rate is not defined, but at least routine measurement of pulse rate is recommended for patients with hypertension [210].

The product of pulse rate times SBP is called “double product (rate-pressure product)” and is known as an indicator of cardiac oxygen consumption [216]. Recently, the association between double product based on home blood pressure measurement and cardiovascular death was reported [217]. However, in integrative meta-analysis of cohorts, the prognostic value of ABPM-based double product was lower than that of ABPM-based SBP [218]. Therefore, the optimal range has not been set for double product, either.

POINT 2c Examination and diagnosis

  1. 1.

    For the examination of hypertension, the overall evaluation of vascular/organ functions and cardiovascular risk in individual patients and examinations for the diagnosis of secondary hypertension should be performed by considering the cost-effectiveness.

  2. 2.

    For the overall evaluation of cardiovascular risk, factors related to metabolic syndrome and chronic kidney disease (CKD) and hypertensive target organ damage are evaluated in addition to blood pressure, including home blood pressure.

  3. 3.

    The evaluation of target organ damage in high-risk patients such as those with diabetes mellitus, CKD or a history of cardiovascular diseases is essential if their blood pressure level is in or higher than the high normal blood pressure range.

  4. 4.

    Echocardiography (UCG), coronary artery CT, carotid ultrasonography and brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) are representative, special methods of examination for evaluating target organ damage, and other recommended examinations should be performed appropriately.

  5. 5.

    If secondary hypertension is suspected from medical interview, physical examination and general laboratory tests, appropriate screening tests should be performed.

6. Examination and diagnosis

For the diagnosis and treatment of hypertensive patients, (1) the severity of hypertension (blood pressure level) should be evaluated, (2) essential and secondary hypertension should be differentiated, (3) the presence or absence of cardiovascular risk factors (particularly those related to diabetes mellitus, metabolic syndrome and CKD), (4) the underlying lifestyle should be clarified, (5) concurrent cardiovascular diseases and organ damage should be evaluated, and (6) the severity of hypertension should be evaluated, considering home blood pressure.

1) History taking (Table 2-8)

Table 2-8 Points regarding medical history

The time of detecting hypertension and its circumstances (health screening, examination and self-measurement), duration, severity and course of treatment should be established. Particularly, if hypertension has been treated, the type of antihypertensive medications used and their effectiveness/the presence or absence of adverse effects should be confirmed.

As past medical histories, low birth weight or overweight in childhood and, in women, whether they have had hypertension, diabetes mellitus or proteinuria during pregnancy should be ascertained. With respect to family history, the presence or absence of hypertension, diabetes mellitus, or cardiovascular diseases and age at onset should be ascertained.

Lifestyle behaviors should be clarified in detail by asking patients about their exercise habits (frequency and intensity), sleep habits (duration and quality of sleep), dietary habits (content of meals, salt content, preference for sweets), intake of alcohol or soft drinks and smoking (amount and length of time), personality/psychological state (anxiety and depressive tendency) and severity of stress (workplace, home).

Hypertensive patients are usually symptom-free, but patients with secondary hypertension and those with complications/organ damage should be checked for the presence or absence of specific symptoms. As for signs suggestive of secondary hypertension, whether the patient has symptoms, such as nocturnal pollakiuria or nocturnal dyspnea, early-morning headache, daytime sleepiness, depression and reduced concentration or whether there are signs of sleep apnea syndrome, such as reports of snoring and apnea by the family, should be checked, in addition to the course of body weight increases and other risk factors related to metabolic syndrome (diabetes and dyslipidemia). Moreover, a history of hematuria, proteinuria and nocturnal pollakiuria, which suggest kidney disease, and the status of use of drugs which can increase blood pressure, such as non-steroidal anti-inflammatory drugs (NSAIDs), Chinese traditional herbal drugs, oral contraceptives, immunosuppressors and molecule-targeted drugs should be confirmed. Inquiries should be made into a history of organ damage and cardiovascular diseases, thereby confirming the presence or absence of symptoms/signs, such as transient ischemic attacks, muscle weakness, dizziness, headache and visual impairment related to cerebrovascular disorders; dyspnea (exertional, nighttime), weight gain, lower limb edema, palpitation and chest pain related to heart disease; pollakiuria, oliguria, nocturia and hematuria related to kidney disease; and intermittent claudication and coldness of the lower limbs related to peripheral artery disease.

2) Examination (physical findings) (Table 2-9)

Table 2-9 Points regarding physical findings

In addition to resting blood pressure and heart rate in a sitting position, left-right differences in pulse (beat) and upper arm blood pressure, upper limb-lower limb differences in pulse and blood pressure and orthostatic changes in pulse and blood pressure should be checked during initial examination.

Height and body weight are measured, and the degree of systemic obesity is evaluated by calculating the body mass index (BMI) (body weight (kg)/(height (m)2). Furthermore, waist circumference is measured (in the standing position at the umbilical level) and the degree of abdominal obesity is evaluated.

Also, the presence or absence of findings suggesting secondary hypertension, sign of heart failure, atherosclerosis and cardiovascular diseases is examined. The skin is examined for abdominal striae and hirsutism; the face and neck region is examined for moon face, myxedematous face, anemia/jaundice, thyroid goiter, cervical vascular murmurs (if findings are present, the presence or absence of orbital murmurs is checked), jugular vein dilation in the sitting position and ophthalmoscopic findings; as for the chest, palpation of the apical beat and thrill (strongest point and palpation area) and auscultation for heart murmurs, gallop rhythms, arrhythmias, dorsal vessel murmurs and rales in the lung fields are performed. The abdominal region is examined for vascular murmurs/directions of their projection, a pulsating phyma on palpation, liver enlargement and kidney enlargement (polycystic kidney); the limbs are examined by palpation (disappearance, weakening and lateral difference) of arterial pulse (radial and dorsalis pedis (lower limb) arteries; if findings are present, the site of palpation is transferred to the central side in the order of the posterior tibial, popliteal and femoral arteries), cold sensation, ischemic ulcer, edema, motor disturbances, sensory disturbances, and increased or weakened tendon reflex.

3) Laboratory examinations (Table 2-10)

Table 2-10 Clinical examination

Laboratory examinations for the overall assessment of target organ damage and cardiovascular risk in individual patients and for the diagnosis of secondary hypertension are performed by always considering cost-effectiveness.

(1) General laboratory examinations

General examinations that should be performed during the initial examination of hypertensive patients and a few times a year during follow-up are general urinalysis, blood cell counting, blood chemistry tests, chest X-ray and electrocardiography. For these examinations, it is also possible to use data from general mass screening and health checkups at the workplace.

On blood chemistry tests during the initial examination, general laboratory parameters are measured. During follow-up examination, creatinine (Cr), uric acid, electrolytes, fasting triglyceride (TG), high-density lipoprotein cholesterol, total cholesterol (or low-density lipoprotein cholesterol), fasting blood sugar and hepatic function are measured in view of risk evaluation. The estimated glomerular filtration rate (eGFR) is calculated from the serum Cr, but eGFR calculated from cystatin C is also utilized if muscle mass decrease (e.g., sarcopenia) is present (see Section on CKD). Particularly in patients receiving oral-dose antihypertensive medication (diuretics, renin–angiotensin [RA] inhibitors) and older patients, sodium (Na) is additionally measured. Urinary Na/K ratio and gCr-corrected Na are useful in the evaluation of dietary profile.

(2) Evaluation of glucose tolerance and inflammatory risk factor

If impaired glucose tolerance is suspected by the screening with fasting blood sugar level, the glycated hemoglobin level measurement and/or 75-g oral glucose tolerance test should be performed [219]. Although the blood level of high-sensitive C-reactive protein (CRP) is lower among the Japanese than in western and south-east Asian populations, its increase even to a minimal degree is related to coronary artery disease and silent cerebral infarction [220,221,222], and is a risk factor for future stroke [223].

(3) Autonomic nerve function test

The frequency of orthostatic dysregulation of blood pressure, as a type of autonomic neuropathy, increases in older people and diabetics. This disorder is associated with the progression of organ damage and deterioration of long-term prognosis [224, 225]. A head-up tilting test with a tilt table is necessary for detailed examination of orthostatic hypotension. However, the standing test is used as a simple testing method in clinical practice. In this method, blood pressure 1–3 min after active standing is measured, and changes in blood pressure in comparison with that measured in a sitting (or supine) position once or twice after a 5-min rest are evaluated. Simultaneously, the pulse is recorded. When an increase in pulse is less marked than a fall in blood pressure, disorder of the pressure reflex arc is suggested. Dizziness and falls are frequently observed immediately after standing. Blood pressure immediately after standing should also be measured. Many patients with orthostatic hypotension or autonomic neuropathy show abnormal, non-dipper-type (the rate of decrease in blood pressure at night is reduced) or riser-type (the nighttime blood pressure increases) diurnal variations in blood pressure [226, 227].

(4) Examinations for secondary hypertension screening

For the screening of patients suspected to have secondary hypertension on the basis of the results of medical interview, physical examinations and general laboratory investigations, the following examinations are performed: examination of the plasma renin activity (or active renin level) and hormone levels, including plasma aldosterone concentration, cortisol, adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), insulin-like growth factor 1 (IGF-1) and three fractions of catecholamines, blood or urinary examination of two fractions of metanephrine, and abdominal ultrasonography are recommended (with respect to details such as measurement conditions, see Section 3 of Chapter 13, ENDOCRINE HYPERTENSION). Specific examinations should be selected from these examinations depending on the diseases concerned. Examination, such as nighttime pulse oximetry, may be performed for the diagnosis of sleep apnea syndrome.

Special examinations performed by experts for the definitive diagnosis of secondary hypertension include hormone load tests, adrenal gland computed tomography (including contrast-enhanced computed tomography), abdominal MRI, renal artery ultrasonography, renography, adrenal venous sampling (AVS) and polysomnography (PSG). Specific tests are selected depending on the diseases suspected.

4) Diagnosis of hypertensive organ failure

When hypertension is managed, comprehensive evaluation of organ failure caused by hypertension is also needed, in addition to evaluation of blood pressure. To this end, it is required to understand the meaning of various examinations reflecting the degree of organ failure and to conduct measurement and evaluation continuously. Such an evaluation of target organ damage should be conducted in high-risk patients with diabetes mellitus or a history of cardiovascular events whose blood pressure is in or higher than the high-normal range, in addition to patients with hypertension.

(1) Brain and fundus

Asymptomatic cerebrovascular disorders (silent cerebral infarcts, cerebral white matter lesions, asymptomatic cerebral hemorrhage and cerebral microbleeds) are strong risk factors for stroke and dementia, and are related to depression and falls in elderly people [228, 229]. MRI is superior to computed tomography for the evaluation of these asymptomatic cerebrovascular disorders. However, during routine clinical practice, neither CT nor MRI is used for screening of organ failure in hypertensive patients.

At present, asymptomatic cerebrovascular disorders are often detected during thorough brain checkup. Asymptomatic brain/neck vascular lesions can advance into symptomatic cerebrovascular disorders and asymptomatic cerebrovascular disorders are closely associated with hypertension and involve a high risk for progression into symptomatic cerebrovascular disorders, thus indicating the importance of antihypertensive treatment [230].

In elderly hypertensive patients, the evaluation of cognitive impairment with the mini-mental state examination (MMSE) or Hasegawa dementia scale and evaluation of depression on the basis of the Geriatric Depression Scale (GDS) or Beck Depression Inventory (BDI) are also useful for estimation of the risk of future occurrence of dementia and cardiovascular disease and prediction of outcome [231, 232].

Ophthalmoscopy is used as a general screening method. In particular, ophthalmoscopy is essential when hypertension is complicated by diabetes mellitus. Arterial stenosis is the first sign of hypertension’s influence on retinal vessels. It is followed by atherosclerosis, and the severity of condition is evaluated on the basis of its cross-reaction with blood pillar reflex or veins. This involves problems related to universality and reproducibility, and contradictory reports describe the association between mild fundus lesions and onset of cardiovascular disease [233, 234]. However, soft exudate/papilledema is seen also in patients with hypertensive encephalopathy (a hypertensive emergency) or malignant hypertension, and fundus bleeding suggests severe hypertension and is associated also with the cardiovascular risk [233, 234]. Immediate actions, including referral to hypertension specialists, are needed when any of these findings is obtained.

(2) Heart

Electrocardiography (ECG) is one of the general examinations. Usually, left ventricular hypertrophy is diagnosed on the basis of high ECG potentials (e.g., Sokolow–Lyon voltage criteria, Cornell voltage criteria), but “strain pattern” also is a risk for onset of cardiovascular disease [235]. However, care should be taken of the fact that high potentials may be shown even in the absence of left ventricular hypertrophy in young patients and slim patients.

Improvement in findings from ECG or UCG following antihypertensive treatment reflects improved prognosis and is an indicator for evaluation of antihypertensive efficacy [235]. The European Society of Cardiology (ESC)/European Society of Hypertension (ESH) Hypertension Treatment Guidelines 2018 list ECG and UCG findings as indicators useful in determining the appropriateness of antihypertensive treatment [236]. In Japan, there are no UCG-based diagnostic criteria for left ventricular hypertrophy, but the left ventricular myocardial weight index among healthy Japanese has been shown [237, 238].

The blood levels of brain natriuretic peptide (BNP), which was isolated and identified in Japan, or N-terminal pro-BNP increase markedly in patients with symptomatic heart failure due to left ventricular systolic and diastolic dysfunction (caution: increase is smaller in obese patients), and they have been widely used clinically for the diagnosis of this condition and for evaluation of therapeutic effects [239]. Clinically, they are useful for the screening of hypertensive patients with dyspnea for heart failure.

For the noninvasive screening of hypertensive patients with chest pain for coronary artery disease, ECG (at rest/during exercise), UCG, cardiac nuclear medicine test, coronary artery CT and coronary artery catheterization should be performed in accordance with the guidelines regarding the Noninvasive Diagnosis of Coronary Artery Lesions, which were established by the Japanese Circulation Society [240].

(3) Kidney

eGFR and proteinuria (qualitative) are used as general examinations for evaluation of renal dysfunction [241]. Because urinary protein (+/-) examined by the test paper method corresponds to a urinary albumin level of approximately 30 mg/gCr, urinary protein should be measured as needed [241]. CKD is a condition in which 0.15 g/gCr or more proteinuria (30 mg/gCr or more microalbuminuria) or GFR<60 mL/min/1.73m2 or both persists for 3 months or longer [241]. The severity of CKD evaluated using these two indicators correlates significantly with CKD progression, progression to terminal-stage renal failure, cardiovascular death and total mortality [241]. Recent studies revealed an association between microalbuminuria and prognosis not only in diabetic patients but also in hypertensive patients [242,243,244,245].

(4) Blood vessels

Evaluation of angiopathy, including atherosclerosis, can be roughly divided into two types: morphological evaluation and functional evaluation.

i) Carotid ultrasonography

Carotid artery intima-media thickness (IMT) is an indicator for morphological evaluation of angiopathy and is an independent indicator for prediction of outcome [246]. IMT≥1.1 mm is abnormal (IMT-C10: Measuring the IMT on the distal wall 10 mm proximal to the common carotid artery-carotid sinus junction) [247, 248], If asymptomatic carotid artery stenosis (diameter stenosis rate 50% or more = moderate stenosis, 70% or more = severe stenosis) has been detected, antihypertensive treatment and other methods of risk control should be considered positively [230].

According to recent meta-analyses, IMT does not markedly improve the evaluation with the use of existing risk models (Framingham risk score) [249], and it is considered as unsuitable as an indicator for evaluation of exacerbation/improvement of the risk following changes in condition or treatment [250, 251].

ii) ABI

ABI is the ratio of the ankle SBP to the brachial SBP (the higher of the right or left brachial SBP) [252]. ABI measurement with the Doppler method is recommended in the AHA2012 Guidelines on ABI Measurement and Evaluation [252], whereas ABI measurement with a simple oscillometric method is used in Japan [253]. There is a good correlation between ABI values measured with these two methods [254].

ABI≤0.90 reflects complication by peripheral artery disease [252, 253], and ABI≤0.90 and between 0.91 and 1.00 involves a higher risk for onset of cardiovascular disease (≥1.40 is also a risk but the frequency is low) [252, 253]. ABI measurement should be considered in high-risk patients [255].

iii) PWV

PWV is an indicator of arterial stiffness, and carotid-femoral PWV (cfPWV) and baPWV have been used [253]. cfPWV and baPWV have been reported to be independent indicators of prognosis in the meta-analyses based on individual participants data (IPD) summarized from published data [256, 257].

Both cfPWV and baPWV have been shown to improve the evaluation results of existing risk models, with the improvement of the prognostic ability larger when baPWV was used in the low-risk group [257]. cfPWV may be useful when measured in cases at moderate or higher risk [256]. baPWV may be applicable to risk assessment also in low-risk cases, but there is a need of verifying the medico-economic efficiency of its measurement, and its measurement may be useful in patients aged 50 and over or patients having risk factors other than blood pressure.

The cut-off level is cfPWV>10 m/sec [236] and baPWV≥18 m/sec (reproduced with simplification from Ref. [258]). However, it should be borne in mind that the cut-off level does not divide the risk into two categories and that the relationship of PWVs to onset of cardiovascular disease is linear.

The cardio–ankle vascular index (CAVI) is an indicator of arterial elasticity determined from pulse wave velocity and upper-arm blood pressure and not dependent on blood pressure at the time of measurement [253, 259]. CAVI is higher in the presence of cardiovascular disease, and its cut-off level 9.0 has been proposed [253, 259]. CAVI also rises in the presence of risk factors for cardiovascular disease and decreases in response to treatment [253, 259]. In an observational study of 1080 patients with hypertension complicated by abnormal glucose or lipid metabolism, CAVI was reported as a significant indicator of predicting the onset of cardiovascular disease [260].

iv) Pulse wave analysis

Central blood pressure is most frequently used for pulse wave analysis [253]. Because sex and cardiovascular risk factors affect the central blood pressure, brachial SBP cannot replace central blood pressure, and a meta-analysis has shown that the ability of predicting outcome is higher with central blood pressure than with brachial SBP [261]. International criteria levels of central blood pressure were reported recently [262]. A recent domestic multicenter study also confirmed the usefulness of central blood pressure as a prognostic indicator [263].

v) Endothelial function test

The endothelial function test aimed at evaluating the endothelial dysfunction (an early sign of atherosclerosis) has been covered by health insurance in Japan [253]. Flow-mediated vasodilation (FMD) and reactive hyperemia peripheral arterial tonometry (RH-PAT) are used for this test [253], but they reflect different conditions [264]. Both FMD and RH-PAT have been reported to be independent prognostic factors by a meta-analysis [265], and standard values of FMD by age and sex among Japanese people have been reported [266].

vi) Aortic aneurysm

Dilatation of the aorta on plain chest X-ray is a finding suggesting thoracic aortic aneurysm or aortic dissension, and the presence of a palpable pulsatile mass in the abdomen suggests abdominal aortic aneurysm or aortic dissection. If any of these abnormalities is detected, CT or MRI should be considered. Abdominal ultrasonography is useful in screening of abdominal aortic aneurysm, but its indications have not been definitely defined [255].

Table 2-11 summarizes the characteristics of each indicator [267]. Of the indicators with high abilities of predicting the outcome (indicators whose usefulness has been confirmed in meta-analysis), ECG, eGFR, proteinuria (qualitative) and ophthalmoscopy may be shown as general examination to be used for evaluation of organ failure. Although there is no clear-cut definition of intervals for measurement of the indicators of organ failure, it is necessary to conduct evaluations at intervals of 1–2 years because organ failure progresses with aging. For indicators largely affected by blood pressure (e.g., pulse wave velocity, pulse wave analysis), it seems essential to conduct evaluation upon stabilization of blood pressure after the start of antihypertensive treatment.

Table 2-11 Indicators of organ damages

CQ1 Is antihypertensive treatment based on home blood pressure recommended rather than that based on office blood pressure in adults with essential hypertension?

Antihypertensive treatment based on home blood pressure is strongly recommended.

Recommendation Grade 1 Evidence Level B

Evidence summarization

We included 12 RCTs, comparing antihypertensive treatment based on home blood pressure with antihypertensive treatment based on office blood pressure, with the reduction in mean of 24-h or daytime ABP level as an outcome. High heterogeneity was observed among these trials. We then conducted meta-analysis after excluding 3 trials in which the same target blood pressure for both home and office blood pressure was employed (this factor possibly responsible for heterogeneity), the heterogeneity disappeared, and the degree of reduction in ambulatory SBP/DBP following antihypertensive treatment based on home blood pressure was larger by −3.64 mmHg (95% confidence internal [CI] −5.04 to −2.23) for systolic pressure and −2.16 mmHg (95% CI −3.18 to −1.14) for diastolic pressure than that following antihypertensive treatment based on office blood pressure. A similar result was obtained also when the analysis was confined to 5 trials with the 24-h ABP level as an outcome. No RCT evaluating the incidence of cardiovascular diseases or mortality was identified.

Commentary

A number of studies have shown that home blood pressure is more reliable and reproducibly than office blood pressure [122, 268] and is more closely associated with cardiovascular diseases and target organ damage [50, 113, 143, 156, 269]. On the basis of such evidence, the Guidelines on Hypertension Treatment 2014 (JSH2014) states clearly: “If the office blood pressure differs from the home blood pressure, priority should be given to diagnosis based on the home blood pressure.” [108] However, a part of clinicians have a view that office blood pressure suffices [106]. To resolve such a difference in awareness/view, it is essential to compare antihypertensive treatment based on home blood pressure with conventional antihypertensive treatment based on office blood pressure and to demonstrate clearly whether the prognosis and hypertension control will be improved by the use of home blood pressure as an indicator.

With such a background, we recently conducted systematic review (SR) by setting this CQ during preparation of JSH2019 [270]. The following three outcomes were set for this review: 1) reduction in the incidence of cardiovascular diseases, 2) reduction in cardiovascular mortality, 3) reduction in mean 24-h ABP levels.

  1. 1)

    Reduction in the incidence of cardiovascular diseases

  2. 2)

    Reduction in cardiovascular mortality

    No RCT corresponding to outcome 1) or 2) was identified.

  3. 3)

    Reduction in mean 24-h ABP levels

Twelve RCTs were included (Table CQ1-1) [271,272,273,274,275,276,277,278,279,280,281,282]. For the trials in which mean 24-h ABP levels had not been evaluated, mean daytime ABP level was used as a surrogate outcome. Meta-analysis of the 12 trials revealed high inter-trial heterogeneity (Figure CQ1-1, I2=75%). When the analysis excluded 3 trials employing the same target blood pressure for both home and office blood pressure (this factor possibly responsible for heterogeneity), the heterogeneity disappeared, and the degree of reduction in ABP following antihypertensive treatment based on home blood pressure was larger by 3.64 mmHg (95% CI −5.04 to −2.23) for systolic pressure and 2.16 mmHg (95% CI −3.18 to −1.14) for diastolic pressure than that following antihypertensive treatment based on office blood pressure (Figure CQ1-2). This difference in antihypertensive efficacy remained unchanged regardless of the presence or absence of home blood pressure data server transfer or healthcare professional’s telemonitoring. Similar results were observed also when the analysis was confined to 5 trials after exclusion of 4 trials having employed the daytime blood pressure as an outcome (inter-group difference in reduction of 24-h ABP levels: −4.08 mmHg in terms of SBP and −2.64 mmHg in terms of DBP).

Table CQ1-1 RCTs included
Fig. CQ1-1
figure12

Results of meta-analysis of all 12 RCTs (Source: Ref. [270])

Fig. CQ1-2
figure13

Results of meta-analysis excluding 3 RCTs having adopted the same goal of antihypertensive treatment. We excluded three studies [271, 281, 282] employing the same target BP for both home and office readings. (Source: Ref. [270])

Conclusions

Antihypertensive treatment based on home blood pressure has been shown to be more useful in reducing mean 24-h ABP levels than treatment based on office blood pressure. All of the three trials, employing the same target blood pressure for both home and office blood pressure (a factor possibly responsible for heterogeneity) [271, 281, 282], had been carried out before wide spread of the knowledge about difference between home and office blood pressures. The results of a recent study clarifying the blood pressure level leading to the same incidence of cardiovascular diseases also demonstrated the validity of home blood pressure which was about 5 mmHg lower than the office blood pressure [143]. Therefore, antihypertensive treatment with the target reduction in home blood pressure to a level 5 mmHg lower than the office blood pressure shown in these guidelines may be useful in reducing mean 24-h ABP levels.

On the other hand, no RCT adopting the reduction in the incidence or mortality of cardiovascular diseases was identified. Thus, there is no evidence directly confirming that antihypertensive treatment based on home blood pressure can reduce the incidence or mortality of cardiovascular diseases compared with antihypertensive treatment based on office blood pressure. However, according to the meta-analysis of observational studies using mean 24-h ABP data among Asian subjects [283], the difference in antihypertensive efficacy by 3.64 mmHg (systolic pressure) and 2.16 mmHg (diastolic pressure) obtained from the above-mentioned meta-analysis of trials (having adopted reduction in mean ABP levels as the outcome) is suggested to be associated with a reduction of the risk for cardiovascular diseases by 16.6 and 16.2%, respectively. Furthermore, in the HOMED-BP Study conducted in Japan, involving patients with essential hypertension, the home blood pressure during antihypertensive treatment was reported to be closely associated with the risk for onset of or death from cardiovascular diseases than office blood pressure [54, 269]. This suggests that antihypertensive treatment aimed at achieving the goal of home blood pressure reduction proposed in these guidelines is useful also in reducing the incidence and mortality of cardiovascular diseases.

After completion of this SR, a report was published concerning the results of TASMINH4 Study in the United Kingdom designed to evaluate the degree of blood pressure reduction in the group managed on the basis of office blood pressure, the group managed on the basis of home blood pressure and the group undergoing home blood pressure telemonitoring [284]. Its primary outcome was the office blood pressure measured with an automated sphygmomanometer, but the goal of home blood pressure reduction was set at a level 5 mmHg lower than that of office blood pressure reduction [284]. In that study, SBP was lower by 3.5 mmHg in the home blood pressure-based management group and by 4.7 mmHg in the home blood pressure telemonitoring group than in the office blood pressure-based management group, thus supporting the results of our SR [284].

For the reasons given above, this CQ strongly recommends implementation of antihypertensive treatment based on home blood pressure. However, it is essential to set the goal of treatment in line with the goal of blood pressure reduction recommended in the present guideline. It is additional required that home blood pressure measurement is conducted appropriately in accordance with the present guideline.

Literature Search

Two SR members independently conducted literature search with PubMed and Cochrane Library to extract papers concerned with this CQ.

CQ2 Is follow-up needed for patients with white coat hypertension?

Patients with white coat hypertension have a higher risk for composite of cardiovascular events than non-hypertensive individuals. Furthermore, a high risk for progression of white coat hypertension to sustained hypertension has been reported. Therefore, careful follow-up is needed for patients with white coat hypertension.

Recommendation Grade 2 Evidence Level C

Evidence summarization

Among antihypertensive drug-naïve individuals, those having white coat hypertension have a higher future risk for composite of cardiovascular events than those without hypertension. The risk for developing sustained hypertension is also significantly higher in individuals with white coat hypertension than in non-hypertensive individuals.

Commentary

Patients with white coat hypertension have hypertensive office blood pressure and non-hypertensive out-of-office blood pressure. According to previous studies, organ damage is milder and the cardiovascular prognosis is more favorable in patients with white coat hypertension than in patients with sustained hypertension whose blood pressure is high also when measured outside the office. In addition, it has also been reported that white coat hypertension in some cases progresses to sustained hypertension, contributing in the long run to a high risk for cardiovascular events. We conducted SR within the framework of this CQ [285]. The term “white coat hypertension” is used for treatment-naïve patients with hypertension in the narrower sense of the term. According to guidelines and statements in Europe and the USA, ABPM is primarily recommended for evaluation of out-of-office blood pressure, whereas importance has been emphasized to home blood pressure in Japan. This SR therefore adopted the following two policies: (1) Any of ABPM or home blood pressure may be used for evaluation of out-of-office blood pressure; and (2) White coat hypertension received antihypertensive treatment were excluded. Because the features of cardiovascular prognosis differ between Japan and western countries, the following five events based on classification of stroke and cardiovascular events were set for this SR: 1) Onset of cardiovascular diseases (composite endpoints consisted of cardiac events and stroke) or its death, 2) Onset of stroke events or its death, 3) Onset of cardiac events or its death, 4) All-cause mortality, and 5) Deterioration to sustained hypertension.

Two SR members independently conducted literature search with PubMed, Cochrane Library and Ichushi-Web. Eleven papers fitting the outcomes for this CQ and enabling meta-analysis were extracted.

1) Onset of cardiovascular diseases (composite endpoints consisted of cardiac events and stroke) or its death

Seven papers corresponding to this outcome were identified [129, 157, 286,287,288,289,290]. Meta-analysis of these papers revealed a significant risk for onset of cardiovascular diseases in the white coat hypertension group compared with normotension group (relative risk [RR] 1.33, 95% CI 1.10–1.62, P=0.003). Open issues, such as insufficient adjustment of confounding factors and small sample size, were identified. The greatest difficulty lay in the difference of definition for white coat hypertension and “normotension” among individual studies. However, also when meta-analysis was confined to 5 papers in which white coat hypertension and “normotesion” had been classified in accordance with the definition given in JSH2014 [84, 157, 286,287,288], the white coat hypertension had a significantly higher risk for onset of cardiovascular diseases than normotension group (RR 1.28, 95% CI 1.06–1.53).

2) Onset of stroke events or its death

Seven papers related to this outcome were extracted. Excluding papers which had used redundant databases, two papers were finally adopted for meta-analysis [157, 286]. The analysis revealed a tendency for higher risk for onset of or death from stroke in the white coat hypertension group than normotesion group, although this difference was not statistically significant (RR 1.44, 95% CI 0.95–2.18, P=0.09).

3) Onset of cardiac events or its death

The two papers identical to those adopted for the outcome “onset of cardiac events or its death” were subjected to meta-analysis of this outcome [157, 286]. The risk for onset of or death from cardiac disease in the white coat hypertension group was comparable to that in normotension group (RR 1.10, 95% CI 0.81–1.50). The risk between the two groups was not statistically significant even when a paper involving hypertensive patients receiving treatment and not adjusted as to the fact of ongoing treatment was included in the analysis [291].

4) All-cause mortality

Five papers pertaining to this outcome were extracted [157, 286, 288,289,290]. The risk for total death in the white coat hypertension group was comparable to that in the normotension group (RR 1.15, 95% CI 0.93–1.43). Of the extracted papers, only one demonstrated that white coat hypertension was a risk for total death compared with non-hypertensive condition [289]. In this paper, however, white coat hypertension was defined as blood pressure <140/90 mmHg when measured by a nurse and <160/95 mmHg when measured by a physician.

5) Progression to sustained hypertension

Three studies reporting this outcome were identified [292,293,294]. All three of these studies reported a higher risk for progression to sustained hypertension in the white coat hypertension group than in normotension group, and a similar result was obtained from meta-analysis (RR 2.85, 95% CI 2.32–3.49).

Conclusions

This SR revealed that among antihypertensive drug-naïve individuals, the risk for progression to sustained hypertension was significantly higher in the white coat hypertension group than in normotension group. Regarding the onset of events, the risk for onset of and death from cardiovascular diseases was significantly higher in the white coat hypertension group than in normotension group, whereas the risk for total death and that for onset of or death from cardiac disease were statistically comparable between the two groups. The risk for onset of and death from stroke tended to be higher in the white coat hypertension group than in normotension group, but this difference was not significant. The incidence of stroke and its contribution of blood pressure is greater in Japanese people than in western people. However, it remains unknown whether the white coat hypertension itself has a risk for events or the risk for events is high as a result of progression of white coat hypertension to sustained hypertension. Therefore, for Japanese patients with white coat hypertension, careful follow-up may be necessary, thereby taking into account not only occurrence of events but also the high probability of progression to sustained hypertension.

During this SR, we adopted both ABPM and home blood pressure as out-of-office blood pressure data for diagnosis of white coat hypertension, but the papers adopted for the SR almost evaluated out-of-office blood pressure using the ABPM data. However, there is a report (although a report of a single cohort study) demonstrating that the risk for stroke differs between “complete white coat hypertension” (both home blood pressure and ABPM are normotension) and “partial white coat hypertension” (only one of them is normonetsion) [156], suggesting the need of paying attention also to the difference in out-of-office blood pressure.

This SR involves the following limitations: (1) the definition of white coat hypertension and/or outcome differed among studies;