Journal of Human Hypertension (2009) 23, 188–195 & 2009 Macmillan Publishers Limited All rights reserved 0950-9240/09 $32.00 Rationale and design of the KYOTOHEART study: effects of valsartan onmorbidity and mortality in uncontrolledhypertensive patients with high risk ofcardiovascular events T Sawada1, T Takahashi1, H Yamada1, B Dahlo¨f2 and H Matsubara1, for the KYOTO HEART Study Group1Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kyoto, Japan and2Department of Medicine, Sahlgrenska University Hospital/O¨stra, Go¨teborg, Sweden It remains to be determined whether the evidence in treatment with valsartan or conventional non-angioten- Western countries for blockade of the renin–angiotensin sin receptor blocker therapies, and the follow-up System in cardiovascular diseases could be directly period will be at least 3 years. The primary end point is applied to East Asian races including the Japanese a composite of defined cardio- or cerebro-vascular population as a long-term strategy. The KYOTO HEART events. Secondary end points include all causes of Study (KHS) is designed to investigate the add-on effect mortality, worsening of cardiac function, new onset or of valsartan versus conventional anti-hypertensive worsening of arrhythmias or diabetes mellitus. The KHS treatment on cardiovascular morbidity and mortality in will provide new evidence for the management of blood Japanese hypertensive patients with uncontrolled blood pressure in hypertensive patients with high risk.
pressure and with high cardiovascular risk. Over 3000 Journal of Human Hypertension (2009) 23, 188–195; high-risk Japanese patients with uncontrolled hyperten- doi:10.1038/jhh.2008.116; published online 18 September sion were randomised to receive either additional Keywords: metabolic syndrome; high risk; angiotensin receptor blockers; cardiovascular mortality and morbidity;valsartan arrhythmias and sudden cardiac death. The eventrates of cardiovascular disease in Japan differ from Hypertension is the most prevalent cardiovascular those in Europe and the United States. Mortality disease in the world and a major public health from CAD in Japan is one-third of that in the United issue.1 Cardiovascular disease is the leading cause of States, and mortality from cerebrovascular disease mortality worldwide2 and is expected to increase in Japan is B1.5 times higher than that in the United with the general ageing of the world’s population.
States.3 Hypertension is the most common cause of The goal of anti-hypertensive therapy is to reduce CAD and heart failure in Japan, and cerebrovascular the incidence of blood pressure-related morbid disease is even more prevalent in the Japanese events and cardiovascular mortality.
population than in Western societies.4 The percen- The heart is an important target organ of hyper- tage of cerebral bleeding is two or three times greater tension. Continuous high blood pressure is asso- than in Caucasian people in Europe and in the United States, and cerebral infarction is mostly increases the burden of coronary artery disease caused by lacunar type ischaemic stroke owing to (CAD). These forms of damage may result in hypertensive small vessel disease.5 The incidence of athero-thrombotic infarction or cardio-embolic in-farction is currently increasing in Japan, and the Correspondence: Dr T Sawada, Department of Cardiovascular dominant pathogenetic factor for stroke is changing Medicine, Kyoto Prefectural University School of Medicine, from small arterial disease to large arterial disease in Kajiicho 465, Kamigyoku, Kyoto 602-8566, Japan.
Japanese hypertensive patients. These differences may be partly explained by differences in the Received 4 June 2008; revised 1 August 2008; accepted 18 August2008; published online 18 September 2008 lifestyle of Japanese and Western populations, which are reflected in body mass index (mean BMI: pressure control, on major cardiovascular events 23–25 and 28–30 kg/m2, respectively).6,7 Most of and in particular the incidences of stroke, heart mortality–morbidity trials have been carried out in failure and coronary artery events. In contrast, the Western country, in which none or only a minority Candesartan Antihypertensive Survival Evaluation of East Asian patients were included. Owing to the in Japan (CASE-J) anti-hypertensive study reported paucity of large-scale trials in East Asian people, that candesartan-based and amlodipine-based regi- it remains to be determined whether the results from mens produced no statistical differences between similar clinical trials in Western societies are therapies on stroke or cardiovascular events in high- internationally applicable to East Asian races or risk Japanese hypertensive patients.17 The KYOTO the Japanese population, or whether genetic back- HEART Study (KHS) will be important to solve this ground can cause different pharmacokinetic and pharmacodynamic responses to the same drug.
A new guideline on metabolic syndrome has The renin–angiotensin system (RAS) has a major been introduced very recently in Japan. When the physiological function in the homoeostasis of patients have hypertension, the definition of meta- blood pressure, electrolytes and fluid balance, and bolic syndrome is made from abdominal obesity circulatory blood volume.8 However, chronic activa- plus either dyslipidemia or glucose intolerance, or tion of RAS contributes to the development of both. Nevertheless, it remains to be determined hypertension or cardiovascular target organ damage, how ARBs affect cardiovascular morbid events and ultimately leading to the manifestation of cardio- mortality in hypertensive patients with metabolic vascular disease.9 Numerous trials have investigated syndrome. The KHS was also designed to examine the benefits of angiotensin-converting enzyme whether valsartan added to conventional anti- (ACE) inhibitors; the Heart Outcomes Prevention hypertensive treatment influences the cardiovascu- Evaluation Study reported that ACE inhibitors lar events in the hypertensive patients with the significantly reduced the rates of death, myocardial metabolic syndrome as well as how it improves the infarction and stroke in high-risk patients.10 The morbidity and mortality in other high-risk Japanese beneficial effect observed was probably in some part patients with uncontrolled hypertension.
independent of ramipril-mediated blood pressurelowering actions, and the direct participation ofRAS in cardiovascular events was strongly sug- gested. Another important study investigating the benefit of RAS-blockade in hypertension, in this The KHS is a multi-centre (31 hospitals), Prospec- case with an angiotensin receptor blocker (ARB), tive, Randomised, Open-labeled, Blinded Endpoints was the Losartan Intervention For Endpoint reduc- (PROBE),18 two-arm parallel treatment group com- tion in hypertension study, where losartan-based parison with a response-dependent dose titration anti-hypertensive therapy prevented more cardio- vascular morbidity and death, and in particularstroke, than an atenolol-based regimen despitesimilar blood pressure control.11 The anti-inflam- matory properties of ARBs have been reported in The objective of KHS is to assess the add-on effect of hypertensive patients,12,13 which may contribute to valsartan, an ARB, on top of conventional anti- the beneficial action of ARBs beside the anti- hypertensive treatment in uncontrolled hyperten- hypertensive effects. Very recently, it was shown sive patients with cardiovascular disease or at least that the ARB telmisartan is equivalent to ramipril in one additional risk factor indicating high-risk with preventing vascular events in patients with cardio- respect to cardiovascular morbidity and mortality, vascular diseases or high-risk diabetes.14 It is beyond compared with titration by non-ARB therapy.
the scope of this introduction to review all thestudies showing beneficial effects on cardiovascularoutcomes from blocking the RAS, in particular with ARBs, in various stages of the cardiovascular The eligible population consists of Japanese hyper- continuum.15 It is important though to point out tensive patients (men and women, X20 years old) that all these studies with a few exceptions have whose blood pressures have been uncontrolled for included at maximum a few percentage of Asian at least 4 weeks. Uncontrolled hypertension was patients in general and very few Japanese patients in defined as a mean sitting systolic blood pressure X140 mm Hg, and/or a mean sitting diastolic blood The Jikei Heart Study was designed to examine pressure X90 mm Hg in the outpatient clinic.
whether the addition of valsartan to conventional Skilled physicians took standard blood pressure cardiovascular treatment is effective in Japanese measurements with patients at rest (5–10 min) in the hypertensive patients with cardiovascular diseases sitting position with a validated mercury sphygmo- manometer in accordance with the guidelines The JIKEI Heart study demonstrated a preventive proposed by the Japanese Society of Hypertension.19 action of valsartan, added to excellent blood The mean of X3 consecutive blood pressure Journal of Human Hypertension
measurements was calculated and recorded. The (11) patients who were unwilling or unable to timing of blood pressure measurement was not constant in relation to patients’ intake of medica-tion. When patients were already treated for hyper-tension, anti-hypertensive drugs other than ARB were administered for the first 4 weeks and then if The protocol was approved by the Ethics Committee still uncontrolled (X140/90), they were considered at each participating centre. At the first clinic visit, as candidates for the study. Uncontrolled hyperten- the trial objectives, study design, and the risks and sive patients treated with ACE inhibitors before benefits of study participation were explained care- randomisation could also participate in this study.
fully to each patient, and subsequently written and Uncontrolled hypertensive patients who had been signed informed consent was obtained.
treated with ARB, but were not treated with ARBwithin 4 weeks before randomisation, could parti-cipate in this study.
When these uncontrolled hypertensive patients The titration schedule of the study is shown in had at least one of CAD signs (angina pectoris Figure 1. After confirming the eligibility for patient’s or a history of myocardial infarction 46 months enrolment into this study, patients were randomised before the screening), cerebrovascular diseases in accordance with the minimisation method,21 (a history of stroke or transient ischaemic attack which consisted of eight factors (age, gender, 46 months before the screening), or peripheral dyslipidemia, diabetes mellitus, smoking, obesity, arterial occlusive disease (previous limb bypass history of CAD and/or cerebrovascular disease and surgery or angioplasty, limb ulcer/gangrene or history of congestive heart failure), either to the intermittent claudication with ankle/brachial blood valsartan add-on group or to the conventional add- pressure index o0.8), and/or one or more of the on treatment group. For the valsartan add-on group, cardiovascular risk factors mentioned below, they valsartan 80 mg once daily was administered in the were randomised into the trial. The cardiovascular morning to the patient as an initial dose and flexibly risk factors included type II diabetes mellitus adjusted to a dose of 40–80 mg per day as needed to (defined as fasting plasma glucose X126 mg per control blood pressure. The dose of valsartan was 100 ml, causal blood glucose X200 mg per 100 ml, doubled after 4 weeks if the initial dose did not glycosylated hemoglobin (HbA1c) X6.5%, and/or achieve the target blood pressure of less than plasma glucose 2 h after 75 g glucose load X200 mg 140 mm Hg for systolic blood pressure and 90 mm Hg per 100 ml or current treatment with anti-diabetic agents), current smoking, lipid metabolism abnorm- patients with diabetes or renal disease, target blood ality (defined as low-density lipoprotein cholesterol pressure was set to less than 130 mm Hg for systolic X140 mg per 100 ml, and/or triglyceride X150 mg blood pressure and 80 mm Hg for diastolic blood per 100 ml or current treatment with anti-dyslipide- pressure.) After 8 weeks an additional administra- mia agents), obesity (defined as body mass index tion of other anti-hypertensive drugs with flexible dosing regimen other than ARB and ACE inhibitors defined by the electrocardiogram (ECG), centrally was allowed if necessary. In contrast, for the con- ventional treatment group, the conventional treat-ment with anti-hypertensive drugs other than ARBand ACE inhibitors were provided for the patients to reach the common goal of blood pressure control.
The exclusion criteria were set as follows: (1) Periodical follow-up was implemented every 6 malignant or secondary hypertension; (2) pregnant months after setting the sustainable dose.
women or women of childbearing potential; (3) Randomisation was automatically executed by the history of worsening heart failure, unstable angina, host computer and all the data recorded at each myocardial infarction, percutaneous coronary inter- centre was managed centrally at the independent vention (PCI) or coronary artery bypass grafting data centre in Kobe, Japan. Randomisation and (CABG) within the preceding 6 months; (4) arrhyth- data management were managed by the wide area mia needing to be treated or accompanied with symptoms including second or third degree atrio-ventricular block; (5) renal impairment (serumcreatinine level 43.0 mg per 100 ml); (6) hepatic impairment (hepatic failure, cirrhosis, etc.); (7) Background data such as sex, age, height, body history of cerebral infarction, cerebral haemorrhage weight, signs and symptoms, and risk factors were or transient ischaemic attack within the past 6 recorded during the enrolment period. The follow- months; (8) allergy of potential clinical concern; ing general clinical laboratory tests were carried out (9) electrolyte abnormality (remarkable change in at baseline and every 6 months. (1) Urinalysis sodium or potassium); (10) history of malignant (proteinuria and urinary occult blood); (2) blood tumour including leukaemia and lymphoma; and chemistry tests (serum creatinine, Na, K, triglyceride, Journal of Human Hypertension
Figure 1 Titration schedule for the KYOTO HEART Study.
low-density lipoprotein cholesterol, high-density infarction (ECG-change and biomarkers for myo- lipoprotein cholesterol, fasting blood sugar, HbA1C, cardial infarction), new occurrence or exacerbation uric acid, blood urea nitrogen, and white blood cell of heart failure (clinical symptoms including dys- count; (3) ECG central reading in a core laboratory in pnoea, shortness of breath and peripheral oedema, Kyoto Prefectural University Hospital; (4) echocar- diogram (examined every year, left ventricular echocardiography according to the guidelines of diastolic dimension, left ventricular systolic dimen- the American Heart Association and American sion, ejection fraction, functional shortening, inter- College of Cardiology (AHA/ACC), new occurrence ventricular septum, posterior wall, isovolumic or exacerbation of angina pectoris (ECG changes relaxation time, the ratio of early ventricular filling (E) to atrial contraction (A) velocity, deceleration guidelines), dissecting aneurysm of the aorta (diag- time, and left ventricular weight;22 and (5) chest X- nosed by imaging technique), lower limb arterial ray (cardiothoracic ratio). In addition, the brain obstruction (ankle brachial pressure index and natriuretic peptide (BNP) and aldosterone levels imaging technique), emergency thrombosis, transi- were measured in patients related to the progression tion to dialysis or doubling of serum creatinine of cardiovascular diseases every year. The oral levels. The first of these to occur in a specific patient glucose tolerance test (OGTT) was implemented in was classified as an event and to be counted as the patients showing the impaired fasting glucose primary end point. The following were set as the stage (110p fasting glucose level o126 mg per secondary end points: all causes of mortality, 100 ml), and the patients who had impaired glucose worsening of cardiac function (clinical symptoms tolerance (IGT: 140p glucose level 2 h after OGTT together with left ventricular dysfunction by echo- o200) was checked by OGTT test every year.
cardiography), new occurrence or exacerbation of Additional Holter ECG measurements were imple- arrhythmias (diagnosed by Holter ECG), new occur- mented every year in patients who were already rence or exacerbation of diabetes mellitus or diagnosed by Holter ECG to have paroxysmal atrial impaired glucose tolerance (according to the guide- lines of American Diabetes Association), or uncon-trolled blood pressure. Any component of compositeprimary end point for which a patient could be counted once in each category was treated as a The primary end point was a composite of cardio- secondary end point. Data from any cause was also and cerebro-vascular events. Components of the designated a second end point. The end points end point include the following: stroke (diagnosed reported will be reviewed and settled by the by imaging technique), new or recurrent transient independent Endpoint Committee. The study was ischaemic attack (neurological deficit persisting for registered at http://clinicaltrials.gov/ with the iden- less than 24 h), new or recurrent acute myocardial Journal of Human Hypertension
sound echocardiogram, and the efficacy of valsartan On the basis of results of large end point studies with/without diabetes and with/without metabolic patients, the number of patients to be enroled wascalculated as 3000 (1500 in each group) to validatethe hypothesis under the assumption that the valsartan add-on group achieves a 20% risk reduc- Recruitment began in January 2004 and follow-up is tion compared with the conventional treatment calculated to go on until 2010 or to a time point group and gives 80% statistical power for detecting when the pre-determined number of patients with a clinically significant between-group differences primary end point has been reached, unless there is with a two tailed 5% statistical significant level.
a decision for discontinuation of this trial ratified by Very limited epidemiological data about cardio- the Steering Committee by recommendation from vascular risk profiles in Japan are available.
the Data and Safety Monitoring Board.
Information about the prognosis of patients treatedby specialist doctors at specialised hospitals is particularly scarce. Although the cardiovascularevent rate in the Japanese population is low, the Earlier large-scaled clinical trials were mainly hospitals participating in this study undertake the targeted for white and black races, and only a few tertiary care of cardiovascular disease; therefore, studies reported the morbidity and mortality of anti- they treat more severely ill patients than those seen hypertensive treatment for East Asian races. Japan is in other hospitals. On the basis of the prevalence of one among the countries where people live the cardiovascular disease in the Japanese cohort,4 longest in the world, and the average life span is 79 it was estimated that the 3-year event rate for years in men and 85.8 years in women in 2007, and cardiac mortality and morbidity for patients with these values are increasing. The incidence of stroke was relatively higher than that of CAD in Japanese approximately 12%. The findings of a retrospective hypertensive patients. The percentage of cerebral investigation of few patients under treatment at the bleeding was two or three times greater than in participating sites were almost identical to this Europe and the United States, and cerebral infarc- estimate. However, as this study was end point- tion was mostly caused by lacunar-type ischaemic driven, the duration of the study was determined by strokes owing to hypertensive small vessel disease.5 the accumulated number of patients with a primary Differences in genetic inheritance among the races, life-style, public health insurance and free Analyses will also be made by an independent access system to hospitals might contribute to the Statistical Analysis Organization based on the excellent longevity in Japan. However, the ratio of intention-to-treat approach and time to first event the elderly will reach one-fourth of the population in accordance with the principle of harmonised in 2020, and the fatty food intake, obesity and high tripartite guideline ‘Statistical Principles for Clin- rate of smoking have been increasing the incidence ical Trials’ developed by International Conference of high-risk hypertension. Although a new guideline on Harmonisation (ICH). All randomised patients on metabolic syndrome has been introduced very were included in the analysis. Patient characteris- recently, few studies have reported whether ARBs tics, corresponding to data characteristics, were checked for uniform distribution among the various mortality in hypertensive patients with metabolic groups. Cox’s proportional hazard regression analy- syndrome. When patients have hypertension, the sis was used for comparing the event rate between definition of metabolic syndrome is made when the patients also have abdominal obesity plus eitherdyslipidemia or glucose intolerance, or both. TheKHS is a clinical trial designed from PROBE and wide area network, and is first designed to evaluate Clinical trials evaluate treatment effects predefined whether the addition of valsartan to conventional as primary and secondary end points in the study anti-hypertensive treatment to improve blood pres- design. However, post-hoc subgroup analyses are sure control influences the cardiovascular outcome frequently added for the reason of the study out- in Japanese high-risk hypertensive patients with or without metabolic syndrome. This study will also Recently, guidelines for reporting subgroup analysis have the power to address the additional benefits of have been reported.23 In the KHS, the subgroup valsartan, which are not related to blood pressure analysis committee also indicated the detailed lowering effects. The KHS is expected to provide planning in the primary end point report; the sub- benefits beyond the anti-hypertensive effects of analyses were deliberately planned for cardiovas- ARBs for hypertensive patients in East Asia with cular events compared with the number of risk metabolic syndrome or high-risk. The KHS will factors, the achievement rate of blood pressure furthermore settle the issue whether the discrepancy control, systolic/diastolic parameters using ultra- between the outcomes of the JIKEI Heart and CASE-J Journal of Human Hypertension
studies is related to molecule specific differences 11 Dahlo¨f B, Devereux RB, Kjeldsen SE, Julius S, between ARBs or related to different study designs.
Beevers G, de Faire U et al. Cardiovascular morbidity The study is ongoing and the first patient was and mortality in the Losartan Intervention For End- randomised January 2004. There are currently 3042 point reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359:995–1003.
12 Vyssoulis GP, Karpanou EA, Kyvelou SM, Adamopoulos DN, Antonakoudis GC, Deligeorgis AD et al. Beneficial effect of angiotensin II type 1 receptor blocker anti-hypertensive treatment on arterial stiffness: the role of Role of the funding source: The study was funded by smoking. J Clin Hypertens 2008; 10: 201–207.
Kyoto Prefectural University School of Medicine, 13 Miura Y, Yamamoto N, Tsunekawa S, Taguchi S, with an unrestricted grant from Novartis Pharma Eguchi Y, Ozaki N et al. Replacement of valsartan KK, Japan. The sponsor had no role in study design, data collection, data analysis, data interpretation or patients with type 2 diabetes: metabolic and anti- writing of the report. The executive committee will atherogenic consequences. Diabetes Care 2005; 28: have full access to all the data at the end of the 14 The ONTARGET Investigators. Telmisartan, ramipril study, and has final responsibility for the decision to or both in patients at high risk for vascular events.
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Journal of Human Hypertension
Medicine, Kyoto Prefectural University of Medi- Matsubara H supervises the KYOTO HEART Study cine is the study chairman. B Dahlo¨f, Department (KHS) as the chief investigator, and several staff of Medicine, Sahlgrenska University Hospital/ have been appointed by the chief investigator ¨ stra, Go¨teborg, Sweden, is the honorary supervisor to support the management of the study as repre- of the logistics, and conducts the reporting of the sentatives of the KHS group secretariat. The KHS is administered by the Steering Committee, whichis composed of academic leaders appointed bythe chief investigator. The role of the Steering Committee is to supervise the overall execution of Kyoto Prefectural University of Medicine—T Sawa- da (Main Steering Committee Member), T Shiraya- In the KHS, the Data and Safety Monitoring Board ma, Y Mori, M Okigaki, A Matsumuro, H Yamada, (DSMB), the Endpoint Committee and the Safety Y Tsutsumi, M Matoba, T Takahashi, H Shiraishi, Committee are organised independently from the K Ikeda, T Nakamura and T Yamada; National study group and each organisation consists of three Hospital Organization Maizuru Medical Center—S external experts. The DSMB members are blinded to Hirano; National Hospital Organization Shiga Hos- the allocation of drug treatment groups, meet pital—A Azuma; Kyoto Prefectural Yosanoumi periodically, have a stopping guideline for terminat- Hospital—S Kimura; Akashi Municipal Hospital— ing the trial prematurely and make recommenda- S Sasaki; Ayabe City Hospital—K Shiga; Omihachi- tions to the Steering Committee about the ethical man Community Medical Center—K Maki; Kyoto aspects of trial continuation by evaluating each case City Hospital—K Furukawa; Kumihama Hospital—S of possible adverse events. This study will finish Okuda; Nantan General Hospital—Y Kajita; Fuku- when the number of primary endpoints reaches the chiyama City Hospital—M Nishio; Kyoto First Red hypothesis after the end of enrolment. The DSMB Cross Hospital—Y Kohno; Kyoto Second Red Cross will review the effectiveness and safety of the study Hospital—M Kitamura; Maizuru Red Cross Hospi- at regular intervals. This board executes three tal—K Nishida; Saiseikai Kyoto Hospital—Y Yama- interim analyses, with the O’Brien–Fleming meth- od. Yagi K, who is a chief biostatistician at the Louis Uji Hospital—S Sawada; Gakkentoshi Hospital—R Pasteur Center for Medical Research, Kyoto, Japan, Sakai; Kameoka Municipal Hospital—T Kuriyama; appointed the DSMB members consisting of two Kyoto Kizugawa Hospital—H Miyanaga; Kyoto physicians who are independent of the study. The Interdisciplinary Institute Hospital of Community Endpoint Committee and the Safety Committee are Medicine—T Kitani; Social Insurance Kyoto Hospi- blinded to the allocation of drug treatment groups tal—H Haruyama; Shakaihoken Kobe Central Hos- and the results of the study, and are managed pital—A Nishio; Kouseikai Takeda Hospital—N separately from investigators and biostatisticians.
Kinoshita; Aijyukai Dohjin Hospital—S Inagaki; The Safety Committee has the role to oversee the Matsushita Memorial Hospital—H Sugihara; Aisei- welfare of patients enroled in the trial from the kai Yamashina Hospital—M Katamura; Midorigaoka ethical point of view. In addition, the Substudy Hospital—T Hachiya; Asahi University Murakami committee is organised according to the agreement Memorial Hospital—S Kato; Meiji University of of the Steering Committee. Investigators are blinded Oriental Medicine Hospital—K Ohtsuki.
to the allocation of drug treatment groups and theresults of the study until the discontinuation reportfrom the DSMB or the final report of the study data J Higaki, Department of Integrated Medicine and Data collection and management, and allocation Informatics, Ehime University Graduate School of for drug treatment groups are conducted by the Medicine, Shitsukawa, Japan; S Kim-Mitsuyama, automatic electronic data-capturing system using Department of Pharmacology and Molecular Ther- the wide area network with a secure server managed apeutics, Kumamoto University Graduate School of by the data centre in Kobe, which is independent of Medical Sciences, Kumamoto, Japan; T Ichiki, the study implementation group. The statistical Department of Cardiovascular Medicine, Kyushu analysis of the data is performed by the biostatisti- University Graduate School of Medical Sciences, cians at the Louis Pasteur Center for Medical Research, Kyoto, Japan, who are blinded to theallocation of drug treatment groups and indepen- dent of the study implementation group and the M Kitakaze, Department of Cardiovascular Medi- funding source. The Data monitoring team periodi- cine, National Cardiovascular Center, Osaka, Japan; cally visits randomly selected investigators to check T Sugiura, Department of Clinical Laboratory the suitability between the hospital data and the Medicine, Kochi Medical School, Kochi University, input data presented by internet network system.
Kochi, Japan; H Rakugi, Department of Geriatric Journal of Human Hypertension
Medicine, Osaka University Graduate School of K Yagi, Louis Pasteur Center for Medical Research,Kyoto, Japan; Nobuo Shirahashi, Department ofPreventive Medicine and Environmental Health, Osaka City University Medical School, Osaka, K Yagi, Louis Pasteur Center for Medical Research, Kyoto, Japan; K Kanda, Department of Cardiovascu-lar surgery, Division of Surgery, Graduate School ofMedical Science, Kyoto Prefectural University ofMedicine, Kyoto, Japan; C Sakakura, Department of Digestive Surgery, Division of Surgery, Graduate M Miki, Kyoto Prefectural University School of School of Medical Science, Kyoto Prefectural Uni- Medicine, Kyoto, Japan; S Toyoda, Kyoto Prefectural University School of Medicine, Kyoto, Japan.
Journal of Human Hypertension

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SWINE FLU AND PREGNANCY How to protect yourself and your baby This leaflet gives information about: • the swine flu vaccination that you can have during pregnancy to help protect you and your baby • precautions you can take to reduce your risk of infection • treatments that are available if you do become ill. Flu. Protect yourself and others. SWINE FLU AND P

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