Strategy of blood pressure intervention in the elderly hypertensive patients (STEP): Rational, design, and baseline characteristics for the main trial

Journal Pre-proof Strategy of blood pressure intervention in the elderly hypertensive patients (STEP): Rational, design, and baseline characteristics for the main trial

Shuyuan Zhang, Shouling Wu, Jie Ren, Xiaoping Chen, Xinjun Zhang, Yingqing Feng, Xiaoyang Zhou, Bingpo Zhu, Jinfeng Yang, Gang Tian, Yinong Jiang, Zihong Guo, Yuming Li, TzungDau Wang, Kazuomi Kario, Weili Zhang, Jun Cai, On behalf of the STEP Study Group PII:

S1551-7144(19)30629-9

DOI:

https://doi.org/10.1016/j.cct.2019.105913

Reference:

CONCLI 105913

To appear in:

Contemporary Clinical Trials

Received date:

15 July 2019

Revised date:

30 November 2019

Accepted date:

10 December 2019

Please cite this article as: S. Zhang, S. Wu, J. Ren, et al., Strategy of blood pressure intervention in the elderly hypertensive patients (STEP): Rational, design, and baseline characteristics for the main trial, Contemporary Clinical Trials(2019), https://doi.org/ 10.1016/j.cct.2019.105913

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© 2019 Published by Elsevier.

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Full title: Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients

(STEP): Rational, Design, and Baseline Characteristics for the Main Trial Short title: Blood pressure control of the elderly people Shuyuan Zhang1 , Ph.D.; Shouling Wu2 , M.D.; Jie Ren3 , M.D.; Xiaoping Chen4 , M.D.; Xinjun Zhang4 , M.D.; Yingqing Feng5 , M.D.; Xiaoyang Zhou6 , M.D.; Bingpo Zhu7 , M.D.; Jinfeng Yang8 , M.D.; Gang Tian9 , M.D.; Yinong Jiang10 , M.D.; Zihong Guo11 , M.D.; Yuming Li12 ,

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M.D.; Tzung-Dau Wang13 , M.D., Ph.D.; Kazuomi Kario14 , M.D., Ph.D.; Weili Zhang1* , M.D.,

State Key Laboratory of Cardiovascular Disease, Hypertension Center, FuWai Hospital,

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1

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Ph.D.; Jun Cai1* , M.D., Ph.D.; On behalf of the STEP Study Group 15

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National Center for Cardiovascular Diseases, Peking Union Medical College & Chinese Academy of Medical Sciences, Beilishi Road 167, Xicheng District, Beijing, 100037, China Kailuan General Hospital, Tangshan, Hebei, 063000, China

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Shanxi Academy of Medical Sciences, Shanxi Dayi Hospital, Taiyuan, Shanxi, 030032,

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China

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West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China

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Guangdong Cardiovascular Institute, Guangzhou, Guangdong, 510080, China

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Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China

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Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure; App, application; CVD, cardiovascular disease; SD, standard difference; MMSE, Mini-Mental State Examination; ECG, electrocardiogram; baPWV, brachial ankle pulse wave velocity; ABI, ankle brachial index; AAMI, American Association for the Advancement of Medical Instrumentation; ARBs, angiotensin receptor blockers; CCBs, calcium channel blockers; β-blockers, beta-adrenergic blockers; ESH-IP revision 2010, European Society of Hypertension International Protocol revision 2010; MI, myocardial infraction; ESRD, end stage renal disease; GCP, Good Clinical Practice; eGFR, estimated glomerular filtration rate; ASCVD, atherosclerotic cardiovascular disease; CONSORT, consolidated standards of reporting trials; TIA, transient ischemic attack; HCM, hypertrophic cardiomyopathy; LV, left ventricular; PCI, percutaneous coronary

intervention; CABG, coronary artery bypass grafting; NYHA, New York Heart Association; ALT, alanine aminotransferase; HbA1, glycated hemoglobin.

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Kang Ya Hospital, Yiyang, Hunan, 413000, China

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The People's Hospital of Ji Xian District, Tianjin, Tianjin, 301900, China

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First Affiliated Hospital, Xian Jiaotong University, Xi'an, Shanxi, 710061, China The 1st Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, China

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Fuwai Yunnan Cardiovascular Hospital, Kunming, Yunnan, 650106, China

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Pingjin Hospital, Logistics University of PAPF, Tianjin, Tianjin, 300162, China

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College of Medicine, National Taiwan University, Taipei, Tanwan, 10051, China

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Jichi Medical University School of Medicine (JMU), Shimotsuke, Tochigi, 329-0498, Japan

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A complete list of the names and affiliations of members of the STEP Study Group appears

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in the Supplemental materials.

* Correspondence to: Weili Zhang, M.D., Ph.D., E-mail: [email protected]; or,

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Jun Cai, M.D., Ph.D., E-mail: [email protected]; Tel: 86-10-60866432, Fax:

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86-10-60866432; FuWai Hospital, National Center for Cardiovascular Diseases, Peking

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Union Medical College & Chinese Academy of Medical Sciences, Beilishi Road 167, Xicheng District, Beijing, 100037, China.

Manuscript: 4,122 words (including the introduction, methods, discussion and conclusions), 250 words (abstract), 480 words (introduction).

Abstract

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The optimal systolic blood pressure (SBP) treatment target in elderly people is full of challenge, and non-adherence is one major cause of uncontrolled BP. The Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial is a multi-center, randomized controlled trial that aims to examine whether an intensive treatment (110SBP<130 mmHg) will provide more benefits in lowering cardiovascular events than a

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mild treatment (130SBP<150 mmHg) among people aged 60-80 years. From January 10,

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2017 to December 31, 2017, 8,511 patients with primary hypertension were recruited at 42

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clinical centers throughout China and randomly assigned to the intensive or standard

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treatment in 1:1 ratio, in which clinical sites are considered as a stratification factor in

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randomization. Participants will be followed for an average of four years. All participants used the same validated home BP device and all centers used the same validated office BP

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device which can automatically upload the readings to a data center. The hospitals were

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randomly classified as the smartphone-based App center or usual care center in 1:1 ratio for

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the secondary purpose to study the effect of App management on BP control. In this trial, mean age of participants was 66.24.8 years, 24.1% were in the range of 70-80 years, and 65% were at high-risk with the 10-year Framingham risk score 15%. In conclusion, STEP will provide evidence not only to address appropriate target of BP control among hypertensive patients aged 60-80 years, but also to assess an effective model of App management for hypertension. Trial Registration number: ClinicalTrials. gov. Unique identifier: NCT03015311. Key words: Randomized clinical trial; essential hypertension; systolic blood pressure; major adverse cardiovascular events; mobile applications

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1. Introduction Hypertension is common in worldwide and China, but it remains inadequately controlled [1]. Several large-scale epidemiological surveys in China have showed a high prevalence of hypertension ranging from 23.2% to 44.7% whereas the low control rate from 5.6% to 15% [2-5]. China is one of the most populous countries and people over 60 years of age account

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for 17.3% of the total population, estimated to be 2.4 billion in 2017 (www.stats.gov.cn), of

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whom more than 50% have hypertension [6]. Obviously, the health burden of hypertension

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and cardiovascular diseases (CVD) is an urging issue along with population aging.

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The optimal systolic blood pressure (SBP) treatment target in the elderly hypertensive

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patients is full of challenges because of a highly complex status such as comorbidity, poly-pharmacy, frailty and cognitive impairment [7], and current clinical guidelines still

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remain inconsistent [8-10]. For example, the European guideline recommended a SBP range

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of 130-139 mm Hg for the elderly (65 years), except those with a high-burden comorbidity

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and limited life expectancy [9], whereas the American College of Cardiology/American Heart Association suggested a SBP treatment goal of <130 mm Hg for the elderly patients [10]. Recent clinical trials are also inconsistent with intensive SBP control. The Systolic Blood Pressure Intervention Trial (SPRINT) showed cardiovascular benefits of a goal of SBP <120 mm Hg, even in elderly patients of 75 years, although accompanied with a little higher rate of adverse events including hypotension, acute kidney injury or failure [11,12]. For stroke risk, it has been reported to be 2.5 times higher in patients on 3+ antihypertensive drugs though SBP successfully reduced to <120 mm Hg [13]. The Systolic Hypertension in Europe (Syst-Eur) suggested that active treatment SBP <150 mm Hg can reduce the cardiovascular

Journal Pre-proof and cerebrovascular events in patients of 60 years [14]. However, the Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients (JATOS) showed no significant difference in outcomes between strict treatment (SBP<140 mm Hg) and mild treatment (140SBP<160 mm Hg) in patients of 65-85 years [15]. Recently, a comprehensive meta-analysis showed that treatment goal of SBP<130 mm Hg can significantly reduce the

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cardiovascular events and mortality, especially in high-risk patients [16]. In addition,

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treatment non-adherence is known as one major cause of uncontrolled BP and may represent a

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greater risk among elderly people [17]. Therefore, more evidence is needed to address the

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optimal SBP target for the elderly.

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Here, we conducted a prospective, multi-center, randomized controlled trial, Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP), to assess whether

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intensive treatment (a goal of 110SBP<130 mm Hg) will provide more benefits in lowering

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CVD risk than standard treatment (a goal of 130SBP<150 mm Hg) in Chinese population

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aged 60-80 years. The secondary purpose of STEP trial is to evaluate whether the smartphone-based blood pressure App management strategy would improve blood pressure control and reduce the CVD events during the follow-up.

2. Methods 2.1. Study design and sample size The STEP is designed to be a prospective, multi-center, randomized controlled trial (NCT03015311) and planned to follow up for 4 years. The diagram was shown in Figure 1. The primary purpose of the trial is to evaluate whether reducing SBP to a lower goal (a goal

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of 110SBP<130 mm Hg, intensive treatment) than currently recommended (a goal of 130SBP<150 mm Hg, standard treatment) will reduce cardiovascular disease events among elderly people aged 60-80 years. Furthermore, the secondary purpose is to examine the effects of the App management strategy on improving blood pressure control and reducing cardiovascular diseases.

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The STEP included a diverse patient population with essential hypertension and co-existing

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cardiovascular diseases, diabetic mellitus, chronic kidney disease, or an elevated estimated

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risk of atherosclerotic CVD based on age and other risk factors. In this trial, the primary CVD

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outcomes included first occurrence of myocardial infarction, first-onset stroke (ischemic or

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hemorrhagic), hospitalization for heart failure or unstable angina, coronary revascularization, atrial fibrillation, or death from cardiovascular causes. The STEP is planned to follow up for 4

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years and aims to have at least 90% power to detect a 20% relative risk reduction (the effect

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size of 0.8) in the incidence of composite CVD outcomes for participants receiving the

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intensive treatment. Considering that the incidence rate of primary CVD outcomes was about 2.5% per year among the elderly hypertensive patients aged 60 years in China [18], with a two-sided α level of 0.05 and a loss to follow-up rate of 0.5% per year, the total number of participants required will be 8,000 (4,000 in each treatment group in a 1:1 ratio) and the trial is expected to accrue at least 722 events for the primary outcomes. For the secondary purpose of comparing BP control between the App management group and the usual BP management group, this target sample size was estimated to detect an absolute mean difference in SBP of 5 mm Hg (Standard difference [SD], 22) (a clinically well-recognized reduction in the relative risk of cardiovascular events) [19] at 12 months from

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baseline, with 88% power and 0.05 level of significance. 2.2. Ethics and dissemination The STEP trial was approved by the Ethics Committee of FuWai Hospital and all collaborating clinic centers. All participants provided written informed consent. The study design followed requirements of the Prospective Randomized Open Blinded End-point

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(PROBE) study [20]. Findings will be disseminated in peer-reviewed publications in future

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and the data will be shared with participating hospitals to promote the clinical management of

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hypertension in China.

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2.3. Patients and public involvement

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Patients and public will not be involved in the development of the research question or in the design of the study. Patients will receive oral and written information about this trial, however,

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they will not be involved in the recruitment and conduct of the study. Besides, the burden of

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the intervention will also be assessed by patients themselves. After signing an informed

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consent by the participants, they will be assessed for eligibility and data collection will begin. 2.4. Patient population

The STEP trial screened and recruited the participants between January 10, 2017 and December 31, 2017. Enrolled participants with essential hypertension were men or women aged in range of 60-80 years at randomization, who consistently had a SBP of 140 to 190 mm Hg during the three screening visits or currently under anti-hypertension treatment. One major exclusion disease was stroke (ischemic or hemorrhagic stroke). The details of inclusion criteria and exclusion criteria for STEP were described in Table 1. A total of 42 clinical centers from 23 provinces/municipalities throughout China participated in the STEP study,

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and the geographical distribution of these hospitals was shown in the Supplemental eFigure 1. Each hospital has a local study group for hypertension control, and the name, location, and principal investigators were listed in the Supplemental eTable 1. Eligible participants were determined by a local investigator based on the inclusion and exclusion criteria. During screening, individuals who showed a significant risk for

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non-adherence to study medication or for completing study visits were also excluded from

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trial participation. Once eligible patients were enrolled, a baseline survey was conducted with

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the use of a standardized questionnaire, including weight, height, waist circumference,

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smoking status, alcohol intake, medical history, and current medications treatment. Smoking

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was defined as smoking at least 1 cigarette per day continuously for at least one year, and participants were categorized as never, former, current smokers on the basis of self-report

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smoking status. Participants were asked to report whether they consumed alcoholic beverages

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in the past 12 months and, if so, the beverage type (beer, wine, and liquor) and the amount and

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frequency of intake. Alcohol consumption was calculated in grams per day by multiplying the average frequency (times per day) by the usual intake amount of each beverage and the average ethanol content (15.0 g for 450 ml beer, 150 ml wine, or 50 ml for hard liquor) according to Chinese Dietary Guidelines Summary 2016 [21]. Heavy alcohol intake was defined when they consumed at least 100 ml of liquor (or 900 ml of beer, 300 ml of wine) per day in the past 12 months. Participants were classified into never, former, or current drinking. The 10-year cardiovascular disease risk was estimated on the basis of the Framingham risk score [22]. The status of frailty based on the Fried phenotype was identified by the presence of three

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or more of the following criteria: shrinking, weakness, poor endurance and energy, slowness, and low physical activity level, and the intermediate frailty status was identified by the presence of one or two criteria [23]. Cognitive dysfunction was evaluated by using the Mini-Mental State Examination (MMSE) [24], and anti-hypertensive medication adherence will be measured using a derived version of the Brief Medication Questionnaire [25]. A

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12-lead electrocardiogram (ECG) taken within the last 3 months was requested. The ankle

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brachial index (ABI) and brachial ankle pulse wave velocity (baPWV) were measured by

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using Omron BP-203RPE (Omron Healthcare, Kyoto, Japan) for assessing the artery

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status of left ventricular hypertrophy.

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atherosclerosis. The color Doppler ultrasonic cardiogram was conducted for assessing the

For blood pressure measurement, participants were required to rest for at least 5 min in a

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seated position before the initial blood pressure reading was obtained, and blood pressure was

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measured three times by trained clinic staffs. In the STEP, the same validated, professional

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office BP measurement device, the Omron HBP-1100U automatic blood pressure monitor [26] (Omron Healthcare, Kyoto, Japan) that meets the American Association for the Advancement of Medical Instrumentation (AAMI) accuracy standards, was used by all participating hospitals at the baseline survey and during the followed-up clinic visits. 2.5. Randomization Patient randomization was generated through a central computerized randomization program via a web-based interface managed by the Medical Research & Biometrics Center at FuWai Hospital, National Center for Cardiovascular Diseases. The random allocation sequence was generated by an independent statistician with the use of SAS 9.4 software (SAS Institute, Cary,

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NC, USA) and uploaded to the central computerized randomization center. Clinical sites at randomization are considered as a stratification factor. The main objective was to minimize the confounding by achieving the treatment and control groups similar in baseline characteristics, including age, gender, baseline BP, and conventional risk factors. If one patient completed the screening and was qualified for the inclusion criteria, a unique

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identification number and intervention arm were assigned by the central random system. In

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each clinic center, eligible patients were randomized in a 1:1 ratio into two targeted treatment

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groups: the intensive treatment group (a goal of 110SBP<130 mm Hg) and the standard

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treatment group (a goal of 130SBP<150 mm Hg). Study investigators and enrolled

all follow-up data were obtained.

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2.6. Blood pressure intervention

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participants were not blinded to group assignment. The data analysts remained blinded until

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Represented antihypertensive drugs were provided by the STEP trial to the patients at no cost,

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including angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs) and thiazide-type diuretics, all of which have robust evidence to reduce blood pressure and prevent cardiovascular events. For all participants, olmesartan medoxomil tablets (Nanjing Chia Tai Tianqing Pharmaceutical Co., Ltd, Nanjing, China) was the preferred ARBs at a daily dose of 20 mg (once daily), and amlodipine besylate tablet (China Resources Saike Pharmaceutical Co., Ltd, Beijing, China) as the preferred CCBs at a daily dose of 5-10 mg (once daily). Hydrochlorothiazide was not designed as the initial therapy. Other antihypertensive drugs such as beta-adrenergic blockers (β-blockers) may also be used when an investigator deems necessary and appropriate. At the randomization visit, all patients on

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previous antihypertensive drug therapy should be converted to STEP medications unless intolerance was reported or there was a compelling indication for other drugs. The investigators are allowed to prescribe an individualized antihypertensive regimen regarding which drugs to use at initiation and during the intensive treatment in order to achieve and maintain SBP targets. Medication to targeted BP is based on the office BP measurements in

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the sitting position during the follow-up visit.

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The treatment algorithms for the two groups were shown in Figure 2. Briefly, in the

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intensive BP goal group, drug doses were increased and/or additional antihypertensive

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treatment was added carefully at each visit until the patient’s goal of 110SBP<130 mm Hg

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was reached. In both groups, participants were evaluated monthly for the first 3 months, and thereafter every three months during the follow-up period.

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2.7. App management intervention

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At study entry, all enrolled participants had an easy-to-use smartphone with compatible

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operating system (Android or iOS) that can download the Hypertension Doctor App software (developed by Beijing Precision Health Management of Hypertension & Angiocardiopathy Co., Ltd, Beijing, China). Each patient was provided free of charge with a validated Omron HEM-9200T automatic blood pressure monitor [27] (Omron Healthcare, Kyoto, Japan) that meets with the requirement of the European Society of Hypertension International Protocol revision 2010 (ESH-IP revision 2010) [28]. Trained study staffs gave instructions on how to download and use the app software, as well as how to link the app with the Omron blood pressure monitor. The participants were taught how to properly measure the blood pressure and upload the readings. For those elderly people who were not skillful at the app software by

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themselves, their relatives or guarders were asked to help with management. To study the effects of App management on BP control, the 42 clinical centers were randomly assigned into either an App management center or a usual BP management center in a 1:1 ratio. Participants in the App center will receive an app BP intervention and the details were shown in the Figure 3. The Hypertension Doctor App platform, based on smartphone,

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aims to help patients adhere to medication and monitor blood pressures by several modules,

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including a link with medication records and antihypertensive treatment plan, graphic data of

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home blood pressure during the follow-up, interactive communications between patients and

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physicians, and cardiovascular health education (Supplemental eTable 2).

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Participants in the usual BP management center will receive usual care by physicians at clinic office visit, shown in the Supplemental eFigure 2. Although they are asked to measure

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and upload their home blood pressure as the same way as participants in the App management

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center, the monthly reports and alerts of BP surveillance will not be sent to them via the app.

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2.8. Endpoint and safety events

The primary outcome is designed as a composite of first occurrence of myocardial infarction, stroke (ischemic or hemorrhagic), hospitalization for unstable angina or acute decompensated heart failure, coronary revascularization, atrial fibrillation, or death from cardiovascular causes. The secondary outcomes are pre-specified and mainly include the following types: (1) the components of primary composite outcome mentioned above, as well as all-cause death, aiming to support the primary hypothesis; (2) decline in renal function or development of end stage renal disease (ESRD); (3) decline in cognitive function including sensory disturbance, memory disorders and thinking disorders assessed by MMSE; (4) major artery stiffness,

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assessed by a decrease in values of ABI or baPWV. Additional secondary outcomes include first occurrence of atrial fibrillation or flutter, diabetes mellitus, and skeletal fracture as well. Endpoints are ascertained at 3-monthly intervals by the site investigators primarily through self-reports and review of medical records using a structured interview questionnaire, which are further confirmed by the Clinical Endpoint Committee blinded to the assigned treatment

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arms. Clinical medical records and imaging evidence are required to support all diagnosis.

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Definitions of the endpoints were presented in the Supplemental eTable 3. If participants died

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during the follow up, the death information were reported by family members, work

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associates and/or obtained from death certificates and medical records.

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Several types of serious adverse events will be observed and recorded during the STEP study, such as serious hypotension, acute kidney injury, and syncope. Definitions of the

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2.9. Follow-up procedures

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principal safety concerns were described in the Supplemental materials.

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After randomization, the follow-up visits are to be scheduled for participants in both treatment groups at months 1, 2, 3, 6, and every 3 months thereafter until months 48 or the close-out visit. Follow-up schedule will be planned to end at December 31, 2021. As shown in the Supplemental eTable 4, procedures performed at the various visits included blood pressure measurements, antihypertensive drug dispensation and adjustment, medical adherence, blood and urine collection, as well as questionnaires on the physical frailty phenotype, MMSE, endpoints and adverse events. The orthostatic hypertension was evaluated at each visit by a sustained reduction of SBP of at least 20 mm Hg or DBP of 10 mm Hg within 3 minutes standing or head-up tilt to at least 60° on a tilt table [29]. At 1 year and at the end of study

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year, the ABI and baPWV are to be measured for evaluating the artery stiffness and potential cardiovascular risk, and the color Doppler ultrasonic cardiogram conducted for assessing ventricular function and heart failure. A 12-lead ECG is conducted at year 2 and 4 visits to assess the occurrence of silent MI, atrial fibrillation and left ventricular hypertrophy. Blood samples after a 12-hour overnight fast are collected at baseline and at 6 months and

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thereafter at each annual visit for the measurement of biochemical parameters. Urine samples

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are collected at baseline and at year 2 and 4 visits for measuring urine micro-albumin and

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creatinine. All measurements were taken at Beijing CIC Clinical Laboratory qualified by the

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Centers for Disease Control and Prevention. Laboratory results will be used to monitor and

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adjust treatment in efforts to maintain blood pressure target goals, assess safety and decline of renal function. In addition, serum, plasma, and urine samples are stored for future analysis of

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other novel cardiovascular risk factors.

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The coordinating centers and investigators will follow the principles of Good Clinical

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Practice (GCP) and assure that trial information will be recorded and stored accurately in the STEP trial. The details of quality control were described in the Supplemental materials. 2.10. Statistical analysis

For comparisons of baseline characteristics between the two treatment groups, we will use the Student t test or the Mann-Whitney nonparametric test for continuous variables, and the chi-square test for categorical variables, when appropriate. A complete statistical analysis plan was shown in the Supplemental materials. Briefly, analysis of the primary and secondary outcomes between intervention groups will be performed according to the intention-to-treat principle, and all randomized participants will be grouped according to their intervention

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assignment at randomization, regardless of adherence. The Cox proportional hazards regression model is applied for comparing the incidence of the primary endpoints between the two treatment arms, and the Kaplan-Meier analysis for estimating the survival rates of two arms. Follow-up time will be censored on the date of the last event ascertainment or at death due to non-cardiovascular causes. Participants may have multiple events, but only 1 event of

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any 1 type will be used in the analyses, depending on which come first. Cognitive impairment

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is analyzed on the basis of MMSE score. In order to eliminate the confounding effect of App

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management, the use of smartphone-based app platform will be adjusted as a covariate in the

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Cox model for primary analysis.

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Sensitivity analysis are also to be performed for primary outcome to examine the consistency of the intervention effect among the subgroups of interest, including age (60-69,

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70-79 years old), gender (men, women), SBP at randomization (<140 mm Hg, 140-159 mm

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Hg, or ≥160 mm Hg), with and without a history of diabetes or coronary heart diseases at

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randomization, the 10-year risk of CVD on the basis of Framingham risk scoring (<15%, ≥15%), and use of App management (yes or no). For each subgroup analysis, the Cox proportional hazards model will be used and the P values for interaction between the treatment effect and the subgroups are reported. During the trial, interim analysis will be periodically performed by an independent data and safety monitoring committee for the primary outcomes to assess the trial progress with respect to intervention efficacy and safety, and the O’Brien-Fleming boundaries determined by the Lan-DeMets method are used [30]. In addition, to assess the impact of App management on longitudinal changes in SBP or medication adherence during the follow-up, the mixed-effect

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models will be used incorporating adjustment for conventional risk factors. Analyses are performed with SPSS. Version 20.0 or above (SPSS Inc, Chicago, USA), and P<0.05 (two-sided) is considered to be significant.

3. Results

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The cohort of patients was enrolled within one-year period from January 10, 2017 to

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December 31, 2017. A total of 9,624 patients were screened for the trial, of whom 763 (7.9%)

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did not meet inclusion criteria, and finally 8,511 patients aged 60-80 years underwent

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randomization. A total of 4,243 (49.9%) eligible participants were randomly assigned to the

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intensive treatment group (a goal of 110SBP<130 mm Hg) and 4,268 (50.1%) to the standard treatment group (a goal of 130SBP<150 mm Hg).

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The baseline characteristics of enrolled participants were presented in Table 2, and no

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significant differences were shown between the intensive treatment and standard treatment

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groups. In this trial, the mean age of participants was 66.2 (SD 4.8) years, of whom aged 70-80 years accounted for 24.1%, men accounted for 46.5%, and 19.1% had prior diabetes mellitus, 6.3% had prior cardiovascular disease, and approximate 65% were at high-risk with the 10-year Framingham risk score 15%. There was no significant difference in frequencies distribution of SBP and DBP at baseline between intensive and standard group (Supplemental eFigure 3). In all, 84.8% participants can use the App to manage their blood pressure by themselves, and 15.2% participants were not skillful at the app and needed their relatives or guarders to help with blood pressure management. As expected, for antihypertensive therapy at the initiation of trial, more patients in the intensive group received 2 or 3 drugs compared

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with those in the standard group (47.9% versus 37.7%).

4. Discussion Hypertension is a complex and heterogeneous pathological status in elderly people, obviously, BP control should be paid more attention. The STEP is multi-center, randomized controlled

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trial which enrolled 8,511 hypertensive patients (aged 60-80 years) at 42 clinical centers at 23

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provinces/municipalities throughout China, aiming to investigate whether an intensive

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treatment (110SBP<130 mm Hg) will provide more benefits in lowering cardiovascular

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events than a mild treatment (130SBP<150 mm Hg). It would be expected to provide new

patients among the elderly population.

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evidence for hypertension guideline regarding the benefits of BP lowering for high-risk

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One important strength of this study is the use of the same validated home BP measurement

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device (the Omron HEM-9200T) for all participants and the same validated office BP

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measurement device (the Omron HBP-1100U) for all collaborating clinical centers, which meets the accuracy standards of ESH-IP revision 2010 and American AAMI. These devices have a built-in memory to store the readings and a blue-tooth function to allow for uploading the readings to the app platform. The standard automated BP device minimizes the potential investigator bias in the determination of blood pressure. Another important strength is that the STEP trial applied a smartphone-based app platform for facilitating the BP management and helping patients adhere to their medications. To date, the rapid development of smart mobile phone and the health-related apps have provided an opportunity for management and prevention of chronic diseases [31-35], however, robust

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evidence is still demanding for its long-term benefits on BP control and cardiovascular disease [36]. The approach of the Hypertension Doctor App platform in this trial has several interesting features. First, it is linked with medication records through the Electronic Data Capture System and accessible to both patients and doctors. Second, via the smartphone, the app is automatically sync with home BP measurement of each patient by linking a validated

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automatic BP monitor. Thus, patients can track the graphical home BP data and any irregular

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readings via the app. A monthly report about the BP surveillance will be generated and sent to

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both patients and study investigators. Third, importantly, the app designed a module of

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interactive communications to help patients contacting with doctors about the medications.

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In this trial, the smartphone is not considered as an inclusion criterion. In recent years, there has been a big increase for smartphone market in China, and it is common for people to have

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a smartphone in their lives for keeping in touch with friends and families through a variety of

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Apps, even among the elderly people. Because the App platform has big advantages in

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monitoring the blood pressure, eligible participants are willing to prepare a smartphone at study entry if they do not have. The STEP will provide evidence to assess an effective model of App management for BP control.

5. Conclusions In summary, the findings of STEP trial will provide new evidence to address appropriate target of blood pressure control in elderly people, but also to evaluate the role of home blood pressure monitoring in the management of hypertension and cardiovascular benefits.

Journal Pre-proof Acknowledgements We would like to acknowledge the physicians and study staffs at the collaborating hospitals for data collection and management. And we would also like to appreciate all participants for their contribution.

Authors’ contributions

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W.Z. and J.C. conceived and designed the trial, and acted as chief investigators to take responsibility for all respect of the study. S.Z. and W.Z. drafted the statistical analysis plan

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and the original protocol. J.R., X.C., X.Z., Y.F., X.Z., B.Z., J.Y., G.T., Y.J., Z.G., Y.L., and

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T.W. made substantial contributions to study design and collected the data. All authors

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critically reviewed drafts of the manuscript and approved the final manuscript.

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Funding

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This work was supported by the Chinese Academy of Medical Sciences Innovation Fund for

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Medical Sciences (2016-I2M-1-006).

Declaration of interests None declared.

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27. Hakuo Takahashi, Masamichi Yoshika, Toyohiko Yokoi. Validation of three automatic devices for the self-measurement of blood pressure according to the

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28. O’Brien E, Atkins N, Stergiou G, et al. Working Group on Blood Pressure Monitoring of the European Society of Hypertension. European Society of Hypertension International Protocol revision 2010 for the validation of blood pressure measuring devices in adults. Blood Press Monit 2010;15:23–38. 29. Freeman R, Wieling W, Axelrod FB, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Auton Neurosci 2011;161(1-2):46-48. 30. Proschan MA, Lan KKG, Wittes JT. Statistical monitoring of clinical trials: a unified approach. New York: Springer, 2006.

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31. Morawski K, Ghazinouri R, Krumme A, et al. Association of a Smartphone Application with Medication Adherence and Blood Pressure Control: The MedISAFE-BP Randomized Clinical Trial. JAMA Intern Med 2018;178(6):802-809. 32. Bobrow K, Farmer AJ, Springer D, et al. Mobile Phone Text Messages to Support Treatment Adherence in Adults with High Blood Pressure (SMS-Text Adherence

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35. Chow CK, Redfern J, Hillis GS, et al. Effect of Lifestyle-Focused Text Messaging on Risk Factor Modification in Patients with Coronary Heart Disease: A Randomized Clinical Trial. JAMA 2015;314(12):1255-1263. 36. Coorey GM, Neubeck L, Mulley J, et al. Effectiveness, acceptability and usefulness of mobile applications for cardiovascular disease self-management: Systematic review with meta-synthesis of quantitative and qualitative data. Eur J Prev Cardiol 2018;25(5):505-521. 37. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of

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Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;124(24):e783-e831. 38. Elliott P, Andersson B, Arbustini E, et al. Classification of the cardiomyopathies: a position statement from the European Society of Cardiology Working Group on

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FIGURE LEGENDS Fig.1 CONSORT diagram of the STEP trial. Abbreviations: SBP, systolic hypertension; CONSORT, consolidated standards of reporting trials; STEP, the strategy of blood pressure intervention in the elderly hypertensive patients. Fig.2 Algorithms for the intensive treatment and standard treatment.

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Abbreviations: SBP, systolic blood pressure; ARB, Angiotensin receptor blocker; CCB,

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Calcium channel blocker. Unless side effects warrant change in therapy.

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Olmesartan Medoxomil tablets, Amlodipine Besylate tablets, hydrochlorothiazide, and

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a

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β-blockers were used to achieve the SBP target in the STEP. Fig.3 BP intervention strategy by smart phone-based App management in the STEP.

Traffic light system includes ‘red light’, ‘yellow light’, and ‘green light’.

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Abbreviations: HBP, home blood pressure.

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Red light: When the daily average blood pressure exceeds the safe range, that is SBP >180 or <110 mm Hg, and DBP >110 or <50 mm Hg, the app will send a text message to patients and study staffs via WeChat that ‘Your average blood pressure is too high/low, beyond the safe range, please contact your doctor as soon as possible’. Yellow light: It means that the daily average blood pressure is not within the range of target goal, that is SBP >125 mm Hg in the intensive group, or SBP <125 or >145 mm Hg in the standard group. If the yellow lights showed 60% in a month, the app will send a text message to patients and study staffs via WeChat that ‘Your average blood pressure did not

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achieve the target goal, please consult your doctor whether you need to adjust the medication or not at the next follow- up visit’.

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Green light: It means that the average blood pressure is within the range of targeted goal.

Journal Pre-proof Table 1. Inclusion and exclusion criteria of the STEP trial Criteria Inclusion

Definition 1. SBP between 140-190 mm Hg in the three screening visits or currently under anti-hypertension treatment. 2. An age of 60-80 years, Han ethnicity. 3. Signed the written informed consent. 1. SBP 190 mm Hg, or DBP <60 mm Hg. 2. Diagnosed secondary hypertension.

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3. History of large atherosclerotic cerebral infarction or hemorrhagic stroke (not including lacunar infarction and transient ischemic attack [TIA]).

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4. Hospitalization for myocardial infarction (MI) within the last 6 months, but remote MI events were included.

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5. Coronary revascularization (PCI or CABG) within the last 12 months.

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6. Planned to perform PCI or CABG in the next 12 months. 7. History of sustained atrial fibrillation or ventricular arrhythmias at entry influencing the

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measurement of electronic blood pressure.

at entry.

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8. NYHA class III-IV heart failure or hospitalization for exacerbation of chronic heart failure

9. Severe valvular disease or valvular disease likely to require surgery or percutaneous valve

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Exclusion

replacement during the trial. 10. Hypertrophic cardiomyopathy (HCM), a disease characterized by unexplained left ventricular (LV) hypertrophy associated with non-dilated ventricular chambers in the absence of another cardiac or systemic disease. HCM is usually recognized by maximal LV wall thickness ≥15 mm unexplained by abnormal loading conditions, or with wall thickness of 13 to 14 mm considered borderline, particularly in the presence of other compelling information, e.g. family history of HCM, based on echocardiography. In

elderly patients with LV hypertrophy and a history of long-standing systemic hypertension, the HCM can be determined by identification of a diagnostic sarcomere mutation or inferred by marked LV thickness >25 mm and/or left ventricular outflow tract obstruction with systolic anterior motion and mitral-septal contact [37].

Journal Pre-proof Continued, Criteria

Definition 11. Dilated cardiomyopathy, rheumatic heart disease, or congenital heart disease [38]. 12. Uncontrolled diabetes mellitus (serum fasting glucose 200 mg/dl [11.1 mmol/L], glycated hemoglobin [HbA1] >8%). 13. Severe liver or kidney dysfunction (ALT 3 times the upper limit of normal value, or end stage renal disease on dialysis or eGFR <30 mL/min/1.73 m2 , or serum creatinine >2.5 mg/dl [>221 mol/L]).

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14. Severe somatic disease such as cancer.

16. Participating in other clinical trials.

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15. Severe cognitive impairment or mental disorders.

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Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; NYHA, New York Heart Association;

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ALT, Alanine aminotransferase; eGFR, estimated glomerular filtration rate.

Journal Pre-proof Table 2: Baseline characteristics of participants in the STEP trial BP Treatment Total

Intensive

Standard

P

Characteristic

(n=8,511)

(n=4,243)

(n=4,268)

Value a

Age, years

66.2 ± 4.8

66.2 ± 4.8

66.3 ± 4.8

0.33

60-70 years

6456 (75.9)

3220 (75.9)

3236 (75.8)

0.94

70-80 years

2055 (24.1)

1023 (24.1)

1032 (24.2)

Men, No. (%)

3959 (46.5)

1990 (46.9)

1969 (46.2)

0.49

25.6 ± 3.2

25.5 ± 3.2

25.6 ± 3.2

0.46

146.0 ± 16.5

0.63

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Body mass index, kg/m2

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Distribution of age, No. (%)

Baseline BP, mm Hg

146.0 ± 16.6

146.1 ± 16.8

DBP

82.5 ± 10.6

82.7 ± 10.6

82.3 ± 10.5

0.08

0.48

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SBP

3136 (36.8)

1556 (36.7)

1580 (37.0)

140-159 mm Hg

3633 (42.7)

1794 (42.3)

1839 (43.1)

1478 (17.4)

764 (18.0)

714 (16.7)

264 (3.1)

129 (3.0)

135 (3.2)

8196 (96.3)

4081 (97.6)

4115 (97.7)

196 (2.3)

99 (2.4)

97 (2.3)

6.2 ± 1.8

6.2 ± 1.8

6.2 ± 1.7

0.30

4.9 ± 1.2

4.9 ± 1.2

4.9 ± 1.1

0.68

1.3 (1.0-1.9)

1.3 (1.0-2.0)

1.4 (1.0-1.9)

0.86

HDL cholesterol

1.3 ± 0.3

1.3 ± 0.3

1.3 ± 0.3

0.56

LDL cholesterol

2.7 ± 0.9

2.7 ± 0.9

2.7 ± 0.9

0.52

426 (5.0)

217 (5.1)

209 (4.9)

0.62

Primary school

1521 (17.9)

755 (17.8)

766 (18.0)

Middle or high school

5641 (66.3)

2794 (65.9)

2847 (66.7)

University or above

920 (10.8)

476 (11.2)

444 (10.4)

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<140 mm Hg

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Distribution of SBP, No. (%)

160-180 mm Hg

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>180 mm Hg

eGFR ≥60 ml/min/1.73 m2

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eGFR <60 ml/min/1.73 m2

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Renal dysfunction, No. (%)

Fasting serum glucose, mmol/L

0.89

Lipids profile, mmol/L Total cholesterol Triglycerides

Educational level, No. (%) No formal school

Journal Pre-proof (Continued) BP Treatment Total

Intensive

Standard

P

(n=8,511)

(n=4,243)

(n=4,268)

Value a

Never

6100 (71.7)

3039 (71.8)

3061 (71.9)

0.98

Former

1016 (11.9)

510 (12.1)

506 (11.9)

Current

1371 (16.1)

683 (16.1)

688 (15.9)

Never

5797 (68.1)

2902 (68.6)

2895 (68.1)

Former

448 (5.3)

216 (5.1)

232 (5.5)

Current

2240 (26.3)

Characteristic Smoking status, No. (%)

1627 (19.1)

Hyperlipidemia

3132 (36.8)

0.74

1114 (26.3)

1126 (26.5)

800 (18.9)

827 (19.4)

0.54

1591 (37.5)

1541 (36.1)

0.19

540 (6.3)

268 (6.3)

272 (6.4)

0.93

Myocardial infarction

163 (1.9)

82 (1.9)

81 (1.9)

0.94

472 (5.5)

226 (5.3)

249 (5.8)

<0.001

4398 (51.7)

1985 (46.8)

2413 (56.5)

3172 (37.3)

1774 (41.8)

1398 (32.8)

469 (5.5)

258 (6.1)

211 (4.9)

1636 (19.2)

823 (19.4)

813 (19.1)

0.70

Aspirin use, No. (%)

730 (8.6)

359 (8.5)

371 (8.7)

0.73

The 10-year risk of CVD, % b

19.3 ± 8.5

19.4 ± 8.5

19.3 ± 8.5

0.87

The 10-year risk of CVD ≥15%, No. (%)

5400 (64.6)

2701 (64.9)

2699 (64.3)

0.60

Mini-mental state examination (MMSE)

28.9 ± 2.1

28.9 ± 1.9

28.9 ± 2.2

0.98

Skillful

7217 (84.8)

3593 (84.7)

3624 (84.9)

0.53

Not skillful

1294 (15.2)

650 (15.3)

644 (15.1)

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Cardiovascular diseases

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Diabetic mellitus

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Medical history, No. (%)

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Alcohol intake, No. (%)

Antihypertensive drugs, No. (%) None

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2

Statin use, No. (%)

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≥3

Use of the App platform, No. (%)

Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; CVD, cardiovascular disease. a Values were given as mean ± SD, number (%), or median (interquartile range). P values were calculated by Student t test or Mann-Whitney nonparametric test for quantitative variables, or by Chi-square test for qualitative variables, when appropriate. b The 10-year CVD risk was estimated by Framingham risk scoring, and patients with a ≥15% risk score were considered at high-risk.

Figure 1

Figure 2

Figure 3