Subjects
Among 3766 subjects who were enrolled for Kor-ABP registry during the period from 1st August, 2009 to the end of 2012, 1242 subjects with relevant clinical information and who were treated with at least one AHM were selected for the study. The subject was registered by 27 referral hospitals as described in the previous study [4]. The exclusion criteria was estimated glomerular filtration rate (eGFR) calculated by CKD-EPI equation [5] less than 30 ml/min/1.73m2 and finally 1230 subjects was analyzed for the study.
Clinical and laboratory variables
Information included from the medical records covered: age, gender, height, weight, abdominal circumference, presence of diabetes mellitus (DM), hyperlipidemia, presence of clinical cardiovascular disease, time of diagnosis, mode of treatment, and prescribed medications.
And the questionnaire for each subjects included: smoking status, alcohol intake, extent of physical exercise, family history of HT and premature cardiovascular death, past medical history; HT, DM, hyperlipidemia, stroke, coronary artery disease (CAD), and heart failure.
The collected information for the AHM was the commercial names of the drugs and dosing at the time of enrollment.
Clinic BP and ABPM data
Clinic BP was measured using an A&D UA-767, which passed European Society of Hypertension protocol and International Protocol [6]. Clinic BP was defined as the average BP of two measurements one minute apart, with 5 min’ rest before the first measurement.
ABPM data were gathered as the form of raw data files uploaded to the study website. The device used in the study institute was all recommended as summarized in the website http://www.dableducational.org or passed the recommended validation protocols [7]. The raw data of ABPM were regarded as valid only when at least 14 readings of the awake blood pressure from 8AM to 9PM were available after omitting erroneous readings according to the following criteria [8]:
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1)
pulse rate above 120 beats per minute
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2)
systolic or diastolic blood pressure more than 25 mmHg above or below the previous and subsequent readings
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3)
pulse pressure below 15 mmHg [9].
Definition of RH and groups according to the control status of BP
The definition of the resistant hypertension was uncontrolled BP even if using three drug classes one of which included diuretics or the BP status requiring treatment using four or more drugs regardless of the control status [1]. Optimal dosage criterion was counted only when the dosage of the each drug was >50 % of the maximum recommended or approved dose for hypertension [10]. For example, for Angiotensin converting enzyme inhibitor (ACEI), ramipril 5mg or perindopril 4mg were minimal dosage needed for optimal treatment. Similarly, for example, losartan 50 mg, valsartan 80mg, amlodipine 5mg, diltiazem 90 mg, bisoprolol 2.5 mg, carvedilol 12.5 mg, nebivolol 2.5 mg, dihydrochlorthiazide 12.5 mg, furosemide 20mg, torsemide 5mg, indapamide 2.5mg spironolacton 12.5mg were the minimal required dosage.
BP was categorized as controlled and uncontrolled status according to the various criteria. By clinic BP criterion, the BP lowered below 140/90 mmHg was regarded as controlled status. As for daytime, nighttime, and 24 h BPs, the BPs lowered below 135/85 mmHg, 120/70 mmHg, and 130/80 mmHg were regarded as controlled status, respectively [2, 11].
For the subjects taking three or more AHM including diuretics, according to the control status defined by various criteria, the subject with controlled BP status was grouped as responsive group, whereas the subject with uncontrolled BP status was grouped as the resistant group.
Definitions of the clinical conditions
Dyslipidemia was defined as the total cholesterol ≥ 240 mg/dL, triglyceride ≥ 150 mg/dL, HDL < 45/50 mg/dL in male and female, respectively, or the use of statin. The diabetes was defined as fasting blood glucose ≥ 126 mg/dL, hemoglobin A1C > 6.5 %, or the use of antidiabetic medication. The chronic kidney disease (CKD) was defined as eGFR calculated by CKD-EPI equation between 30 and 60 ml/min/1,73m2 [5]. Smoking was defined as current smoker and drinking was defined as current drinking by the questionnaire. Regular physical exercise was defined as the three or more times of structured exercise per week. Metabolic syndrome (Mets) was defined when the subject had three or more components of impaired fasting blood glucose or diabetes mellitus, obesity defined by increased abdominal circumference (≥90 cm in male; ≥ 80 cm in female) or BMI ≥ 25 kg/m2, triglyceride level ≥ 150 mg/dL, low HDL level, and blood pressure ≥ 130/85 mmHg or a history of hypertension [12]. Global cardiovascular risk (GCR) profiles were determined according to the 2013 Korean Society of Hypertension Guideline [2].
The study protocol was approved by the clinical research ethics committees in all hospitals involved in the study.
Statistical analyses
All data were expressed as mean ± standard deviation. The statistical significance of the differences in mean values was evaluated using student t-test or analysis of variance (ANOVA). The chi square test and Fisher’s exact test were used to ascertain the statistical significance of the categorical difference between groups. The differences in diagnostic category between clinic versus ambulatory BPs were evaluated using McNemar’s test. Test for inter-rater reliability using the kappa test statistics with 95 % confidence interval were performed to determine the consistency of the two methods of measuring blood pressure.
Multiple logistic regression analysis was performed to examine the association between resistant group defined by various BP criteria and the clinical factors. The independent variable included age, sex, Mets, family history of HTN, physical activity, drinking and smoking status, DM, CKD, history of stroke, CAD, heart failure, the use of ACEI or angiotensin receptor blocker (ARB) as renin angiotensin system (RAS) blockade, beta blocker (BB), calcium channel blocker (CCB), and loop diuretics, and the use of optimal dosage. Statistical significance was defined by a confidence interval of 95% and p < 0.05. All data processing and analysis were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA).