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24-Hour Blood Pressure Response to Lower Dose (30 Mg) Fimasartan in Korean Patients with Mild to Moderate Essential Hypertension

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24-Hour Blood Pressure Response to Lower Dose (30 Mg) Fimasartan in Korean Patients with Mild to Moderate Essential Hypertension ORIGINAL ARTICLE Korean J Intern Med 2017;32:1025-1036 https://doi.org/10.3904/kjim.2016.094 24-Hour blood pressure response to lower dose (30 mg) fimasartan in Korean patients with mild to moderate essential hypertension Hae-Young Lee1, Cheol-Ho Kim2, Jae-Kwan Song3, Shung Chull Chae4, Myung Ho Jeong5, Dong-Soo Kim6, and Byung-Hee Oh1 Department of Internal Medicine, Background/Aims: Fimasartan is an angiotensin type 1 receptor blocker (ARB) 1Seoul National University Hospital, Seoul; 2Seoul National University which has comparable efficacy and tolerability with other ARBs. The aim of this Bundang Hospital, Seongnam; study was to evaluate 24-hour blood pressure (BP) lowering efficacy and the toler- 3 Asan Medical Center, University of ability of the low dose fimasartan compared with valsartan in patients with mild Ulsan College of Medicine, Seoul; 4Kyungpook National University to moderate hypertension. Hospital, Daegu; 5The Heart Center Methods: This study was a phase II, prospective, multicenter, randomized, dou- of Chonnam National University ble-blind, parallel-grouped trial. A total of 75 hypertensive patients, whose mean Hospital, Gwangju; 6Inje University Busan Paik Hospital, Busan, Korea ambulatory BP monitoring values were ≥ 135/85 mmHg, were randomized to ei- ther fimasartan 30 mg or valsartan 80 mg daily. The primary efficacy endpoint was the change in the mean 24-hour systolic BP (SBP) values from the baseline and at the week 8. Secondary endpoints included the change in the mean 24-hour diastolic BP values, the daytime and the nighttime mean BP values at week 8, the trough-to-peak (T/P) ratio and the smoothness index. Results: At week 8, the mean 24-hour SBP values significantly decreased in both groups; –10.5 ± 11.9 mmHg (p < 0.0001) in the fimasartan group and –5.5 ± 11.6 Received : March 20, 2016 mmHg (p = 0.0307) in the valsartan group. The difference between two groups Revised : July 6, 2016 was 4.3 ± 2.9 mmHg but there was no statistical significance (p = 0.1392). The glob- Accepted : August 23, 2016 al T/P ratio in the fimasartan 30 mg groups were 0.48 and 0.40 in the valsartan Correspondence to 80 mg group, respectively (p = 0.3411). The most frequent adverse events (AEs) were Byung-Hee Oh, M.D. acute pharyngitis and there were no cases of severe AEs. Department of Internal Medicine, Seoul National Conclusions: In mild-to-moderate hypertensive patients, low dose (30 mg) fima- University College of Medicine, sartan showed comparable 24-hour BP lowering efficacy compared with valsartan 101 Daehak-ro, Jongno-gu, Seoul (80 mg). There was no difference in tolerability between two groups. 03080, Korea Tel: +82-2-2072-3345 Fax: +82-2-3674-0805 Keywords: Hypertension; Angiotensin II type 1 receptor blockers; Blood pressure E-mail: [email protected] monitoring, ambulatory INTRODUCTION cardiovascular morbidity and mortality [2,3]. Among the different classes of antihypertensive drugs, angiotensin Hypertension is the most common cause of cardiovas- type 1 receptor blockers (ARBs), which regulate the re- cular disease [1]. Blood pressure (BP) control by anti- nin-angiotensin-aldosterone system by restricting the hypertensive medication is effective strategy to reduce action of angiotensin II, are recommended as a first-line Copyright © 2017 The Korean Association of Internal Medicine pISSN 1226-3303 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ eISSN 2005-6648 by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. http://www.kjim.org The Korean Journal of Internal Medicine Vol. 32, No. 6, November 2017 therapy in all guidelines [4-8]. hypertension defined as mean sitting diastolic blood Fimasartan, developed by Boryung Pharmaceutical pressure (SiDBP) ≥ 110 mmHg or mean sitting systolic Co. Ltd., Seoul, Korea, is the eighth ARB out of nine cur- blood pressure (SiSBP) ≥ 180 mmHg at the screening, rently available ARBs [9,10]. Fimasartan at the range of baseline and randomization visits; (2) a change in SiDBP 30 to 120 mg once daily showed an effective BP lower- ≥ 10 mmHg or a change in SiSBP ≥ 20 mmHg measured ing effect in hypertensive patients [11-14]. Also in large in the same arm at the screening visit; (3) secondary hy- population observation study, fimasartan showed ex- pertension including pheochromocytoma, renal artery cellent safety profile [15,16]. Several pharmacokinetic/ stenosis, and functional adrenal adenoma; (4) symptom- pharmacodynamic studies were performed to evaluate atic orthostatic hypotension; (5) uncontrolled diabetes the possible drug or food interactions [17-20] and the before the screening visit (glycosylated hemoglobin > drug metabolism in the elderly population and in he- 9%), current treatment with insulin, or a change in oral patic dysfunction [21,22]. In patients with moderate he- hypoglycemic agent dosage/usage within the 12 weeks patic impairments, the bioavailability of fimasartan was before the screening visit; (6) history of myocardial in- 5-fold higher than that of healthy controls [20,21]. The farction or coronary arterial disease, clinically signifi- co-administration of fimasartan with amlodipine, hy- cant congestive heart failure or valvular heart disease drochlorothiazide, or digoxin did not show any signifi- identified within the past six months; and (7) serum cre- cant interactions [23-25]. Conversely, fimasartan raised atinine ≥ 1.5 times upper normal limit (< 1.40 mg/dL), plasma atorvastatin concentrations [20]. aspartate aminotransferase or alanine aminotransferase Previously, fimasartan 60 mg was the minimum per- ≥ 2 times upper normal limit (< 40 IU/L), and other clini- mitted dose for hypertension treatment. However, in cally significant abnormal laboratory test results. real world situation, half tablet (30 mg) of fimasartan was often used and was suggested to have sufficient BP Study design lowering efficacy. Also, fimasartan 30 mg showed supe- This study was a phase II, prospective, multicenter, ran- rior office BP lowering efficacy than valsartan 80 mg in domized, double-blind, parallel-grouped trial to com- patients with mild to moderate hypertension [26]. With pare 24-hour BP lowering efficacy and the tolerability this background, this study was conducted to evaluate of the low-dose fimasartan and valsartan in patients whether once daily administration of the low dose (30 with mild to moderate essential hypertension. All of the mg) fimasartan is able to maintain BP lowering toward study protocols were reviewed and approved by the In- the end of the dosing interval. Ambulatory blood pres- stitutional Review Board of each participating hospital sure monitor (ABPM) was performed to evaluate 24-hour prior to any patient enrollment (IRB No. 1102-072-352). BP lowering efficacy of the low dose fimasartan (30 mg In addition, the study was conducted in accordance with once daily) compared with valsartan (80 mg once daily) the current Good Clinical Practices and other applicable in patients with mild to moderate hypertension. laws and regulatory requirements in Korea. This study was registered in Clinicaltrials.gov (NCT01878201). Subjects went through a screening period after volun- METHODS tary agreement to participate in the study including a 7-day washout period for those patients who had been Patients taking other medication. After 2 weeks’ placebo run-in, Male or non-childbearing female patients aged 20 to 70 the eligible hypertensive patients, whose mean ABPM with mild to moderate hypertension whose mean 24- values were ≥ 135/85 mmHg, were randomized to either hour ABPM values ≥ 135/85 mmHg were eligible for the fimasartan 30 mg daily or valsartan 80 mg daily. Patients study. For office BP measurement, patients should be were instructed to orally take the assigned drug once seated at least for 5 minutes and refrain from smoking daily at the same time after a meal in the morning while or ingesting caffeine during the 30 minutes prior to the they came to the clinic without taking the drug when measurement. Patients were excluded from the study if study procedures were scheduled at weeks 0, 4, and 8. they met any of the following exclusion criteria: (1) severe During these study visits, BP measurements, physical 1026 www.kjim.org https://doi.org/10.3904/kjim.2016.094 Lee HY, et al. Low dose fimasartan: ABPM examinations, clinical laboratory tests (i.e., hematology, were subtracted from baseline values to determine 24- blood chemistry, and urinalysis), and 12-lead electrocar- hour, daytime, and nighttime mean changes. diogram (ECG) were performed. The trough-to-peak (T/P) ratio was calculated to eval- Compliance was assessed by investigators based on uate the sustainability of BP reduction toward the end the rate of return and amount of administration of in- of the dosing interval. The trough was defined as the vestigational products. Clinical pharmacists recorded ambulatory BP reduction over the last 2 hours of the the amount of returned product when a subject deliv- dosing interval (i.e., 23 to 24 hours post-dose) [27]. The ered the remaining product to pharmacist. Compliance peak effect was defined as the maximal decrease in am- was assessed as below: compliance (%) = (total number of bulatory BP from baseline over any 1-hour period after administered tablets / total number of tablets to be ad- drug administration using 2-hour moving averages [27]. ministered according to the protocol) × 100. The study ABPM data were then matched by measurement time design was summarized in Fig. 1. in each patient, and values at 8 weeks of treatment were subtracted from the baseline values to determine the 24-Hour ambulatory blood pressure monitoring trough and peak effects. From these effects, global T/P We used the same protocol as previous ABPM study ratio was calculated from all patients for a single effect with fimasartan 20 to 180 mg [11,12].
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