为了正常的体验网站,请在浏览器设置里面开启Javascript功能!
首页 > 10. 平滑指数高

10. 平滑指数高

2012-07-18 11页 pdf 105KB 36阅读

用户头像

is_650291

暂无简介

举报
10. 平滑指数高 1753 Hypertens Res Vol.31 (2008) No.9 p.1753-1763 Original Article A Randomized Trial of the Effect of an Angiotensin II Receptor Blocker SR47436 (Irbesartan) on 24-Hour Blood Pressure in Patients with Essential Hypertension Yuhei KAWANO1), Yoichi SATO2), a...
10. 平滑指数高
1753 Hypertens Res Vol.31 (2008) No.9 p.1753-1763 Original Article A Randomized Trial of the Effect of an Angiotensin II Receptor Blocker SR47436 (Irbesartan) on 24-Hour Blood Pressure in Patients with Essential Hypertension Yuhei KAWANO1), Yoichi SATO2), and Kaoru YOSHINAGA3) The aim of this placebo-controlled, double-blind randomized study was to evaluate the duration of the effect of once-daily administration of irbesartan in patients with essential hypertension. After a placebo run-in baseline period (of 2–4 weeks), 79 patients were randomized to either irbesartan (one 100 mg tablet per day) or placebo, for 6 weeks. The primary outcome was the reduction in the mean 24-h blood pressure (BP) as assessed by ambulatory BP monitoring under standardized conditions. Seventy-six patients completed the study protocol. In the irbesartan group, the average reductions in 24-h systolic and diastolic BPs were 5.8 and 3.4 mmHg, respectively (95% confidence interval: 3.2–8.4/1.6–5.1 mmHg), and in the placebo group, they were –1.7 and –0.5 mmHg, respectively (95% confidence interval: –4.3 to 1.0/–1.8 to 0.7 mmHg). There were statistically significant differences in the average reductions of 24-h BP (7.5/3.9 mmHg, p<0.001), daytime BP (8.6/4.0 mmHg, p<0.001) and nighttime BP (6.1/3.4 mmHg, p<0.05) as well as casual BP (9.0/5.0 mmHg, p<0.001). The trough/peak (T /P ) ratios for the systolic and diastolic BPs were 0.84 and 0.78, respectively, in the irbesartan group. The incidence of adverse events was similar in both groups. The results showed that irbesartan administered 100 mg once daily was well tolerated in the treatment of essential hypertension and was effective in producing sustained 24-h BP control. (Hypertens Res 2008; 31: 1753–1763) Key Words: SR47436, irbesartan, double-blind randomized study, ambulatory blood pressure monitoring, essential hypertension Introduction Hypertension is a major risk factor for cardiovascular dis- eases (1). The aim of antihypertensive therapy is to lower the morbidity and mortality from cardiovascular diseases, and a number of intervention studies have shown that such therapy is effective (2). Given the long-term objectives of antihyper- tensive treatment aimed at cardiovascular disease prevention, it is desirable to use an antihypertensive agent which reliably controls blood pressure (BP) with few adverse drug reactions when administered once daily. Blood pressure can now be measured non-invasively for 24 consecutive hours (3–5). Several studies have shown that the average BP measured by ambulatory BP monitoring (ABPM) correlates more strongly with the severity of hypertensive organ damage than the values measured during outpatient vis- its (6). In addition, the guidelines for clinical assessment of antihypertensive drugs in Japan recommend the use of trough/ peak (T/P) ratios based on ABPM measurements to investi- gate the duration of therapeutic effects (7). SR47436 (irbesartan) is a non-peptide angiotensin II (AII) receptor blocker that can be administered orally. Irbesartan selectively binds to a type 1 AII receptor and lowers BP by From the 1)Division of Hypertension and Nephrology, National Cardiovascular Center, Suita, Japan; 2)Strategic Development Department, Shionogi & Co., Ltd., Osaka, Japan; and 3)Miyagi Foundation for the Prevention of Adult Diseases, Sendai, Japan. Address for Reprints: Yuhei Kawano, M.D., Division of Hypertension and Nephrology, National Cardiovascular Center, 5–7–1 Fujishirodai, Suita 565– 8565, Japan. E-mail: ykawano@hsp.ncvc.go.jp Received May 7, 2008; Accepted in revised form July 2, 2008. 1754 Hypertens Res Vol. 31, No. 9 (2008) competing with AII to bind to the receptor. In Japan, single- dose and repeated-dose studies have been conducted among healthy male volunteers. Among those with mild to moderate essential hypertension, two studies of irbesartan have been conducted: a pilot study and a late phase II clinical study (8). The results of these studies showed that irbesartan could safely and effectively lower BP when administered once daily, and the optimal clinical doses were estimated at 50–100 mg/d. The present study investigated the duration of the anti- hypertensive effect of irbesartan using ABPM. The effect of once-daily administration of 100 mg of irbesartan was evalu- ated in a placebo-controlled, double-blind randomized study. Methods The present study was conducted according to the “Good Clinical Practice for Trials on Drugs (GCP)” ordinance of Japan (Pharmaceutical Affairs Law, Article 14, Section 3 and Article 80, Sections 2-1, 4 and 5) established in accordance with the Declaration of Helsinki. The study was also approved by the institutional review board of each participat- Fig. 1. Flowchart depicting the inclusion and exclusion of study subjects. Enrolled patients n = 94 Discontinuation/ withdrawal during baseline period n = 14 Drug allocation Not treated/tests not performed Irbesartan 100 mg Placebo n = 0 n = 1 Irbesartan 100 mg Placebo n = 0 n = 0 Irbesartan 100 mg Placebo n = 0 n = 0 Irbesartan 100 mg Placebo n = 0 n = 0 Irbesartan 100 mg Placebo n = 2 n = 1 GCP non-compliance Non-qualifying cases Progressed to treatment period Excluded Excluded Safety analysis set 24-h bloodpressure analysis set Efficacy analysis set Irbesartan 100 mg Placebo n = 40 n = 40 Irbesartan 100 mg Placebo n = 40 n = 39 Irbesartan 100 mg Placebo n = 38 n = 38Irbesartan 100 mg Placebo n = 40 n = 39 Irbesartan 100 mg Placebo n = 40 n = 39 Kawano et al: ABPM Study of Irbesartan in Hypertension Patients 1755 ing medical institution. Subjects Eligible subjects were patients with essential hypertension who visited one of the ten medical institutions listed in the Appendix between August 2001 and June 2002. Prior to the start of the baseline period, the investigators used a GCP- compliant consent form to explain the details of the present study to the subjects, and informed consent was obtained in writing from all subjects. Inclusion criteria at the start of the recruitment were as fol- lows: 1) age from 25 to 79 years, 2) men or postmenopausal women, 3) outpatients with essential hypertension, 4) untreated with antihypertensive agents or, if treated, willing to forgo current medication during the 4-week placebo run-in baseline period and the 6-week main study period. Inclusion criteria at the start of the study period were as follows: 1) sta- ble sitting BP in the last two measurements during the base- line period, 2) sitting systolic BP of 150 mmHg or above and diastolic BP of 95 mmHg or above, or systolic BP of 160 mmHg or above and diastolic BP of 90 mmHg or above, 3) sit- ting diastolic BP of less than 120 mmHg, 4) mean 24-h sys- tolic BP of 130 mmHg or above, or diastolic BP of 80 mmHg or above. The reason we used several criteria for casual BP was that we wanted to include only patients with definite sys- tolic-diastolic hypertension. Patients with secondary or malig- nant hypertension, cardiovascular diseases such as stroke, myocardial infarction and heart failure, renal failure or liver dysfunction, and patients judged unsuitable for participation by the investigator were excluded from the present study. A total of 94 subjects were enrolled in the present study (Fig. 1). Of these patients, 14 discontinued or withdrew dur- ing the baseline period. Hence, drug allocation was performed in 80 patients (irbesartan group: n=40; placebo group: n=40). One patient in the irbesartan group was excluded from the study because the proper allocated drug was not adminis- tered. Consequently, 79 patients (irbesartan group: n=39; placebo group: n=40) progressed to the treatment period, and their data were used for the evaluation of safety and efficacy. During the treatment period, GCP compliance guidelines were upheld for all 79 patients. Ambulatory BP monitoring was not properly performed in three patients (irbesartan group: n=1; placebo group: n=2); therefore, for the analysis of 24-h BP, we used data from the remaining 76 patients (irbesartan group: n=38; placebo group: n=38). Based on the findings of another ABPM study of irbesartan (9), it was estimated that the mean difference in the reduction in mean 24-h BP between the irbesartan group and placebo group would be 5.0 mmHg with a SD of 6.0 mmHg. Using these values, the required number of subjects to detect a dif- ference between the two groups was estimated to be 23 per group (power of test: 80%, α=0.05, two-sided). Therefore, the target number of cases was set at 30 subjects per group (total number of subjects: 60), allowing for dropouts and withdrawals. Investigational Drugs Irbesartan (100 mg) tablets and placebo tablets, indistinguish- able in appearance, were used. The tablets were randomly dis- tributed within each of the 30 blocks used; each block consisted of four patients (two in the irbesartan group and two in the placebo group). Administration of the Drugs During the baseline run-in period, one placebo tablet was administered once daily after breakfast for 2 weeks to patients with untreated essential hypertension and for 4 weeks to patients who stopped antihypertensive therapy before enroll- ing (Fig. 2). During the treatment period, one tablet (either 100 mg of irbesartan or placebo) was administered once daily after breakfast for 6 weeks. Fig. 2. Study timeline. *Lengthened by up to 2 weeks depending on patient circumstances. **Shortened or lengthened by 1 week depending on patient circumstances. Irbesartan 100 mg group (100 mg tablet once-daily) Placebo Placebo group (once-daily administration of a placebo tablet) -4 -2 0 2 4 6 weeks Baseline period* (2-4 weeks) Treatment period** (6 weeks) ABPM (in hospital) ABPM (in hospital) 1756 Hypertens Res Vol. 31, No. 9 (2008) Use of other antihypertensive drugs was prohibited during the baseline and treatment periods. Use of the following drugs was also prohibited unless necessary: psychotropic agents, anti-anxiety drugs, sedatives, hypnotic agents, analgesics, central acting muscle relaxants, phenothiazine antihista- mines, or phosphodiesterase-5 inhibitors. Measurements Casual BP and pulse rate were measured at 2-week intervals in a sitting position after sufficient rest. A tablet of irbesartan or placebo was taken before the measurement. Casual BP was measured twice, and the average values were used for analy- sis. At the end of the baseline period and at the end of the treatment period, casual BP was also measured in the supine, and standing positions. At the end of the baseline period and at the end of the treat- ment period, ABPM was carried out for 26 consecutive hours in the hospital using a portable automatic sphygmomanome- ter (TM-2421; A&D Co., Ltd., Tokyo, Japan) at 15-min inter- vals during the day (6:00–21:00) and at 30-min intervals at night (21:00–6:00). The same sphygmomanometer was used for each patient. During ABPM, the investigational drug was administered at 10 AM. The patients were instructed to relax the upper arm as a cuff was fastened in place and to remain in a sitting position while BP was monitored at peak (3–6 h after administration) and trough (23–24 h after administration) hours. The patients were also instructed to record daily activ- ities, such as the times of meals, sleeping and getting up. At the end of the baseline period and at the end of the treat- ment period (or at discontinuation of treatment), the follow- ing tests were conducted: hematology, blood chemistry, urinalysis, chest X-ray, electrocardiography, and funduscopy (if possible). Table 1. Characteristics of the Study Population Item Irbesartan 100 mg group Placebo group Total Total number of subjects 38 (100.0) 38 (100.0) 76 (100.0) Gender Male 28 (73.7) 25 (65.8) 53 (69.7) Female 10 (26.3) 13 (34.2) 23 (30.3) Age (years) 58.9±8.3 58.8±9.4 58.9±8.8 Body weight (kg) 66.5±13.4 64.6±10.9 65.5±12.2 Height (cm) 162.1±7.6 161.0±8.3 161.5±7.9 Complications No 9 (23.7) 7 (18.4) 16 (21.1) Yes 29 (76.3) 31 (81.6) 60 (78.9) WHO-ISH 1993 Guidelines Stage I 13 (34.2) 15 (39.5) 28 (36.8) Stage II 25 (65.8) 22 (57.9) 47 (61.8) Stage III 0 (0.0) 1 (2.6) 1 (1.3) History of antihypertensive therapy No past history 8 (21.1) 11 (28.9) 19 (25.0) Drug taken in the past 9 (23.7) 9 (23.7) 18 (23.7) Drug taken until just before the study 21 (55.3) 18 (47.4) 39 (51.3) Data are mean±SD or n (%). Table 2. Distribution of Baseline Values Item Irbesartan 100 mg group (n=38) Placebo group (n=38) Total (n=76) Mean 24-h BP during baseline period (mmHg) Systolic BP 145.0±10.9 142.9±10.6 143.9±10.7 Diastolic BP 95.0±8.8 92.0±7.8 93.5±8.4 Casual BP during baseline period (mmHg) Systolic BP 163.4±11.3 163.7±9.1 163.6±10.2 Diastolic BP 100.0±5.4 99.2±5.7 99.6±5.5 Casual pulse rate during baseline period (beats/min) 73.2±13.1 72.2±11.4 72.7±12.2 Data are mean±SD. BP, blood pressure. Kawano et al: ABPM Study of Irbesartan in Hypertension Patients 1757 Adverse Events All subjective symptoms and objective findings or diseases which newly appeared or which were exacerbated during the study were noted and the details were recorded. Any abnor- mal changes in laboratory data were evaluated based on a comparison of observed values in the baseline and treatment periods. If possible, follow-up investigations were performed until recovery. Overall Safety To investigate the severity of adverse drug reactions, overall safety of use was rated on a scale of 1–5: 1, safe (no safety Fig. 3. Twenty-four-hour blood pressure in the irbesartan and placebo groups. Mean±SD. SBP, systolic blood pressure; DBP, diastolic blood pressure. 40 80 120 160 200 10 11 12 13 14 15 16 17 18 19 20 21 22 23 0 1 2 3 4 5 6 7 8 9 10 (mmHg) Irbesartan group Baseline period Treatment period Time 40 80 120 160 200 10 11 12 13 14 15 16 17 18 19 20 21 22 23 0 1 2 3 4 5 6 7 8 9 10 (mmHg) Baseline period Treatment period Placebo group Time Administration Administration SBP DBP SBP DBP 1758 Hypertens Res Vol. 31, No. 9 (2008) problems, i.e., no adverse effects occurred); 2, slightly unsafe (mild adverse reaction occurred but no special treatment was needed and treatment was continued); 3, probably unsafe (dosage reduction or other measures were required); 4, unsafe (treatment with the investigational drug was, or should have been, discontinued); 5, no information available. In the event that treatment was discontinued for some reason, the investi- gator also evaluated the overall safety of use on the same scale. Patients for whom an evaluation could not be made for some reason were classified as “no information available.” Analysis The primary objective was to compare the efficacy of 100 mg irbesartan compared with placebo group on reducing the mean 24-h BP from ABPM data. The statistical analysis was conducted using SAS version 6.12 (SAS Japan Inc., Tokyo, Japan). The differences between groups were evaluated by Fig. 4. Twenty-four-hour pulse rate in the irbesartan and placebo groups. Mean±SD. 20 40 60 80 100 120 10 11 12 13 14 15 16 17 18 19 20 21 22 23 0 1 2 3 4 5 6 7 8 9 10 (beats/min) Placebo group Time Baseline period Treatment period 20 40 60 80 100 120 10 11 12 13 14 15 16 17 18 19 20 21 22 23 0 1 2 3 4 5 6 7 8 9 10 Administration Irbesartan 100 mg group Baseline period Treatment period Time (beats/min) Administration Kawano et al: ABPM Study of Irbesartan in Hypertension Patients 1759 the t-test. The secondary objectives were to assess some other measures of antihypertensive effects and the overall safety of use. The overall safety of use was assessed in an exploratory manner by tabulating the incidence, calculating descriptive statistics, and preparing tables and figures. All tests were two- sided and conducted at the 5% level of significance, unless otherwise specified. Values are expressed as mean±SD and 95% confidence intervals were used. The Clopper-Pearson method was used to estimate the confidence interval of ratios. Results Baseline Characteristics The patient characteristics, baseline values of BPs and pulse rate are shown in Tables 1 and 2. There were no significant differences between the irbesartan and placebo groups. The mean 24-h BP during the baseline period in the irbesartan group were 145.0±10.9 mmHg systolic and 95.0±8.8 mmHg diastolic and 142.9±10.6 mmHg systolic and 92.0±7.8 mmHg diastolic in the placebo group. Changes in BP and Pulse Rate during ABPM Systolic and diastolic BPs and pulse rate, as measured by ABPM, are shown in Figs. 3 and 4. At all measurement points, systolic and diastolic BPs during the treatment period in the irbesartan group were lower than those during the base- line period. In contrast, no marked differences in systolic and diastolic BPs were noted between the baseline and treatment periods for the placebo group. For pulse rate, no marked changes were observed between the baseline and treatment periods for either the irbesartan or the placebo group (Fig. 4). In the irbesartan group, 24-h systolic and diastolic BPs were significantly reduced whereas the values in the placebo group were unchanged (Table 3). The differences between the groups in the mean reduction in BP were 7.5/3.9 mmHg in 24 Table 3. Reductions in 24-h, Daytime and Nighttime BP Item and time period Group n Baseline period mean Treatment period mean Reduction Difference between treatment groups Mean 95% confidence interval p* Mean 95% confidence interval Systolic BP 24 h Irbesartan 38 145.0 139.2 5.8 3.2–8.4 0.0001 7.5 3.8–11.1 Placebo 38 142.9 144.6 −1.7 −4.3–1.0 Daytime (11:00–21:00) Irbesartan 38 150.1 143.8 6.3 3.2–9.5 0.0001 8.6 4.4–12.8 Placebo 38 146.9 149.1 −2.3 −5.1–0.6 Nighttime (0:00–5:00) Irbesartan 38 134.8 129.5 5.3 2.3–8.3 0.0100 6.1 1.5–10.7 Placebo 38 134.8 135.6 −0.8 −4.4–2.7 Diastolic BP 24 h Irbesartan 38 95.0 91.7 3.4 1.6–5.1 0.0004 3.9 1.8–6.0 Placebo 38 92.0 92.5 −0.5 −1.8–0.7 Daytime (11:00–21:00) Irbesartan 38 98.6 95.2 3.4 1.3–5.4 0.0018 3.9 1.5–6.4 Placebo 38 95.0 95.6 −0.6 −2.0–0.8 Nighttime (0:00–5:00) Irbesartan 38 87.7 84.4 3.3 1.2–5.4 0.0218 3.4 0.5–6.2 Placebo 38 86.0 86.1 −0.1 −2.1–2.0 Unit: mmHg. BP, blood pressure. *t-test. Table 4. T/P ratios as Determined by ABPM Item Group T value (mmHg) P value (mmHg) T/P ratio Placebo-corrected T value (mmHg) P value (mmHg) T/P ratio Systolic BP Irbesartan 100 mg 6.6 7.8 0.84 6.9 9.0 0.77 Placebo −0.3 0.1 Diastolic BP Irbesartan 100 mg 4.3 5.4 0.78 3.7 5.8 0.64 Placebo 0.5 0.5 T, trough; P, peak; ABPM, ambulatory blood pressure monitoring; BP, blood pressure. 1760 Hypertens Res Vol. 31, No. 9 (2008) h, 8.6/4.0 mmHg in daytime, and 6.1/3.4 mmHg in nighttime. The reductions in trough systolic and diastolic BPs were 6.6 and 4.3 mmHg, respectively, in the irbesartan group and −0.3 and 0.5 mmHg, respectively, in the placebo group (Table 4). The differences in the reductions for both the trough systolic and diastolic BPs were statistically significant. Trough and peak values were calculated from the mean reduction in BP during 24 h. The T/P ratios for systolic and diastolic BPs in the irbesartan group were 0.84 and 0.78, respectively (Table 4). Placebo-corrected T/P ratios were also calculated by taking the mean reduction in trough and peak BPs and correcting it for the mean reduction in the placebo group. The placebo-corrected T/P ratios for systolic and dias- tolic BPs were 0.77 and 0.64, respectively. Changes in Casual BP and Pulse Rate Changes in outpatient readings for sitting BP and pulse rate are shown in Fig. 5. In the irbesartan group, both systolic and diastolic BPs were significantly decreased at the second week (by 9.1 and 6.0 mmHg, respectively) of the treatment period, and remained significantly low up to the sixth week. In the placebo group, small but significant reductions in BPs were observed from the fourth week of the treatment. No ma
/
本文档为【10. 平滑指数高】,请使用软件OFFICE或WPS软件打开。作品中的文字与图均可以修改和编辑, 图片更改请在作品中右键图片并更换,文字修改请直接点击文字进行修改,也可以新增和删除文档中的内容。
[版权声明] 本站所有资料为用户分享产生,若发现您的权利被侵害,请联系客服邮件isharekefu@iask.cn,我们尽快处理。 本作品所展示的图片、画像、字体、音乐的版权可能需版权方额外授权,请谨慎使用。 网站提供的党政主题相关内容(国旗、国徽、党徽..)目的在于配合国家政策宣传,仅限个人学习分享使用,禁止用于任何广告和商用目的。

历史搜索

    清空历史搜索