12-相比缬沙坦

CLINICAL PHARMACOLOGY TRIALS An ambulatory blood pressure monitoring study of the comparative antihypertensive efficacy of two angiotensin II receptor antagonists, irbesartan and valsartan Giuseppe Manciaa, Krishna Korliparab, Peter van Rossumc, Giuseppe Villad and Barry Silverte Background The primary objective of this study was to compare the change from baseline in mean diastolic ambulatory blood pressure (ABP) at 24 h post dose (trough measurement) after 8 weeks of treatment with irbesartan or valsartan in subjects with mild-to-moderate hypertension. Secondary objectives included comparing the mean changes from baseline in systolic ABP at trough; 24-h ABP; morning and night-time ABP; self- measured systolic blood pressure (SBP) and diastolic blood pressure (DBP); and office-measured SBP and DBP at trough. Design After a 3-week, single blind, placebo lead-in period, 426 subjects were randomized to receive either irbesartan 150 mg or valsartan 80 mg for 8 weeks. Methods Ambulatory blood pressure measurements were obtained at baseline and at week 8. Self-measured morning and evening DBP and SBP readings were obtained at home over a 7-day period at baseline and at week 8. Office-measured seated DBP and SBP measurements were obtained at trough, at baseline, and at week 8. Results Irbesartan demonstrated significantly greater reductions than valsartan for mean change from baseline in diastolic ABP at trough (�6.73 versus �4.84 mmHg, respectively; P¼0.035). Irbesartan produced significantly greater reductions than valsartan for mean systolic ABP at trough (�11.62 versus �7.5 mmHg, respectively; Po0.01) and for mean 24-h diastolic ABP (�6.38 versus �4.82 mmHg, respectively; P¼ 0.023) and systolic ABP (�10.24 versus �7.76 mmHg; Po0.01). Irbesartan also produced significantly greater reductions than valsartan for office-measured seated DBP (�10.46 versus 7.28 mmHg, respectively; Po0.01) and SBP (�16.23 versus �9.96 mmHg, respectively; Po0.01) and for self-measured morning DBP (�6.28 versus �3.75 mmHg, respectively; Po0.01) and SBP (�10.21 versus �6.97 mmHg, respectively; Po0.01). Both drugs were well tolerated. Conclusion Irbesartan was more effective than valsartan in reducing DBP and SBP at trough and in providing greater overall 24-h blood pressure-lowering efficacy. Blood Press Monit 7: 135–142 & 2002 Lippincott Williams & Wilkins. Blood Pressure Monitoring 2002, 7:135^142 Keywords: ambulatory blood pressure monitoring, angiotensin II receptor antagonists, irbesartan, valsartan aOspedale S. Gerardo and Universita` Milano-Bicocca, Milan, Italy; bPike View Medical Centre, Bolton, UK; cBeatrix Ziekenhuis, Gorinchem, The Nether- lands; dFondazione S. Maugeri, Pavia, Italy and eStonehill Medical Centre, Bolton, UK. Sponsorship: This study was supported by Bristol-Myers Squibb and Sanofi-Synthelabo Conflicts of interest: none Correspondence and requests for reprints to Giuseppe Mancia, MD, Professor of Medicine, University of Milan-Bicocca, Ospedale S. Gerardo, Monza, Department of Medicine, Via Donizetti, 106, 20052 Monza, Italy. Fax: þ39 039 322 274; e-mail: mancia@gcst.inimi.it Received 25 October 2001 Revised 06 December 2001 Accepted 28 December 2001 Introduction Angiotensin II receptor antagonists (AIIRAs) are a recently developed class of antihypertensive agents that have gained widespread use in clinical practice because of (1) antihypertensive efficacy similar to that of all agents classically employed to treat hypertension [i.e., calcium channel blockers (CCBs), beta-blockers, angiotensin-con- verting enzyme (ACE) inhibitors, and diuretics], and (2) a placebo-like tolerability profile, which holds the promise of favorably impacting long-term compliance with antihyper- tensive treatment [1]. This placebo-like tolerability profile has been documented for all AIIRAs and should thus be regarded as a class-related feature [2]. Evidence has been produced, on the other hand, that compared with the first available AIIRA, losartan, subsequent agents of this class including cande- sartan, irbesartan, and telmisartan, may have greater blood pressure (BP)-lowering ability, possibly because of differ- ences in pharmacodynamic or pharmacokinetic properties [3–8]. Little information, however, is available on the comparative antihypertensive efficacy among the newer AIIRAs. The 1359-5237 & 2002 Lippincott Williams & Wilkins I0054851 高亮 I0054851 高亮 I0054851 高亮 present study addressed this question by comparing two agents for which a greater angiotensin II antagonistic and BP-lowering effect has been demonstrated compared with losartan, irbesartan and valsartan [9–13]. Antihypertensive efficacy in the current analysis was assessed by BP measurements in the physician’s office, at home, and by ambulatory monitoring to base results on multiple data collected in different environmental conditions. Methods Subjects Subjects were males and females aged between 18 and 75 years old with mild-to-moderate essential hypertension [defined as seated diastolic blood pressure (DBP) between 95 mmHg and 110 mmHg]. Subjects provided informed written consent and were willing to discontinue previous antihypertensive medicine if necessary. Subjects were enrolled from 45 sites in Italy, the UK, and the Netherlands (Appendix 1). Study design This randomized, multicenter, double blind, parallel-group study compared the antihypertensive efficacy of irbesartan 150 mg with that of valsartan 80 mg, administered once daily for 8 weeks. Three methods of obtaining BP were used: 24-h ambulatory blood pressure (ABP) monitoring; at-home, self-measured BP; and office-measured BP at 247 3 h after the last dose of study medication (i.e., at trough). The primary objective was to compare the change from baseline in diastolic ABP at trough after 8 weeks of treatment. Secondary objectives included comparing the changes from baseline in systolic ABP at trough; 24-h mean systolic and diastolic ABP; morning mean and evening mean systolic and diastolic ABP; self-measured DBP and systolic blood pressure (SBP); and office-measured seated DBP and SBP and heart rate at trough. Another secondary objective was to determine the percentage of subjects whose office-measured BP at trough was normalized (DBPo90 mmHg) and who responded to therapy (i.e., whose office-measured DBP was normalized or changed from baseline X 10 mmHg). A medical history that included a complete physical examination and an electrocardiogram was obtained at screening. Brief physical examinations were performed at each visit, and a complete examination was performed again at study conclusion. Fasting blood samples were obtained for complete blood count and serum chemistries at screening and at study conclusion. All medications known to affect BP were prohibited. Subjects were withdrawn from participation in the study if, at any time, mean office BP measurements over a 3-day period were SBP4 200 mmHg or DBP4 115 mmHg. Ex- clusion criteria included known or suspected secondary hypertension; office seated DBP4 110 mmHg or seated SBP4 200 mmHg; history of significant cardiac, hepatic, or renal disease; or uncontrolled diabetes, defined as fasting blood glucose 4 180 mg/dl (4 10 mmol/l) or non-fasting blood glucose 4 220 mg/dl (4 11.2 mmol/l), and clinically abnormal serum creatinine level, defined as X 1.5 mg/dl (X 132mmol/l). After a 3-week, single blind, placebo lead-in period, qualified subjects were randomized on a 1 : 1 ratio and entered 8 weeks of double-blind treatment. At each study visit, subjects were monitored for adverse events. Subjects were instructed to arrive at the clinic in the morning, before taking their study medication. Subjects were asked to refrain from consuming alcoholic beverages for 6 h prior to BP measurements and from smoking for 2 h beforehand. Measurements ABP measurements Twenty-four hour ABP readings were obtained with the same type of ABP monitor (model 90207; Spacelabs Medical, Redmond, Washington, USA) for all subjects. The device was set to obtain readings every 15 min throughout a 24-h period. ABP readings were conducted at baseline (at the end of the lead-in period) and at week 8. During the 24th hour of ABP recording, measurements were obtained every 3 min, with the patients in controlled conditions at the clinic (seated, at rest, quiet, and not smoking). Office BP and heart rate measurements Seated office ABP and heart rate measurements were obtained at baseline and at weeks 4 and 8 at trough. Subjects were instructed to arrive at the physician’s office between 0700–1000 h, without having taken that day’s study medication, eaten breakfast, smoked within 2 h prior to the BP readings, or consumed alcohol within 6 h prior to the BP readings. All readings were taken 247 3 h following the last dose of study medication, in the dominant arm, and by the same observer. Blood pressure was measured with a standard, calibrated, mercury sphygmomanometer, follow- ing 10 min of rest in the seated position. Three consecutive BP measurements were obtained at least 1 min apart and the values were averaged, after which heart rate was measured by pulse count for 30 s and multiplied by two. If the three consecutive seated DBP readings were not within 8 mmHg of each other, two additional readings were obtained at least 1 min apart, and heart rate was re- measured. For safety reasons, if at any time during the study seated SBP was 4 200 mmHg or seated DBP was 4 115 mmHg based on the mean of three readings, and these values were confirmed by follow-up within 3 days, the subject was removed from the study. Standing BP and heart rate were measured in the same manner, after the subject had stood in place for 2 min. 136 Blood Pressure Monitoring 2002, Vol 7 No 2 Home BP measurements All subjects were trained to use a validated, calibrated, semi-automatic BP self-measurement device (Pressolink-T; Tam Telesante, Aix-en-Provence, France). The device includes an Omron HEM-705 BP monitoring device (Omron Healthcare, Inc, Vernon Hills, Illinois, USA), software for data collection, and hardware for data transmission. Self-measured BP was obtained at baseline and at week 8. Blood pressure values were automatically recorded and stored by the BP self-measurement device. Subjects were instructed to take twice-daily (morning and evening) sequences of three BP readings over seven consecutive days for each of the two periods while seated. Three self-measurements were taken twice daily: in the morning on awakening (before breakfast and study drug intake) in a seated position, and in the evening at bedtime in a seated position. Subjects were not instructed to follow a specific sleep regimen, although awakening and bedtimes were recorded. Values recorded on the first day of each 7-day period were excluded from analysis. The remaining values (n¼ 18) were averaged. Methods of analysis Patient characteristics Key baseline variables were age, sex, race, weight, baseline ABP measurements, baseline self-measured BP, and base- line office-measured BP at trough. Sample size In order to detect a 3 mmHg difference between irbesartan and valsartan in mean diastolic ABP at trough at week 8 compared with baseline, a two-sided test at a significance level of a¼ 0.05 with a power of 1�a¼ 0.9, including 155 subjects per group, was required. Total sample size was n¼ 388 (194 in each group), which was calculated to anticipate loss to follow-up and unacceptable BP data. Statistical tests Descriptive summaries and statistical tests were per- formed. Subjects maintained a diary of their sleeping patterns, and these data were used to define daytime hours (i.e. , hours from awakening until going to bed) and night- time hours (i.e., hours from going to bed until awakening). The mean daytime ABP was defined as the arithmetic mean of the hourly mean values during the hours that the subject was awake after the morning drug intake, and the hours from awakening until completion of the 24th hour post dose the next morning. The mean night-time ABP was defined as the arithmetic mean of the hourly mean values while the patient was asleep. The transitional hours, (i.e., the time between going to bed and falling asleep, and upon awakening) were included in the night-time average if the subject slept at least 30 min during the hour, or in the daytime average if the patient slept less than 30 min during the hour. The variables analysed for change from baseline at week 8 were mean diastolic and systolic ABP at trough; mean 24-h diastolic and systolic ABP; daytime and night-time mean diastolic and systolic ABP; morning and evening mean self-measured DBP and SBP; and seated and standing mean office-measured DBP and SBP. Group comparisons were calculated for irbesartan versus valsartan for the percentage of subjects who were normalized and subjects who were responders. The primary efficacy analysis was performed on all randomized subjects with acceptable ABP data (n¼ 303). Secondary efficacy analyses were based on data from all subjects with valid data that could be evaluated. Rigorous criteria for compliance with each of the efficacy analyses were employed. Subjects were excluded from individual efficacy analyses if (1) ABP recording started too early or too late (7 1 h); (2) the number of valid readings was less than the percentage of the expected number of readings; (3) the number of 24-h readings was less than the percentage of the expected number of readings; and (4) 15 self-measured readings were not available over 5 days. For the primary efficacy analysis of change in trough ABP at Week 8, acceptable data was defined as at least 15 valid readings in the repetitive trough ABP measurement interval and at least 69 valid readings for the first 23 h post dose. Of the 426 subjects randomized, 11 discon- tinued treatment before study completion, and 112 had data that were not acceptable for statistical analysis according to the criteria defined earlier. Of the 11 subjects who discontinued treatment, one subject discontinued because of hypertension. In total, 303 subjects were included in the primary efficacy analysis. Table 1 depicts the number of patients analysed for each study end-point. For the secondary end-points of self-measured mean morning ABP, self-measured mean evening ABP, and self- measured mean overall ABP, different criteria were used to define the readings as acceptable for statistical analysis. For Table 1 Number of subjects included in analysis per endpoint Randomized subjects per analysis at week 8 Valsartan 80 mg (n) Irbesartan 150 mg (n) Total (n) Subjects included in analysis of ABPM data 215 211 426 Subjects with valid ABPM data 156 147 303 Subjects included in self-measured BP data analysis Morning 140 139 279 Evening 121 117 238 Total 99 98 197 Subjects included in trough office seated BP data analysis 211 202 413 Subjects included in safety analysis 215 211 426 ABPM, ambulatory blood pressure monitoring; BP, blood pressure. Efficacy of irbesartan versus valsartan Mancia et al. 137 mean morning measurements, at least 15 valid readings were required; for mean evening measurements, at least 12 valid readings were required; and for mean overall measurements, at least 27 valid, paired readings (valid morning and evening readings on the same day) were required. In addition, all three end-points had to have at least 5 days (not necessarily consecutive) of valid readings. For morning, evening, and overall self-measured ABP, a total of 279, 238, and 197 subjects were included in the analyses, respectively. Summary statistics included mean, standard deviation, and mean plus standard deviation change from baseline for each treatment group. For the percentage of subjects who were normalized and who were responders, within-group 95% confidence intervals were calculated. The 95% confidence intervals and P values for the risk ratios of the therapeutic response variables were calculated post hoc using the Cochran–Mantel–Haenszel test. An analysis of covariance (ANCOVA) model was used to compare the treatment arms with regard to the following variables: changes in mean diastolic or systolic ABP (at trough, 24-h, and daytime and night-time); changes in mean self-measured DBP or SBP; and office-measured seated and standing DBP and SBP at trough. Treatment comparisons were carried out using the ANCOVA model with treatment and country as main factors and baseline values as a covariate. A second covariate, the ‘number of awake hours during week 8 of ABP monitoring,’ was also included in the ANCOVA model for the change from baseline in daytime and night-time hours. Safety analysis All subjects who received at least one dose of study medication were included in the analysis of safety data. No statistical tests were performed because of lack of power to determine statistical significance. Adverse events were classified as either a concomitant experience (CE) (unrelated or unlikely to be related to study medication) or an adverse drug experience (ADE) (related, probably related, or possibly related to study medication). Extent of exposure to study drug (i.e., number of days of exposure) was summarized, and the mean duration of exposure was calculated for each treatment group. Results In this study, 426 subjects were randomized to receive either irbesartan 150 mg or valsartan 80 mg. Each group was balanced in demographic characteristics and baseline BP values (Table 2). The mean age was approximately 55 years, and subjects were predominantly white and male. Table 3 shows the frequency of common comorbidities within the two groups. The values for various BP changes induced by treatment are shown in Figure 1. While both irbesartan and valsartan significantly reduced BP from baseline, in the 303 subjects included in the efficacy analysis for the study’s primary objective, irbesartan produced a statistically greater reduc- tion in mean diastolic ABP at trough (�6.73 versus �4.84 mmHg, respectively; P¼ 0.035). Irbesartan also produced a statistically greater reduction in mean systolic ABP at trough (�11.62 versus �7.5 mmHg, respectively; Po 0.01). In addition, irbesartan caused a significantly greater reduction compared with valsartan in mean 24-h diastolic and systolic ABP (P¼ 0.023 and Po 0.01, respectively); mean daytime diastolic and systolic ABP (P¼ 0.017 and P¼ 0.02, respectively); and mean morning self-measured DBP and SBP (Po 0.01 for both). There was no substantial difference between the two drugs for mean night-time ABP or for mean evening self- measured BP change from baseline. Hourly BP profile was lower with treatment than at baseline in both groups. During treatment, hourly BP values were usually lower in the irbesartan than in the valsartan group, the difference being more evident during the day than during the night (Fig. 2). There were 413 subjects included in the efficacy analysis for office-measured seated and standing DBP and SBP at Table 2 Baseline demographics and clinical characteristics Characteristics Valsartan 80 mg Irbesartan 150 mg n 215 211 Sex (% male) 67 62 Race (% white) 97 96 Mean age (y)/(SD) 55.4 (9.9) 55.1 (9.7) n 213 209 Mean weight (kg)/(SD) 81.8 (14.5) 79.3 (12.4) n 179 178 Trough 24th-h ABP (SBP/DBP; mmHg) 150.0/95.7 148.3/94.2 [SD] [9.9/15.0] [9.2/14.3] n 175 173 Mean ABP (SBP/DBP; mmHg) 143.8/89.1 142.2/88.2 [SD] [12.0/8.3] [12.7/8.3] n 214 211 Seated office BP (SBP/DBP; mmHg) 158/100.8 159.3/100.7 [SD] [14.1/4.6] [13.6/4.2] n 170 169 Self-measured morning BP (SBP/DBP; mmHg) 149.2/96.4 149.1/96.6 [SD] [15.0/10.1] [17.8/10.2] n 159 147 Self-measured evening BP (SBP/DBP; mmHg) 149.8/95.2 148.8/94.3 [SD] [14.6/10.2] [17.1/9.8] n 213 210 Seated office HR (bpm) 75.2 74.1 [SD] [10.5] [7.8] ABP, ambulatory blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; BP, blood pressure; HR, heart rate. Val