The Efficacy and Tolerability of Barnidipine Hydrochloride in Thai Patients with Hypertension

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1 The Journal of International Medical Research 2004; 32: The Efficacy and Tolerability of Barnidipine Hydrochloride in Thai Patients with Hypertension P BURANAKITJAROEN 1, B KOANANTAKUL 2, M PHOOJAROENCHANACHAI 1 AND C CHAWANTANPIPAT 2 1 Division of Hypertension, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand; 2 Department of Medicine, Bhumibol Adulyadej Hospital, Royal Thai Air Force, Bangkok 10210, Thailand This open-label, blinded study was performed to evaluate the efficacy and tolerability of barnidipine at a titrated dose of mg once daily for 8 weeks in the treatment of essential hypertension in 40 Thai patients. Office blood pressure (BP) and 24-h ambulatory BP measurements were recorded. A systolic BP/ diastolic BP (SBP/DBP) reduction of 18.0 ± 13.6/9.1 ± 6.6 mmhg was obtained. The full response rate among patients with systolic and diastolic hypertension was 63% using either SBP or DBP criteria, and 54% using both SBP and DBP criteria. One of the two patients with isolated systolic hypertension had a full response, and the BP in two of the three patients with isolated diastolic hypertension was normalized. The trough-to-peak ratio and smoothness index for SBP/DBP were acceptable (0.76 ± 0.63/0.55 ± 0.26 and 1.2 ± 0.4/1.2 ± 0.3, respectively). In conclusion, once-daily barnidipine monotherapy provides effective 24-h BP control and is generally well tolerated in ambulatory patients. KEY WORDS: BARNIDIPINE; CALCIUM-CHANNEL BLOCKER; HYPERTENSION; EFFICACY Introduction The benefits of using long-acting dihydropyridine calcium-channel blockers to treat hypertension (HT) include a marked reduction in cardiovascular and cerebrovascular morbidity and mortality, a fact which has been well documented in many prospective studies. 1 6 Long-term clinical trials show further benefits in patients with diabetes and HT. 5 8 Barnidipine, an L-type dihydropyridine calcium-channel blocker, has recently become available in Thailand. The purpose of this study was to evaluate the efficacy and tolerability of this drug in Thai patients with essential HT. Since 24-h ambulatory blood pressure monitoring (24-h ABPM) is a better predictor of clinical outcomes than office blood pressure (BP) values, 9,10 both office BP measurements and 24-h ABPM were performed to confirm the clinical efficacy of the drug and to eliminate any patients with white coat HT. Patients and methods This open-label, single-blinded, multicentre study involved treatment with placebo for 4 weeks followed by titrated doses of 185

2 barnidipine for 8 weeks. The study protocol was approved by the Siriraj Hospital Ethics Review Committee. PATIENTS Participants were men and women aged years with essential HT, recruited from the out-patient departments of the Siriraj and Bhumibol Adulyadej hospitals, Thailand. HT was defined as a mean sitting diastolic BP (DBP) of 95 mmhg and/or a mean systolic BP (SBP) of 160 mmhg. Women of childbearing age could not be pregnant or lactating, and were required to be using adequate contraception. Major exclusions were: known or suspected secondary HT; significant cardiovascular, cerebrovascular, renal or hepatic impairment; and significant retinal exudates or haemorrhages. Patients with type 1 or poorly controlled type 2 diabetes mellitus, those who were chronic users of anticoagulants, digoxin, imipramine group antidepressants, lithium, neuroleptics, short-acting nitrates, high doses of nonsteroidal anti-inflammatory drugs or aspirin, or salt substitutes containing potassium chloride, and those who abused alcohol or drugs were excluded. In addition, patients receiving any investigational therapy within the month prior to signing the informed consent, those with a known hypersensitivity to calcium-channel blockers and night-shift workers were not eligible for enrolment. Informed consent was required from all patients before enrolment. The age, gender, body mass index (BMI) (calculated from the weight and height) and duration of previous treatment were recorded for each patient. DRUG REGIMEN In Thailand, barnidipine is available in 10 and 15 mg capsules. One 10 mg capsule every day was used as a low-dose regimen, and one 15 mg capsule every day as a highdose regimen. On visit 1 (week 4), eligible participants meeting the study criteria entered a 4-week, single-blinded placebo period. At visit 2 (week 0), if the morning mean sitting DBP was 95 mmhg and/or the SBP was 160 mmhg, patients were given an initial 4-week regimen of 10 mg once-daily barnidipine. At visit 3 (week 4), those with an adequate BP response (DBP < 90 mmhg and SBP < 140 mmhg) continued on the same dose for another 4 weeks. Those without adequate BP control had their dose of barnidipine increased to 15 mg once daily for another 4 weeks. Visit 4 (week 8) was at the end of the study. At each visit any adverse drug reactions were recorded. Patients were instructed to take their medication at the same time every morning, maintaining an interval as close as possible to 24 h between doses. They were asked not to take the medication on the days of their office visits. Compliance was evaluated at each visit by patient interview and drug count. Non-compliance was defined as taking < 80% or > 120% of the prescribed medication. MEASUREMENT OF OFFICE BP At each office visit, the weight and height were recorded in order to calculate the BMI for each individual. Patients were then asked to rest for 5 min and heart rate and BP were measured. Sitting SBP (Korotkoff I) and DBP (Korotkoff V) were measured three times at 2-min intervals using a well-calibrated mercury sphygmomanometer. The same arm was used throughout the study and the measurements were always made in the morning (08.00 ± 1 h). During the active treatment period, this arrangement allowed trough BP measurements to be obtained approximately 24 ± 2 h after patients had received their preceding barnidipine doses. Cigarette smoking and the consumption of 186

3 beverages containing caffeine or alcohol were prohibited for at least 2 h before the BP measurements were made. A mean office BP for each visit was calculated from the three sitting BP measurements. Patients were divided at visit 2 into one of three groups according to the type of HT: (i) DBP 90 mmhg and SBP 140 mmhg systolic and diastolic HT (SDHT); (ii) SBP 140 mmhg and DBP < 90 mmhg isolated systolic HT (ISH); (iii) SBP < 140 mmhg and DBP 90 mmhg isolated diastolic HT (IDH). Patients with SDHT were further divided according to the degree of diastolic HT, with category 1 having a DBP 95 mmhg and category 2 a DBP 90 mmhg and < 95 mmhg. Patients were subsequently stratified into three groups according to the BP response to treatment: (i) Full response, defined as a relative reduction in trough sitting DBP/SBP of 10/ 20 mmhg from baseline, and/or a trough sitting DBP/SBP of < 90/< 140 mmhg; (ii) Partial response, defined as a reduction in trough sitting DBP/SBP of 5 to < 10/10 to < 20 mmhg with a trough sitting DBP/SBP of 90/ 140 mmhg; (iii) Minimal response, defined as a reduction in trough sitting DBP/SBP of < 5/< 10 mmhg with a trough sitting DBP/SBP of 90/ 140 mmhg, or any increase in trough sitting DBP or SBP. AMBULATORY BLOOD PRESSURE MONITORING In this study, 24-h ABPM was carried out at visit 2 (week 0) and visit 4 (week 8) in all patients, using the same model of 24-h ABPM device in each individual patient (either a Quiet Trak Model , Welch Allyn Tycos Inc., NC, USA, or A&D Model TM-2421, A&D Co. Ltd, Tokyo, Japan); equipment performance has been described and validated previously. 11 The 24-h ABPM device was attached in the morning (08.00 ± 1 h). The BP was then automatically recorded at intervals throughout a 24-h period: every 30 min during the day (06.00 to 23.00) and every 1 h during the night (23.00 to 06.00). Patients were asked to follow their ordinary daily activities, but to remain motionless and keep their arms still whenever the device was in operation and the BP was being recorded. 12 Only data from patients with 80% successful BP readings were acceptable for analysis. Heart rate, daytime BP levels, night-time BP levels and differences between the daytime and night-time BP levels were calculated. Patients with an average daytime SBP < 135 mmhg and an average daytime DBP < 85 mmhg on 24-h ABPM with an office SBP and/or DBP of 140 mmhg and/or 90 mmhg, respectively, were defined as having white coat HT (WCH). 13,14 Subjects with a > 10% decline in the mean daytime SBP and/or DBP levels compared with the night-time values on 24-h ABPM were classified as dippers. 13 A morning surge was defined as a rise in SBP of > 50 mmhg during the 3 h after waking compared with the SBP 3 h before waking. 13 The trough:peak ratio (T:P ratio) and smoothness index (SI) were calculated for both SBP and DBP in patients achieving adequate BP control by dose titration. The SI was calculated in the following manner. First, the average BP values for each hour of the 24-h monitoring periods, both before and after active treatment, were calculated. The hourly changes in BP induced by treatment ( BP) were computed, together with their standard deviations [SD( BP)], which represent the dispersion of the antihypertensive effect over the 24-h values. 187

4 Finally, the mean BP was divided by the mean SD( BP) to give the SI. 15 The T:P ratio, defined as the ratio between the effect of an antihypertensive agent at the end of the interval between doses (trough) and at the time of its maximum effect (peak), 16,17 was calculated by dividing trough values by peak values. 18,19 Trough values were defined as the mean of the differences in values taken h after drug administration (excluding the time of administration), and peak values were defined as the mean of the differences in values taken 2 8 h after drug administration, between the placebo period and the active treatment period. The BP loads, defined as the percentage of BP readings recorded by ABPM that were elevated (SBP > 140 mmhg and DBP > 90 mmhg) during the 24-h period, were also calculated. 20 LABORATORY INVESTIGATIONS Laboratory investigations were performed at visits 1 and 4, and included a complete blood count, urine analysis and standard 12-lead electrocardiography. Serum electrolytes, creatinine, blood urea nitrogen, glucose, uric acid, cholesterol, triglycerides, low-density and high-density lipoprotein cholesterol, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, albumin, globulin and total bilirubin were also measured. STATISTICAL ANALYSES Results are shown as the mean ± SD or percentage (%) as appropriate. Statistical analyses were performed using SPSS version 9.0 (SPSS Inc., Chicago, IL, USA). The Student s t-test and χ 2 test were used to compare the continuous and categorical data between each pair of values from the placebo and barnidipine treatment periods, respectively. Repeated measures analysis of variance (with the Bonferroni method for multiple comparisons) was used to compare different measurements of the same attribute (BP). Intention-to-treat analyses were performed in patients with both systolic and diastolic HT. A P-value of 0.05 was considered to be statistically significant. Results Of the 46 participants screened, 32 patients with mild to moderate HT and 11 patients with severe HT were enrolled. Three patients were excluded because they did not meet the inclusion criteria. The patient characteristics are given in Table 1. All but two patients had been previously treated for HT. The mean office SBP on entry was ± 14.1 mmhg (range mmhg) and the mean office DBP was 95.8 ± 7.1 mmhg (range of mmhg). The mean heart rate (HR) on entry was 78.4 ± 9.5 beats/min (range beats/min). There were no TABLE 1: Patient characteristics (n = 43) on entry to this study of the efficacy and tolerability of barnidipine hydrochloride in Thai patients with hypertension Age (mean ± SD) 55.7 ± 11.5 years (range years) Gender Female 27 (62.8%) Male 16 (37.2%) Duration of treatment (mean ± SD) 8.5 ± 6.9 years (range < 1 25 years) Body mass index (mean ± SD) 25.1 ± 3.8 kg/m 2 (range kg/m 2 ) 188

5 significant changes in mean heart rate throughout this study (visit 2, 80.8 ± 8.3 beats/ min; visit 3, 81.0 ± 8.4 beats/min; visit 4, 81.0 ± 7.5 beats/min). There was, however, a statistically significant reduction in the mean sitting SBP/DBP between visit 3 (after 4 weeks of barnidipine treatment) and visit 2 (baseline; by 15.3 ± 16.1/6.8 ± 7.9 mmhg; P < 0.001). Two women who failed to adjust the drug dosages according to the protocol and one man with an adverse event were excluded after visit 3; therefore, only 40 patients completed the trial. After 8 weeks of barnidipine treatment, the mean SBP/DBP was significantly decreased compared with baseline levels (by 18.0 ± 13.6/9.1 ± 6.6 mmhg; P < 0.001). There were no significant differences in mean BMI and heart rate between the visits (Table 2). There were also no significant changes in most of the laboratory results and electrocardiographic findings between visit 1 and visit 4. The white blood cell and basophil counts were lower and the plasma potassium levels were higher at visit 4 compared with visit 2, but the levels were still within normal limits and these changes were not clinically significant (Table 3). There were 17 cases with adverse events at visit 2 (placebo period): six cases of dizziness, seven cases of headache, one case of dry cough and three cases of both headache and dizziness. Only five patients experienced adverse events while they were taking the active drug: one case of headache and one case of dizziness, constipation and arthralgia at visit 3 (low-dose regimen) and constipation and polyuria at visit 4 (high-dose regimen), one case of dizziness, one case of palpitation noted 3 days after visit 3 (high-dose regimen), and one case of headache and sweating. All of them tolerated barnidipine well, except for one patient who had to discontinue the drug because of palpitations and was withdrawn from the study. After 8 weeks of barnidipine treatment, four patients (10%) remained on a dose of 10 mg/day, while 36 patients (90%) required 15 mg/day. There were two cases of ISH and three cases of IDH; these were evaluated and considered separately. The intention-to-treat analyses were performed in patients with SDHT. After a 4-week course of 10 mg/day barnidipine, the mean office SBP/DBP measurements were significantly reduced from baseline by 16.8 ± 15.9/7.5 ± 7.8 mmhg (P < for both systolic and diastolic). After an 8-week course of barnidipine treatment, further reductions in SBP/DBP were observed, with significant mean reductions of 19.4 ± 13.4/9.5 ± 6.7 mmhg (P < for both systolic and diastolic) from baseline. When compared with the mean BP at visit 3, further average reductions of 3.7 ± 14.5/2.8 ± 6.6 mmhg were achieved, but these changes were not statistically significant (Table 2). Since only 31 patients with SDHT required 15 mg/day barnidipine after visit 3, further examination of blood pressure response to the high-dose regimen was performed in these patients: there was a significant reduction in SBP/DBP (6.2 ± 12.2/4.1 ± 5.6), with values of ± 13.4/93.5 ± 6.7 mmhg versus ± 12.2/89.5 ± 7.2 mmhg (P = 0.07 for SBP and P = 0.03 for DBP). Subgroup analyses were performed on SDHT patients according to the degree of diastolic HT (Table 4). After a 4-week course of 10 mg/day barnidipine treatment, the mean office SBP/DBP was reduced from baseline by 16.0 ± 16.5/8.0 ± 7.8 mmhg (P < for both SBP and DBP) in category 1 patients (DBP 95 mmhg), and by 20.5 ± 3.4/ 5.7 ± 7.9 mmhg (P = for SBP and P = 0.09 for DBP) in category 2 patients (DBP 90 mmhg and < 95 mmhg). After an 8-week course of barnidipine treatment, further reductions in SBP/DBP from baseline were observed, with significant average 189

6 TABLE 2: Body mass index, office blood pressure (BP) and heart rate measurements on entry into the study (visit 1), after 4 weeks of treatment with placebo (visit 2), and after 4 weeks (visit 3) and 8 weeks (visit 4) of barnidipine treatment. Patients are divided according to the type of hypertension (HT) Type of HT Visit 1 Visit 2 Visit 3 Visit 4 SDHT (n = 38) a Body mass index (kg/m 2 ) 25.1 ± ± ± ± 3.6 Sitting SBP (mmhg) ± ± ± 15.4 b ± 12.7 b Sitting DBP (mmhg) 96.4 ± ± ± 8.3 b 89.1 ± 7.1 b Sitting heart rate (beats/min) 78.7 ± ± ± ± 6.9 ISH (n = 2) Body mass index (kg/m 2 ) 27.0 ± ± ± ± 6.6 Sitting SBP (mmhg) ± ± ± ± 33.0 Sitting DBP (mmhg) 82.7 ± ± ± ± 9.4 Sitting heart rate (beats/min) 78.0 ± ± ± ± 5.7 IDH (n = 3) Body mass index (kg/m 2 ) 25.0 ± ± ± ± 5.1 Sitting SBP (mmhg) ± ± ± ± 1.8 b Sitting DBP (mmhg) 97.1 ± ± ± ± 2.3 b Sitting heart rate (beats/min) 75.3 ± ± ± ± 16.0 Values given are the mean ± SD. a Excluding two cases who failed to increase to the appropriate dosage plus a case who dropped out after visit 3. b P-value significant at < 0.05 for visit 2 versus visit 3, and visit 2 versus visit 4. SDHT, systolic and diastolic HT (DBP 90 mmhg and SBP 140 mmhg); SBP, systolic blood pressure; DBP, diastolic blood pressure; ISH, isolated systolic HT (SBP 140 mmhg and DBP < 90 mmhg); IDH, isolated diastolic HT (DBP 90 mmhg and SBP < 140 mmhg). 190

7 TABLE 3: Laboratory results for the 40 Thai patients with hypertension in this study of the efficacy and tolerability of barnidipine hydrochloride on entry into and at the end of the study Variable Visit 1 Visit 4 P-value Haemoglobin (g/dl) 13.5 ± ± Haematocrit (%) 40.6 ± ± Red cell count ( /l) 4.7 ± ± White cell count ( 10 9 /l) 9.3 ± ± a Platelet count ( 10 9 /l) ± ± Neutrophil (%) 57.3 ± ± Lymphocyte (%) 32.5 ± ± Monocyte (%) 6.0 ± ± Basophil (%) 1.4 ± ± a Blood glucose (mg/dl) ± ± Creatinine (mg/dl) 1.1 ± ± Blood urea nitrogen (mg/dl) 15.0 ± ± Aspartate aminotransferase (IU/l) 24.7 ± ± Alanine aminotransferase (IU/l) 23.8 ± ± Alkaline phosphatase (IU/l) 89.1 ± ± Albumin (g/dl) 4.4 ± ± Globulin (g/dl) 3.6 ± ± Total bilirubin (mg/dl) 0.7 ± ± Sodium (mmol/l) ± ± Potassium (mmol/l) 4.0 ± ± a Chloride (mmol/l) ± ± Bicarbonate (mmol/l) 27.0 ± ± Cholesterol (mg/dl) ± ± Triglyceride (mg/dl) ± ± High-density lipoprotein (mg/dl) 50.5 ± ± Low-density lipoprotein (mg/dl) ± ± Uric acid (mg/dl) 6.7 ± ± Values given are the mean ± SD. a P-value significant at <

8 TABLE 4: Body mass index, office blood pressure (BP) and heart rate measurements on entry into the study (visit 1), after 4 weeks of placebo (visit 2), and after 4 weeks (visit 3) and 8 weeks (visit 4) of barnidipine treatment. Patients with systolic and diastolic hypertension are divided according to category Visit 1 Visit 2 Visit 3 Visit 4 Category 1 a (n = 31) Body mass index (kg/m 2 ) 25.3 ± ± ± ± 3.4 Sitting SBP (mmhg) ± ± ± 16.6 b ± 13.3 b Sitting DBP (mmhg) 97.4 ± ± ± 7.8 b 90.6 ± 6.1 b Sitting heart rate (beats/min) 79.3 ± ± ± ± 7.2 Category 2 a (n = 7) Body mass index (kg/m 2 ) 24.2 ± ± ± ± 4.7 Sitting SBP (mmhg) ± ± ± 12.9 b ± 8.6 b Sitting DBP (mmhg) 91.6 ± ± ± ± 7.7 b Sitting heart rate (beats/min) 76.0 ± ± ± ± 5.7 Values given are the mean ± SD. a Excluding two cases who failed to increase to the appropriate dosage (category 1 and category 2) plus a case who dropped out after visit 3 (category 1). b P-value significant at < 0.05 for visit 2 versus visit 3, and visit 2 versus visit 4. SBP, systolic blood pressure; DBP, diastolic blood pressure. Systolic and diastolic hypertension, DBP 90 mmhg and SBP 140 mmhg; category 1, DBP 95 mmhg and SBP 140 mmhg; category 2, DBP 90 and < 95 mmhg and SBP 140 mmhg. 192

9 reductions of 18.0 ± 13.8/9.7 ± 6.6 mmhg (P < for both SBP and DBP) in category 1 patients and 25.8 ± 9.3/8.4 ± 7.4 mmhg (P < for SBP and P = 0.01 for DBP) in category 2 patients. Compared with the mean BP at visit 3, average reductions of 3.1 ± 15.8/2.7 ± 6.4 mmhg in category 1 patients and 6.9 ± 5.4/3.4 ± 8.1 mmhg in category 2 patients were achieved by the end of the study, but these changes were not statistically significant. There were no significant differences in the mean reductions in SBP/DBP after 4 weeks (16.0 ± 16.5/8.0 ± 7.8 mmhg versus 20.5 ± 3.4/5.7 ± 7.9 mmhg) or 8 weeks (18.0 ± 13.8/9.7 ± 6.6 mmhg versus 25.8 ± 9.3/8.4 ± 7.4 mmhg) of active treatment between patients in categories 1 and 2. Different patterns of BP response were observed in each category (Table 5). When DBP alone was considered for drug responsiveness, among those with a DBP level 90 mmhg, normalization (to < 90 mmhg) was found in 13 out of 38 patients (34%) after 4 weeks of drug treatment, and in 12 out of 35 patients (34%) after 8 weeks of drug treatment. A full response was achieved in 45% (17 out of 38) on visit 3 compared with 63% (22 out of 35) at visit 4. Orthostatic hypotension was not observed in this study. Among barnidipine-treated individuals with elevated DBP ( 95 mmhg), the responder rates were significantly higher in those who took high-dose barnidipine at visit 4 compared with those taking low-dose barnidipine at visit 3 (56.3% versus 30.3%, P = 0.03). When both SBP and DBP were used to measure drug responsiveness, a full response was observed in 37% (14 out of 38) at visit 3 and 54% (19 out of 35) at visit 4. There were no significant differences between patients in categories 1 and 2 in the percentages of full responders after 8 weeks of drug treatment (17 out of 29 versus five out of six for SBP; 18 out of 29 versus four out of six for DBP; 15 out of 29 versus four out of six for both SBP and DBP). One of the two patients with ISH (SBP 140 and DBP < 90 mmhg) achieved a full BP response on visits 3 and 4, while the other was a minimal responder after 8 weeks treatment. Two of the three patients with IDH (SBP < 140 and DBP 90 mmhg) achieved normalization on visit 4, while the other was a minimal responder, even after 8 weeks treatment. All patients underwent 24-h ABPM to evaluate treatment response and eliminate any individuals with WCH. Since 40 patients were able to complete an 8-week course of active treatment, 24-h ABPM data from 40 patients obtained prior to active treatment and at the end of the study was available for analysis. No patient was identified as having WCH. Mean hourly SBP, DBP and heart rate values before and after 8 weeks of barnidipine treatment in 40 patients are shown in Fig. 1. There is a significant positive correlation between the BP levels before the administration of barnidipine and the degree of BP reduction after an 8-week course of treatment (Fig. 2). The efficacy of barnidipine in lowering the BP was evaluated using the 24-h ABPM data from the 35 patients with SDHT. At the final visit (visit 4), barnidipine produced significant reductions in the mean 24-h SBP/DBP levels (8.1 ± 15.2/6.4 ± 9.9 mmhg) and daytime SBP/DBP levels (11.3 ± 19.4/7.6 ± 10.3 mm Hg) compared with those obtained at visit 2 (Table 6); night-time SBP/DBP levels were also decreased (6.1 ± 18.8/3.3 ± 11.7 mmhg), but the difference was not statistically significant. When only 25 barnidipinetreated patients in the non-dipper subgroup were examined, we observed a significant decrease in night-time SBP/DBP levels 193

10 TABLE 5: Treatment response in patients with systolic and diastolic hypertension after 4 weeks (visit 3) and 8 weeks (visit 4) of barnidipine treatment. Patients are divided according to category Visit 3 (n = 38) Visit 4 (n = 35) a SBP DBP SBP and DBP SBP DBP SBP and DBP Category BP response No. % No. % No. % No. % No. % No. % All (n = 38) Normalization Full Partial ND ND ND ND Minimal ND ND ND ND 1 (n = 31) Normalization Full Partial ND ND ND ND Minimal ND ND ND ND 2 (n = 7) Normalization Full Partial ND ND ND ND Minimal ND ND ND ND a Excluding two cases who failed to increase to the appropriate dosage (category 1 and category 2) plus a case who dropped out after visit 3 (category 1). SBP, systolic blood pressure; DBP, diastolic blood pressure; ND, not determined. Systolic and diastolic hypertension, DBP 90 mmhg and SBP 140 mmhg; category 1, DBP 95 mmhg and SBP 140 mmhg; category 2, DBP 90 and < 95 mmhg and SBP 140 mmhg; normalization, a fall in DBP to < 90 mmhg; full response, a relative reduction in trough sitting DBP/SBP of 10/ 20 mmhg from baseline and/or a trough sitting DBP/SBP of < 90/< 140 mmhg; partial response, a reduction in trough sitting DBP/SBP of 5 to < 10/10 to < 20 mmhg with a trough sitting DBP/SBP of 90/ 140 mmhg; minimal response, a reduction in trough sitting DBP/SBP of < 5/< 10 mmhg with a trough sitting DBP/SBP of 90/ 140 mmhg, or any increase in trough sitting DBP or SBP. 194

11 Pre-treatment Post-treatment 200 BP 110 Heart rate mmhg Beats/min Time (h) Time (h) FIGURE 1: Mean (± SD) systolic and diastolic blood pressure (BP) and heart rate throughout a 24-h period before and after 8 weeks of barnidipine treatment (n = 40). SBP DBP r = r = 0.77 mmhg 10 0 mmhg Mean 24-h BP at baseline (mmhg) Mean 24-h BP at baseline (mmhg) FIGURE 2: Relationship between baseline 24-h mean blood pressure (BP) levels (visit 1) and the degree of BP reduction after an 8-week course of barnidipine treatment. Results are presented for systolic BP (SBP) and diastolic BP (DBP) (n = 40). (150.2 ± 14.5/ 91.7 ± 9.9 mmhg versus ± 14.2/86.1 ± 7.7 mmhg; P = 0.01 for SBP and P = 0.03 for DBP). The observed BP loads were also significantly reduced in the active treatment period (visit 4) compared with those in the placebo period (visit 2), with values of 46.1 ± 25.1% versus 64.2 ± 25.0% for the SBP (P = 0.004) and 29.5 ± 20.4% versus 50.9 ± 29.6% for the DBP (P = ). The 24-h SBP and DBP load reduction rates were decreased by 18.1 ± 25.8% and 21.4 ± 27.3%, respectively, from the baseline. The SBP and DBP were considered to be normalized (< 135/85 mmhg) in 10 out of 35 (29%) patients. The proportion of non-dippers 195

12 TABLE 6: Blood pressure (BP) measurements following 24-h ambulatory blood pressure monitoring after 4 weeks of placebo (visit 2) and 8 weeks of barnidipine treatment (visit 4). Patients are divided according to type of hypertension (HT) 24-h BP (mmhg) Daytime BP (mmhg) Night-time BP (mmhg) Type of HT Visit 2 Visit 4 P-value Visit 2 Visit 4 P-value Visit 2 Visit 4 P-value SDHT (n = 38) SBP ± ± a ± ± a ± ± 17.3 NS DBP 89.7 ± ± a 90.5 ± ± a 87.1 ± ± 8.3 NS ISH (n = 2) SBP ± ± a ± ± a ± ± 26.2 NS DBP 81.0 ± ± 2.8 < a 81.0 ± ± 2.1 < a 81.5 ± ± a IDH (n = 3) SBP ± ± 14.2 NS ± ± 4.9 NS ± ± 9.5 NS DBP ± ± a ± ± 8.7 NS 98.3 ± ± 2.1 NS Values are the mean ± SD. a P-value significant at < 0.05 for visit 2 versus visit 4. SBP, systolic blood pressure; DBP, diastolic blood pressure; SDHT, systolic and diastolic HT (DBP 90 mmhg and SBP 140 mmhg); ISH, isolated systolic HT (SBP 140 mmhg and DBP < 90 mmhg); IDH, isolated diastolic HT (DBP 90 mmhg and SBP < 140 mmhg); NS, not significant. 196

13 increased from 71% (25 out of 35) at baseline to 83% (29 out of 35) at the end of the study period, but this change was not statistically significant. BP circadian profiles from all the patients analysed, either at baseline or at the end of the study, were classified as non-surge in type. There were average peak SBP/DBP reductions of 22.8 ± 10.7/18.7 ± 8.3 mmhg and average trough SBP/DBP reductions of 17.9 ± 13.5/11.5 ± 7.0 mmhg after an 8-week course of barnidipine treatment in full responders. The T:P ratio was 0.76 ± 0.63 (range ) and 0.55 ± 0.26 (range ) for SBP and DBP, respectively. The SI was 1.2 ± 0.4 (range ) and 1.2 ± 0.3 (range ) for SBP and DBP, respectively. Discussion The present study shows an antihypertensive effect of barnidipine in treating patients with SDHT similar to that reported in the studies of Liau et al. 21 and Kuwajima et al. 22 After 4 weeks of treatment, barnidipine significantly reduced both SBP and DBP in patients with SDHT when compared with baseline data. Giving titrated doses of barnidipine for an additional 4 weeks further reduced the BP, but the difference was not statistically significant. Previous studies have usually reported on the effect of a double dose of the studied drug In contrast, in the present study, only a half dose (5 mg of barnidipine) was added at visit 3. Nevertheless, significant reductions in SBP/DBP (6.2 ± 12.2/4.1 ± 5.6 mmhg) were noted when those with SDHT who had taken 15 mg of barnidipine (31 cases) after visit 3 were considered. There were no significant changes in heart rate observed among all 43 patients throughout this study. Similarly, analysis of the 40 HT patients who received 8 weeks of treatment showed that barnidipine had no effect on heart rate over 24 h. These results suggest that barnidipine does not cause sympathetic stimulation. The absence of reflex tachycardia after oral administration of barnidipine could be explained by the slow diffusion of the drug from the cell membrane depots where it accumulates after distribution. 26 The percentage of responders in the barnidipine-treated individuals with elevated DBP ( 95 mmhg), that is those with SDHT or IDH, increased with increasing dosage. The responder rates were significantly higher in those who took high-dose barnidipine at visit 4 compared with those taking low-dose barnidipine at visit 3. Our findings are consistent with those of Hart and Holwerda, 23 who reported responder rates of 57.0% and 41.0% for high-dose (20 mg) and low-dose (10 mg) barnidipine (P = 0.003). The high response rate confirms the efficacy of this drug. The slight increase in the serum potassium level and the decreases in the white blood cell and basophil counts found in our patients treated with barnidipine were of no clinical significance and the levels remained within normal limits. The 24-h ABPM data produced some interesting results. Although 24-h ABPM is not commonly required for antihypertensive drug monitoring regulations, this technique has been shown to be superior to the traditional office BP measurements. The use of 24-h ABPM devices enables physicians to enrol HT patients to the trial and subsequently eliminate individuals with WCH, since the inclusion of subjects with WCH may falsely improve the results of the studied drug. 13 Data obtained from 24-h ABPM are more reliable for excluding normotensive subjects than data obtained from office BP measurements The progressive lowering of office BP measurements during an 8-week course of barnidipine 197

14 treatment was confirmed by 24-h ABPM. There were significant reductions in the mean 24-h BP, daytime BP and BP load without interference with the normal BP circadian profiles. In addition, the antihypertensive effect of barnidipine increased with the baseline BP levels. However, there was only a slight decrease in the mean night-time BP levels after active drug treatment. As previously reported by Kuwajima et al., 22 barnidipine was unable to produce a further reduction in the nocturnal BP when this was already decreased (the so-called dipper pattern ). We therefore examined further the 25 patients in the non-dipper subgroup, in whom barnidipine was shown to notably decrease the night-time SBP/DBP after an 8-week course of treatment. When the present study was compared with that of Spieker, 25 the average reduction in the daytime SBP/DBP was 11.3/7.6 mmhg versus 13.5/8.0 mmhg and in the night-time SBP/DBP was 6.2/3.3 versus 6.8/3.2 mmhg. An excessive reduction in nocturnal BP induced by antihypertensive drugs can potentially lead to ischaemic cerebrovascular and cardiovascular complications at night. 30,31 This minimal effect of barnidipine on the nocturnal BP may therefore be beneficial, especially in patients with high cardiovascular risks. There was no significant difference between the percentage of cases with normalization at the end of the trial using office BP criteria (< 140/90 mmhg) compared with that using 24-h ABPM criteria (< 135/ 85 mmhg) (14.3% versus 28.5%). This implies that accurate office BP measurements could be as good as those obtained from 24-h ABPM. Since BP loads are better predictors of cardiac and vascular complications than either office BP measurements or mean 24-h ABPM values, the reduction in the BP load demonstrated with barnidipine in this study supports the clinical importance of this drug. 20 The T:P ratio and SI are important indicators to show whether the drug is appropriate for once-daily dosing. Based on the assumption that patients with HT are likely to receive the most benefit from therapy if the antihypertensive effects do not vary greatly during the day, US Food and Drug Administration guidelines indicate that the effect of any antihypertensive drug at the end of the dose interval (trough) should be no less than one-half to two-thirds of the peak effect, and a T:P ratio of 50 66% is generally required to ensure that drug doses can be given once daily. 17 In this study, the T:P ratios for barnidipine were higher than 50% for both SBP and DBP. This confirmed that its antihypertensive effect was still present in the last hours of the dosing interval, as a result of the long duration of action of this drug. 32 As in previous reports, the high T:P ratios indicate a favourable effect over 24-h BP control for once-daily barnidipine. 33 In conclusion, barnidipine used as oncedaily monotherapy provides effective control of 24-h BP and is generally well tolerated in ambulatory patients with HT. Acknowledgements We are grateful to Mr Surachai Saravich for his work on 24-h ABPM attachment and Mrs Pantip Sangprasert for office BP measurements at Siriraj Hospital. We also thank Mrs Cholarose Mokprom for office BP measurements at Bhumibol Adulyadej Hospital. This study was supported by Yamanouchi Pharmaceutical (Thailand) Co. Ltd. Received for publication 10 September 2003 Accepted subject to revision 17 September 2003 Revised accepted 6 January 2004 Copyright 2004 Cambridge Medical Publications 198

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