Efficacy and Safety of Barnidipine
Compared with Felodipine in the
Treatment of Hypertension in
Chinese Patients
CS L
IAU, KL C
HIEN, CL C
HAO ANDTM L
EEDepartment of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China
The efficacy and safety profiles of barnidipine in the treatment of hyper-tension were evaluated in an open parallel-group study. Fifty-nine Chinese patients with mild-to-moderate essential hypertension were randomized to receive either barnidipine or felodipine (5 mg once daily, titrated to 10 mg or 15 mg once daily, as indicated) for 12 weeks. Both drugs reduced blood pressures significantly with ≥68% of cases obtaining marked or moderate blood pressure reduction. Mean reductions in systolic and diastolic blood pressure for barnidipine
treatment were 23.7 ± 13.5 mmHg and 12.7 ± 7.9 mmHg, and for felodipine, 24.3 ± 18.4 mmHg and 14.5 ± 10.0 mmHg, respectively. There was no significant difference between these two drugs in anti-hypertensive effect, heart rate, laboratory measurements or incidence of adverse events. The only difference was that more patients taking felodipine experienced palpitations. We conclude that barnidipine has similar efficacy and a similar safety profile to felodipine in the treatment of mild-to-moderate essential hypertension in Chinese patients.
KEY WORDS: BARNIDIPINE; FELODIPINE; CALCIUM CHANNEL BLOCKER; HYPERTENSION; CHINESE
Introduction
Hypertension is common in Taiwan. In a community study of individuals aged
≥35 years, the prevalence of hypertension was 28.5%.1In another study in Chinese patients
aged ≥ 65 years living in Taiwan, the prevalence was 37%.2 The control of
hypertension is not satisfactory in most populations.3,4 Compliance is one factor
affecting blood pressure control, and medications with fewer adverse effects that
allow once-daily administration are more acceptable to the patients.5 Barnidipine is a
long-acting calcium channel blocker with a long half-life, and therefore only requires once-daily dosing.6 – 8 The efficacy of
barn-idipine in treating patients with hypertension has been demonstrated in oriental people9 – 11
as well as in Caucasians.12 – 17
We conducted this clinical trial to compare the efficacy and the safety profile of barnidipine with felodipine in the treatment of hypertension in Chinese patients.
Felodipine was chosen as the comparator drug because of its common usage in Taiwan, its established effectiveness in the treatment of hypertension, and the similarity in the half-life of these two drugs.
Patients and methods
Chinese people living in Taiwan with mild-to-moderate hypertension were recruited to this trial. The inclusion criteria were: Chinese nationality; age 30 – 75 years; essential hypertension with systolic blood pressure
≥160 mmHg and/or diastolic blood pressure
≥95 mmHg but ≤110 mmHg; and no severe systemic diseases (as listed in exclusion criteria). Patients with any of the following conditions were excluded from the trial: diastolic blood pressure > 110 mmHg; secondary hypertension; severe heart failure; significant arrhythmias; severe dysfunction involving respiratory system, liver, kidney, gastrointestinal system, neurological system, endocrine system or cardiovascular system; and significant metabolic abnormalities.
Eligible patients who provided informed consent were assigned randomly to receive a starting dose of either 5 mg barnidipine (Hypoca®, Yamanouchi, Tokyo, Japan) once
daily or 5 mg felodipine (Plendil®, AstraZeneca,
Bedfordshire, UK) once daily for 12 weeks. Other anti-hypertensive drugs and any other drugs that might affect blood pressure were prohibited during the trial period. Patients were followed up regularly in the out-patient clinic every 4 weeks to check blood pressure changes after treatment, compliance and adverse events. At each follow-up visit, if blood pressure did not reach ‘adequate control’ (defined below), the drug dose was titrated up by an increment of 5 mg each time.
Blood pressure changes after treatment were classified as ‘marked decrease’ if the decrease in systolic blood pressure was
≥ 30 mmHg and/or in diastolic blood pressure ≥15 mmHg. When the decrease of systolic blood pressure was 20 – 29 mmHg and/or the decrease of diastolic blood pressure 10 – 14 mmHg, the change of blood pressure was considered a ‘moderate decrease’. Either marked or moderate decrease of blood pressure after treatment was considered as ‘adequate control’ of hypertension. A lesser reduction in blood pressure and/or no reduction was defined as ‘inadequate control’ of hypertension.
Laboratory examinations performed before and after the trial included electro-cardiography, chest radiography, blood chemistry determinations (fasting glucose, aspartate aminotransferase, alanine amino-transferase, urea nitrogen, creatinine, uric acid, cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, sodium, potassium, chloride and calcium), complete blood count and urinalysis.
All data were collected and analysed according to the intention-to-treat model and also the per-protocol model. The blood pressure changes before and after treatment in the two treatment groups were compared using Student’s paired t-test. The categories of blood pressure change were presented with a contingency table and compared using the χ2
test. The incidence of adverse events was analysed with Fisher’s exact test. P < 0.05 was defined as statistically significant.
Results
A total of 63 hypertensive patients were included in this trial, 31 in the barnidipine group and 32 in the felodipine group. Four patients, three in the barnidipine group and one in the felodipine group, were lost to follow-up after the first course of medication was dispensed. The remaining patients received at least 2 weeks’ treatment with the
TABLE 2:
Systolic and diastolic blood pressures before and after treatment with barnidipine (5 – 15 mg once daily) or felodipine (5 – 10 mg once daily) in Chinese patients with hypertension who completed the study according to the intention-to-treat model
Baseline After 12 weeks of Difference Group Parameter (mmHg) treatmenta(mmHg) (mmHg)
Barnidipine SBP 164.8 ± 13.4 141.1 ± 14.0 –23.7 ± 13.5
(n = 28) DBP 97.3 ± 8.1 84.6 ± 9.6 –12.7 ± 7.9
Felodipine SBP 160.0 ± 12.8 135.7 ± 15.0 –24.3 ± 18.4
(n = 31) DBP 100.7 ± 4.7 86.2 ± 9.5 –14.5 ± 10.0
All data are expressed as means ± SD. SBP, systolic blood pressure; DBP, diastolic blood pressure.
aComparing blood pressure in the two treatment groups at baseline with that after 12 weeks’ treatment,
P < 0.001; comparing blood pressure between the barnidipine group and felodipine group, no significant difference.
TABLE 1:
Doses of barnidipine and felodipine in a comparative trial of efficacy and safety in Chinese patients
Barnidipine (patient numbers) Felodipine (patient numbers)
Dose (mg) ITT PP ITT PP
5 17 9 26 16
10 8 7 5 4
15 3 3 0 0
Total 28 19 31 20
ITT, intention-to-treat; PP, per-protocol
trial medicine: 28 patients in the barnidipine group and 31 patients in the felodipine group. Data from these 59 patients were analysed.
Among the patients in the barnidipine group, 12 were male and 16 female. In the felodipine group, the numbers of male and female patients were 15 and 16, respectively. The mean age of the patients in the barnidipine group was 54.0 ± 11.9 years, and in the felodipine group, 53.4 ± 10.5 years.
A total of 20 patients did not complete the trial, but received at least 2 weeks of barnidipine (nine patients) or felodipine (11 patients). The most frequent cause of early withdrawal from the trial was the occurrence of adverse effects (three in the barnidipine group and five in the felodipine group). Other reasons for withdrawal included inadequate blood
pressure control in two cases, unrelated disease or injury in a further two cases, and, in four patients, difficulty in attending the clinic at 4-week intervals. In the remaining four patients, the cause of withdrawal was not specified. Table 1 shows the doses of the anti-hypertensive drugs administered to patients. The doses of felodipine used were lower than those of barnidipine (P = 0.066 for the intention-to-treat model; P = 0.056 for the per-protocol model).
Using both the intention-to-treat model (Table 2) and the per-protocol model (Table 3) for analysis, both barnidipine and felodipine reduced systolic and diastolic blood pressures significantly (P < 0.001). There was no significant difference between these two groups of patients in baseline blood pressure, blood pressure after
TABLE 3:
Mean blood pressures before and after treatment with barnidipine (5 – 15 mg once daily) or felodipine (5 – 10 mg once daily) in Chinese patients with hypertension who
completed the study according to the per-protocol model
Baseline After 12 weeks of Difference Group Parameter (mmHg) treatmenta(mmHg) (mmHg)
Barnidipine SBP 166.3 ± 15.7 139.5 ± 15.0 –26.8 ± 13.4
(n = 19) DBP 98.1 ± 6.7 83.7 ± 9.2 –14.4 ± 8.2
Felodipine SBP 162.5 ± 13.3 131.6 ± 11.6 –30.9 ± 14.1
(n = 20) DBP 101.5 ± 3.9 83.9 ± 7.7 –17.6 ± 8.7
All data are expressed as means ± SD.
SBP, systolic blood pressure; DBP, diastolic blood pressure.
aComparing blood pressure in the two treatment groups at baseline with that after 12 weeks’ treatment,
P < 0.001; comparing blood pressure between the barnidipine group and felodipine group, no significant difference.
TABLE 4:
Adequacy of blood pressure control after treatment with barnidipine (5 – 15 mg once daily) or felodipine (5 – 10 mg once daily) in Chinese patients with hypertension according to the intention-to-treat model
Group Parameter Adequate control (n) Inadequate control (n)
Barnidipine SBP 19 9
(n = 28) DBP 22 6
Felodipine SBP 23 8
(n = 31) DBP 21 10
SBP, systolic blood pressure; DBP, diastolic blood pressure.
No statistically significant difference between barnidipine and felodipine groups.
TABLE 5:
Adequacy of blood pressure control after treatment with barnidipine (5 – 15 mg once daily) or felodipine (5 – 10 mg once daily) in Chinese patients with hypertension according to the per-protocol model
Group Parameter Adequate control (n) Inadequate control (n)
Barnidipine SBP 15 4
(n = 19) DBP 16 3
Felodipine SBP 17 3
(n = 20) DBP 17 3
SBP, systolic blood pressure; DBP, diastolic blood pressure.
No statistically significant difference between barnidipine and felodipine groups.
treatment, and changes in both systolic and diastolic blood pressures after treatment (Tables 4 and 5). There was no significant difference between the two treatment groups
in heart rate before and after treatment, and heart rate did not change significantly after treatment in either group.
TABLE 6:
Adverse effects experienced by Chinese patients with hypertension after 12 weeks’ treatment with barnidipine (5 – 15 mg once daily) or felodipine (5 – 10 mg once daily)
Number of adverse events
Effect Barnidipine Felodipine
Palpitations 2 7a Facial flushing 2 6 Headache 3 5 Chest tightness 2 1 Oedema 2 2 Weakness 4 4 Dizziness 1 4 Constipation 1 0 Rash 0 2 Total episodes 17 31b aP = 0.01. bP = 0.083.
observed, and only some mild unwanted reactions were reported (Table 6). There was no difference between the two treatment groups, except that more patients treated with felodipine experienced palpitations (P < 0.01). Overall, there were 31 episodes of adverse reactions in the felodipine group and 17 episodes in the barnidipine group (P = 0.083). Laboratory tests showed no significant changes after drug treatment with the exception of an elevation in high-density lipoprotein cholesterol level in barnidipine-treated patients (43.7 ± 9.2 mg/dl versus 48.6 ± 9.4 mg/dl [P = 0.042]).
Discussion
Calcium channel blockers have been recommended as a class of anti-hypertensive drug for the initial treatment of hypertension in some guidelines.4,18 Calcium channel
blockers have been proven to be effective and have a good safety profile for the treatment of hypertension.18 The long-acting, once-daily
preparations are preferred, and it has been suggested that short-acting dihydropyridines, such as immediate-release nifedipine, be avoided or used only with caution.4,18
Barnidipine is a long-acting calcium channel blocker with a long half-life after oral intake.6 – 8 The efficacy and safety profiles of
barnidipine have been well demonstrated in clinical studies.9 – 17 In this trial, we showed
that once-daily administration of barnidipine in Chinese patients with mild-to-moderate hypertension was highly effective and well tolerated. The efficacy of barnidipine was comparable to that of felodipine for the reduction of both systolic and diastolic blood pressures. It can be proposed, as shown in Table 1, that a 10 – 15-mg dose of barnidipine may have equivalent efficacy to 5 – 10 mg felodipine when used to treat Chinese patients with mild-to-moderate hypertension.
The safety analysis showed that neither barnidipine nor felodipine induced severe adverse events in the study patients. Side-effects were mild. It is interesting to note that palpitations were more frequently experienced by patients taking felodipine than by patients taking barnidipine (P = 0.01). The cause for this difference is not known. Argenziano et al.12 demonstrated
that barnidipine did not induce reflex neurohormonal activation, which may offer
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a partial explanation for our observation that fewer patients taking barnidipine experienced palpitations. There were no significant changes in laboratory examination findings in patients taking these two drugs. The effect of significant elevation of serum high-density lipoprotein cholesterol level after barnidipine admin-istration may require further study. A similar observation was reported by Horiuchi et al.,19
but not by Kurihara et al.20
In conclusion, barnidipine, a long-acting dihydropyridine calcium channel blocker,
has been shown in this study to be effective with a good safety profile in the treatment of Chinese patients with mild-to-moderate hypertension. This preparation was well tolerated and did not cause severe adverse effects. The long-acting, once-daily prep-aration of barnidipine provides another option for physicians in the clinical manage-ment of hypertensive patients.
Acknowledgement
This trial was supported by Yamanouchi Pharmaceutical Co. Ltd, Taiwan.
• Received for publication 19 February 2002 • Accepted 27 February 2002 ©2002 Cambridge Medical Publications
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Miyagawa J, Nanba M, Hanabusa T: Effect of barnidipine hydrochloride (Hypoca) on uric acid metabolism in patients with diabetes (in Japanese). Jpn J Med Consult New Remed 1998; 35: 61 – 64.
Address for correspondence
CS Liau, MD
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan 100, Republic of China.
