Antihypertensive efficacy and safety of benidipine and its effects on cardiac structure and function in elderly Chinese patients with mild to moderate hypertension: an open-label, long-term study

Abstract

Benidipine (CAS 91599-74-5) has been reported as an effective antihypertensive treatment and its cardioprotective effects have been shown in several basic and clinical studies. However, the long-term efficacy and safety of benidipine remain unknown in elderly Chinese patient with hypertension. In this prospective, multicenter, open-label clinical trial, 152 eligible patients aged 60 to 75 years with mild to moderate essential hypertension (sitting systolic blood pressure (BP) ≥ 140 mmHg and/or sitting diastolic BP ≥ 90 mmHg) entered a 52-week study. All patients initially received benidipine 2–4 mg once a day, followed by titration to benidipine 8 mg/day to achieve the target BP (< 140/90 mmHg in non-diabetics and < 130/80 mmHg in diabetics). Add-on hydrochlorothiazide (CAS 58-93-5) and/or metoprolol tartaric acid (CAS 3750-58-6) were permitted during the study. Overall, 132 patients completed the 52-week treatment with benidipine as monotherapy or combination therapy. It showed that the regimen based on benidipine provided an obvious mean trough BP reduction of 13.8 ± 12.4/8.3 ± 9.2 mmHg (p < 0.001), and 62.5% of patients reached the target BP. In patients with left ventricular hypertrophy, the left ventricular mass index significantly decreased from 147.1 ± 27.6 g/m² at baseline to 136.0 ± 17.5g/m² at 52 weeks (p = 0.036). Clinical adverse events (AEs) were found in 15.1% of all patients, and six patients discontinued the treatment due to drug-related AEs during the entire trial. Patients' compliance was an average of 98.7%. Benidipine, with a favorable tolerability profile, provides a long-term antihypertensive effect and potential benefit for the heart in elderly patients with mild to moderate hypertensive, suggesting that it is suitable for elderly patients with hypertension.

Key words

Benidipine - Calcium channel antagonist - CAS 91599-74-5 - Elderly patients - Hypertension - Left ventricular hypertrophy

*)

^*) Fan, W; Qi, W; Xi, Y: Huashan Hospital of Fudan University. Lu, G; Liu, Y; Li, L; Ruijin Hospital of Shanghai Jiaotong University. Wu, Z; Zhang, Y; Tang, Y; Changzheng Hospital of the Second Military Medical University. Zhang, Y; Zhang, J; Liu, R; Gu, Y; Shanghai Sixth People's Hospital of Shanghai Jiaotong University. Ni, Y; Liu, H; Chest Hospital of Shanghai Jiaotong University. Wu, S; Xie, Y; Huang, H; Cheng, C; Shanghai Ninth People's Hospital of Shanghai Jiaotong University School of Medicine. Zheng, X; Zhang, J; Xu, B; Li, S; Changhai hospital of the Second Military Medical University. He, B; Shen, J; Sun, Y; Renji Hospital of Shanghai Jiaotong University. Dai, Q; Wang, W; Wu, Y; Shanghai first People's Hospital of Shanghai Jiaotong University. Li, Y; Chen, S; Jiang, J; Lu, Q; Liu, X; Chen, T; Xinhua Hospital of Shanghai Jiaotong University

• References

• 1 Noda H, Fujita T. The antihypertensive effect and pharma-cokinetics after single oral administration of benidipine hydrochloride in patients with essential hypertension. Jpn Pharmacol Ther. 1990; 18: S703-11
• 2 Tsukiyama H, Osada H, Irimajiri S, Goto Y, Tanabe T, Hara F et al. Efficacy and safety of long-termtreatment with benidipine hydrochloride in elderly hypertension. Geriat Med. 1997; 35: 989-1007
• 3 Hirono O, Fatema K, Nitobe J, Takeishi Y, Kaneko K, Shiga R et al. Long-term effects of benidipine hydrochloride on severe left ventricular hypertrophy and collagen metabolism in patients with essential hypertension. J Cardiol. 2002; 39: 195-204
• 4 Wang HY, Wang CF, Pan ZH, Wu H, Zhong Y, Chen XC et al. Efficacy and safety of benidipine therapy of essential hypertension in elderly Chinese patients. Arzneimittelforschung. 2008; 58: 505-9
• 5 Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D et al. HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008; 358: 1887-98
• 6 Turnbull F. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of pro-spectively-designed overviews of randomised trials. Lancet. 2003; 362: 1527-35
• 7 Ishii A, Toyama J. Binding properties of (+/−)[³H]benidipine hydrochloride to rat heart membranes. J CardiovascPharmacol. 1993; 21: 191-6
• 8 Ishii A, Nishida K, Oka T, Nakamizo N. Slow dissociation of the new slow-onset and long-acting calciumantagonist benidipine hydrochloride from ³H-nitrendipine binding sites. Arzneimittelforschung. 1988; 38 (11 Suppl) 1681-3
• 9 Lavie CJ, Milani RV, Ventura HO, Messerli FH. Left ventricular geometry and mortality in patients > 70 years of age with normal ejection fraction. Am J Cardiol. 2006; 98: 1396-9
• 10 Bombelli M, Facchetti R, Carugo S, Madotto F, Arenare F, Quarti-Trevano F et al. Left ventricular hypertrophy increases cardiovascular risk independently of in-office and out-of-office blood pressure values. J Hypertens. 2009; 27: 2458-64
• 11 Fouad FM, Nakashima Y, Tarazi RC, Salcedo EE. Reversal of left ventricular hypertrophy in hypertensive patients treated with methyldopa: lack of association with blood pressure control. Am J Cardiol. 1982; 49: 795-801
• 12 Simpson HJ, Gandy SJ, Houston JG, Rajendra NS, Davies JI, Struthers AD. Left ventricular hypertrophy: reduction of blood pressure already in the normal range further regresses left ventricular mass. Heart. 2010; 96: 148-52
• 13 Paquette PA, Duguay D, El-Ayoubi R, Menaouar A, Danalache B, Gutkowska J et al. Control of left ventricular massby moxonidine involves reduced DNA synthesis and enhanced DNA fragmentation. Br J Pharmacol. 2008; 153: 459-67
• 14 Okin PM, Devereux RB, Jern S, Kjeldsen SE, Julius S, Nieminen MS et al. Regression of electrocardiographic left ventricular hypertrophy by losartan versus atenolol: the Losartan Intervention for Endpoint reduction in Hypertension(LIFE) study. Circulation. 2003; 108: 684-90
• 15 Mino-Leon D, Reyes-Morales H, Galvan-Plata ME, Ponce-Monter H, Palma-Aguirre JA, Amato D et al. Drug treatment of hypertension: compliance and adverse reactionsin a cohort of hypertensive patients in a primary care setting. Rev Invest Clin. 2007; 59: 8-14
• 16 Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH et al. Randomised double-blind comparisonof placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension inEurope (Syst-Eur) Trial Investigators. Lancet. 1997; 350: 757-64
• 17 Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005; 353: 487-97
• 18 Leonetti G, Magnani B, Pessina AC, Rappelli A, Trimarco B, Zanchetti A. Tolerability of long-term treatment with lercanidipine versus amlodipine and lacidipine in elderly hypertensives. AmJ Hypertens. 2002; 15: 932-40
• 19 Barrios V, Escobar C, Navarro A, Barrios L, Navarro-Cid J, Calderon A. Lercanidipine is an effective and well tolerated antihypertensive drug regardless the cardiovascular riskprofile: the LAURA study. Int J Clin Pract. 2006; 60: 1364-70
• 20 Yao K, Nagashima K, Miki H. Pharmacological, pharmacokinetic, and clinical properties of benidipine hydrochloride, a novel, long-acting calcium channel blocker. J Pharmacol Sci. 2006; 100: 243-61
• 21 Kang L Liy, Hu D, Guo J, Zhang L, Huang J, Wang F et al. Multicenter clinical trial on benidipine in the treatment of hypertension. Chin J Clin Pharmacol. 2005; 21: 3-7
• 22 Uji Y, Kobayashi H, Kobayashi S. Phase I clinical study of benidipine hydrochloride (KW-3049). Jpn Pharmacol Ther. 1990; 18: S689-S702