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A J-BRAVE Substudy Clinical and Experimental Hypertension, 33(5):275–280, (2011) Copyright © Informa Healthcare USA, Inc. ISSN 1064-1963 print /1525-6006 online DOI: 10.3109/10641963.2011.577483 Treatment of Hypertension in Patients 85 Years of Age or Older: A J-BRAVE Substudy Ikuo Saito,1 Hiromichi Suzuki,2 Shigeru Kageyama,3 Takao Sar uta 4 1Health Center, School of Medicine, Keio University, Kanagawa, Japan, 2Department of Nephrology, Saitama Medical School, Saitama, Japan, 3Division of Clinical Pharmacology & Therapeutics, Jikei University School of Medicine, Tokyo, Japan, 4Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan Abstract Whether the strict control of blood pressure (BP) of patients with hypertension who are aged 85 years or older is beneficial is unclear. The Japan’s Benidipine Research on Antihypertensive Effects in the Elderly study is a prospec- tive, observational 3-year study to evaluate the safety and effectiveness of treatment with a calcium channel blocker benidipine in 8897 hypertensive patients aged 65 years or older as a post-marketing surveillance. We examined the relationship between the achieved BP and cardiovascular events (i.e., stroke, myocardial infarction, and heart failure) in a subgroup of 415 patients aged 85 years or older (mean age 88 years). BP decreased significantly from 165 ± 14/84 ± 10 mmHg to 130 ± 11/71 ± 10 mmHg during treatment in patients with a treated systolic BP (SBP) < 140 mmHg (n = 230) and BP decreased significantly from 169 ± 16/86 ± 12 mmHg to 143 ± 13/75 ± 10 mmHg in those with a treated SBP ≥ 140 mmHg (n = 185). There was a nonsignificant trend toward a lower rate of cardiovascular events and higher rate of total death in patients with a treated SBP < 140 mmHg. On-treatment SBP ≥ 160 mmHg is tended to associate with a higher incidence of cardiovascular events. There was no significant difference in the incidence of adverse reactions between the controlled BP group (3.04%) and the less well controlled BP group (3.24%). In conclu- sion, although this study was not powered for definitive conclusion, there was a nonsignificant trend toward a lower rate of cardiovascular events and higher total death in patients aged 85 years or older with a treated SBP < 140 mmHg. Keywords: benidipine, cardiovascular events, elderly hypertensive patients, blood pressure, adverse reactions INTRODUCTION patients aged 65 years or older as a post-marketing surveillance (5). Benidipine, a long-acting dihydropyri- Hypertension becomes more common with age. dine calcium channel blocker developed in Japan, exerts According to the National Health and Nutrition Sur- its antihypertensive effect by approaching dihydropyri- vey in Japan, 72% of people aged 70 years or older have dine calcium channel blocker binding sites through the hypertension (1). The effectiveness of calcium channel cell membrane (i.e., the membrane approach) (6). BP blockers for treating elderly hypertensive patients has decreased significantly from 165 ± 14/88 ± 10 mmHg been reported (2,3). There are few contraindications for to 137 ± 14/76 ± 10 mmHg and the percentage of using calcium channel blockers, and they can be used in patients who achieved BP < 140/90 mmHg was 57.2% combination with various other antihypertensive drugs. after 3 years. The incidence of cardiovascular events was For these reasons, calcium channel blockers are rec- 7.54/1000 patient-years. In patients aged 65–74 years ommended as a first-line treatment for hypertension in (n = 5092) and patients aged 75 years or older (n = elderly patients by the Japanese Society of Hypertension 3805), the percentages of patients who achieved the BP Guidelines for the Management of Hypertension 2009 target of <140/90 mmHg were 57.5% and 56.6% after (JSH2009) (4). JSH2009 recommended a blood pres- 3 years, respectively, and the incidence of cardiovascular sure (BP) target of <140/90 mmHg with an intermedi- events was higher in patients with on-treatment systolic ate BP target of <150/90 mmHg for elderly hypertensive BP (SBP) ≥ 160 mmHg in both age subgroups. patients. The increase in risk with increasing BP has been The Japan’s Benidipine Research on Antihyper- found in all age groups, but the strength of the associa- tensive Effects in the Elderly (J-BRAVE) study was tion declines with increasing age. There were concerns a prospective, 3-year observational study of a cal- related to the inverse epidemiologic association of death cium channel blocker-based treatment in hypertensive Address correspondence to Ikuo Saito, Health Center, School of Medicine, Keio University, Hiyoshi 4-1-1, Kouhoku-ku, Yokohama, Kanagawa 223-8521, Japan. E-mail: [email protected] Received 17 November 2010; revised 25 January 2011; accepted 29 January 2011. 275 276 I. Saito et al. from any cause and BP in the very elderly and about the incidence of cardiovascular events. Cardiovascular the efficacy and safety of antihypertensive drug ther- events were diagnosed by the physician in charge of each apy in this subgroup (7). A subgroup meta-analysis by patient based on the typical clinical symptoms, imag- Gueyffier et al. (8) showed a trend toward increased ing findings, and/or information from the hospital to mortality in the treated group in the very elderly (80 which the patient was referred. Cardiovascular events years or older). However, the Hypertension in the Very were confirmed by an independent physician unaware of Elderly Trial (HYVET) showed a benefit in treating the BP during treatment for event assessment on the basis of very elderly patients (80 years or older). Compared with all available information documented in the case report placebo, active treatment was associated with a 21% form. reduction in the relative risk of death from any cause and a 64% reduction in the relative risk of stroke (9). As Statistical Analysis the population grows older, the number of persons who Values are expressed as mean ± standard deviation. are 85 years or older in Japan has increased nearly 10 Changes over time in BP and pulse rate were compared times in the past 5 decades. For the patients 85 years or between the mean values before and after treatment older with hypertension, there are a few reports of the using Dunnett’s test. Any patients with only pretreat- association between BP and adverse outcomes. ment data were excluded from the Dunnett’s test. The This analysis focuses on the relationship between relationship between mean BP from 6 months to the end achieved BP and the incidence of cardiovascular events of treatment with benidipine and cardiovascular events in elderly hypertensive patients aged 85 years or older in was analyzed using a Cox proportional hazard model. Japan. For the analysis of characteristics of patients stratified by on-treatment SBP, variables were compared using the Kruskal–Wallis test and the χ2 test. All statistical METHODS tests were two-sided using a significance level of 0.05. Statistical analyses were performed using SAS Release Patients and Methods of Study 8.2 (SAS Institute, Inc., Cary, NC, USA). J-BRAVE study was conducted as a prospective study using a central registration system between June 2002 and March 2007. This study consisted of two stages: the RESULTS initial stage between entering this study (June 2002) and the end of March 2004, and the follow-up stage in years From a total of 8897 patients included in the J-BRAVE 1–3 (2004, 2005, and 2006, respectively). Between June study, this study analyzed data in 415 patients aged 85 2002 and December 2003, hypertensive patients meet- years or older after stratifying patients by on-treatment ing all of the following criteria were enrolled in this SBP (<140 or ≥140 mmHg). The baseline charac- study: (1) aged 65 years or older at the start of treat- teristics of the two groups of patients are shown in ment; (2) SBP ≥ 140 mmHg measured on each of Table 1. The mean age was 88 years. SBP was higher in two different days (including the first day of treatment) the patients with a treated SBP ≥ 140 mmHg. About within 28 days before entering this study; (3) no con- 40% of patients had not been previously treated by traindications to benidipine; and (4) no prior benidipine any other antihypertensive drugs for 4 weeks before the therapy within 28 days before entering this study. administration of benidipine. Two groups of the patients Patients received 2–4 mg benidipine orally, once daily were similar in terms of comorbid diseases and prior after breakfast, and the dose was increased up to 8 mg medical conditions. During the treatment period, beni- in patients with an inadequate response. A target BP dipine was administered at a mean daily dose of 4.4 level was set by the physician in charge of each patient ± 1.6 mg (Table 2). The number of antihypertensive according to the patient’s condition, and other concomi- drugs was higher in the patients with a treated SBP tant antihypertensive drugs than the calcium channel ≥ 140 mmHg. Two groups of patients were similar blocker were added as needed at the physician’s dis- in terms of concomitant antihypertensive drug classes. cretion. No restrictions were placed on concomitant Angiotensin receptor blockers were most often used, therapy such as diet and exercise therapies. Clinic BP followed by angiotensin-converting enzyme inhibitors was measured by the usual method in sitting position and diuretics. at each institution. BP and pulse rate were examined Changes over time in BP and pulse rate from baseline before and at the start of treatment with benidipine, to completion of
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