A J-BRAVE Substudy

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 prospective, 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 conclusion, 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 the 3-year treatment with benidipine and thereafter at 3-month intervals until March 2007. are shown in Figure 1. SBP and diastolic BP (DBP) sig- From the reported adverse events, which were classified nificantly decreased from 169 ± 16 mmHg to 143 ± 13 using MedDRA (Japanese Maintenance Organization, mmHg (p < 0.0001) and from 86 ± 12 mmHg to 75 ± Tokyo, Japan), cerebral hemorrhage, cerebral infarction, 10 mmHg (p < 0.0001), respectively, after 3 years in the and subarachnoid hemorrhage were extracted as cere- patients with a treated SBP ≥ 140 mmHg and 165 ± 14 brovascular events, and myocardial infarction and heart mmHg to 130 ± 11 mmHg (p < 0.0001) and from 84 ± failure were extracted as cardiac events to determine 10 mmHg to 71 ± 10 mmHg (p < 0.0001), respectively,

Clinical and Experimental Hypertension Benidipine in Very Elderly Hypertensive Patients 277

Table 1. Patient characteristics SBP < 140 (n = 230) SBP ≥ 140 (n = 185) P-value Age (years) 88.1 ± 3.0 87.4 ± 2.3 0.0795* Men, n (%) 46 (20.0) 36 (19.5) >0.2** BMI (kg/m2) 22.0 ± 3.6 22.2 ± 3.6 >0.2* SBP (mmHg) 165 ± 14 169 ± 16 0.0261* DBP (mmHg) 84 ± 10 86 ± 12 >0.2* Pulse rate (bpm) 75 ± 10 76 ± 11 0.1374* HT duration (years) 11 ± 912± 10 >0.2* HT treatment history, n (%) 128 (55.7) 110 (59.5) >0.2** Smoking history, n (%) 13 (5.7) 9 (4.9) >0.2** Comorbid disease, n (%) Diabetes mellitus 26 (11.3) 23 (12.4) >0.2** Hyperlipidemia 53 (23.0) 47 (25.4) >0.2** Cerebrovascular disease 32 (13.9) 33 (17.8) >0.2** Heart disease 65 (28.3) 42 (22.7) 0.198** Renal disease 5 (2.2) 7 (3.8) >0.2** Hyperuricemia 4 (1.7) 8 (4.3) 0.1183** Other vascular disorders 2 (0.9) 6 (3.2) 0.080** Previous antihypertensive medications, n (%) Calcium channel blocker 61 (26.5) 50 (27.0) >0.2** ACE inhibitor 30 (13.0) 29 (15.7) >0.2** ARB 44 (19.1) 52 (28.1) >0.2** Diuretic 15 (6.5) 10 (5.4) >0.2** β-blocker 12 (5.2) 7 (3.8) >0.2** Other antihypertensive drugs 15 (6.5) 12 (6.5) >0.2** Values are mean ± SD. Abbreviations: BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; HT, hypertension; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker. *Kruskal–Wallis test; **χ2 test. after 3 years in the patients with a treated SBP < 140 countries including Japan. Previous study reported that mmHg. The percentage of patients who achieved their BP of very elderly patients was inadequately controlled SBP target of <140 mmHg was 59.1% after 3 years. (10). In this study, SBP < 140 mmHg was reached There was a nonsignificant trend toward lower inci- in nearly 50% of very elderly patients with benidipine- dence of cardiovascular events (5.0/1000 vs. 9.1/1000 based treatment at relatively low dose. In the Japan patient-years) and higher incidence of total death Hypertension Evaluation with Angiotensin II Antag- (19.9/1000 vs. 16.0/1000 patient-years) in the patients onist Losartan Therapy (J-HEALTH) study, BP was with a treated SBP < 140 mmHg compared with the controlled at <140/90 mmHg in 45% of the patients patients with a treated SBP ≥ 140 mmHg (Figure 2). aged 85 years or older (11). Benetos et al. (12) reported The incidence of cardiovascular events tended to that SBP was controlled (<140 mmHg) in 51% of the increase at a SBP ≥ 160 mmHg compared with <130 treated patients in 1130 patients aged 80 years and over mmHg (Figure 3). living in nursing homes. There was no difference in the incidence of adverse The results of this study is in keeping with a reactions (3.04% vs. 3.24%) in the two groups of recent meta-analysis including HYVET on hyperten- patients. sive patients 80 years and older which indicated that drug treatment of hypertension reduced stroke and heart failure with no benefit on total mortal- DISCUSSION ity (13). J-HEALTH study indicated that the inci- In this study, the percentage of patients who achieved dence of cardiovascular events was significantly lower < SBP target of <140 mmHg was 55.7% after 3 years in patients with a treated SBP 140 mmHg in in 415 hypertensive patients aged 85 years or older. 692 patients aged 85 years or older compared with ≥ There was a nonsignificant trend toward lower inci- those with a treated SBP 140 mmHg (8.5/1000 dence of cardiovascular events and higher incidence of patient-years vs. 19.4/1000 patient-years). Per-protocol total death in the patients with a treated SBP < 140 analysis of the Japanese Trial to Assess Optimal Sys- mmHg compared with the patients with a treated SBP tolic Blood Pressure in Elderly Hypertensive Patients ≥ ≥ 140 mmHg. (JATOS) indicated elderly patients in whom SBP 160 Hypertension is common in the oldest old that rep- mmHg during treatment demonstrated high incidence resents the fastest growing age group in developed for cardiovascular diseases (14). As the population

Table 2. Antihypertensive and other medications in this study SBP < 140 (n = 230) SBP ≥ 140 (n = 185) P-value Benidipine Mean daily dose (mg/day) 4.4 ± 1.6 4.4 ± 1.6 >0.2* ≤4mg/day,n (%) 185 (80.4) 148 (80.0) >0.2** ≤8mg/day,n (%) 45 (19.6) 37 (20.0) >8mg/day,n (%) 0 (0.0) 0 (0.0) Duration of treatment (day) 959.6 ± 481.7 861.4 ± 498.3 0.057* Number of antihypertensive drugs (including benidipine), n (%) 1-drug 118 (51.3) 86 (46.5) 0.046 2-drug 71 (30.9) 74 (40.0) 3-drug 32 (13.9) 14 (7.6) ≥4-drug 8 (3.5) 11 (6.0) Concomitant antihypertensive medication, n (%) Calcium channel blocker 0 (0.0) 0 (0.0) – ACE inhibitor 27 (11.7) 23 (12.4) >0.2** ARB 72 (31.3) 65 (35.1) >0.2** Diuretic 31 (13.5) 24 (13.0) >0.2** α-blocker 11 (4.8) 8 (4.3) >0.2** β-blocker 10 (4.4) 11 (6.0) >0.2** αβ-blocker 7 (3.0) 6 (3.2) >0.2** Other antihypertensive drugs 2 (0.9) 1 (0.5) >0.2** Concomitant medication other than antihypertensive drugs, n (%) Lipid-lowering drug 41 (17.8) 27 (14.6) >0.2** Antiarrhythmic drug 9 (3.9) 9 (4.9) >0.2** Antianginal drug 34 (14.8) 29 (15.7) >0.2** Other cardiovascular drugs 44 (19.1) 39 (21.1) >0.2** Digestive organs drug 90 (39.1) 71 (38.4) >0.2** Antidiabetic drug 19 (8.3) 10 (5.4) >0.2** Central nervous system drug 69 (30.0) 52 (28.1) >0.2** Antigout drug 5 (2.2) 10 (5.4) >0.2** Antithrombotic drug 57 (24.8) 43 (23.2) >0.2** Other drugs 90 (39.1) 66 (35.7) >0.2** Values are mean ± SD. Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker. *Kruskal–Wallis test; **χ2 test. grows older, the number of persons aged 85 years benidipine-based treatment of very elderly hypertensive or older in Japan has increased nearly 10 times in patients in ordinary clinical practice in Japan. the past 5 decades. The optimal level of target BP In conclusion, the results of this study show that in the very elderly is still an important issue to be on-treatment SBP < 140 mmHg is safely reached in addressed (15). nearly 50% of very elderly patients and is associated Some limitations of this study should be considered. with a nonsigniﬁcant trend toward lower cardiovascular First, this study was a prospective observational study events and increased total death in very elderly Japanese without a comparator group and was not a random- hypertensive patients. Additional studies are needed to ized, controlled study. Selection of the target BP level, address the optimal treatment for very elderly patients use of concomitant drugs, and so on, were left to the with hypertension. discretion of individual physicians in charge. The baseline BP was higher in the subgroup of patients with on-treatment SBP ≥ 140 mmHg. Second, analyses per- ACKNOWLEDGMENT formed in this study were exploratory. Third, this study We thank all concerned, physicians, medical staff was a small study indicating only a nonsigniﬁcant trend members, and other contributors for their commit- toward lower incidence of cardiovascular events with a ment to the J-BRAVE study. treated SBP < 140 mmHg compared with the patients with treated SBP ≥ 140 mmHg. Declaration of interest: IS, HS, and TS were Despite such limitations, the results of the J-BRAVE remunerated for lectures by Kyowa Hakko Kirin Co., study provide valuable real-world information about the Ltd.

Clinical and Experimental Hypertension Benidipine in Very Elderly Hypertensive Patients 279

250 SBP (treated SBP ≥ 140 mmHg) SBP (treated SBP < 140 mmHg)

200

* * * * * * * * 150

* * * * * * * * BP (mmHg) 100 * * * * * * * *

* 50 * * * * * * * DBP (treated SBP ≥ 140 mmHg) DBP (treated SBP < 140 mmHg) 0

Treated SBP ≥ 140 mmHg n 185 99 155 185 155 123 106 96 81 TreatedSBP < 140 mmHg n 230 116 210 224 203 176 152 139 127

PR (treated SBP ≥ 140 mmHg) 100 PR (treated SBP < 140 mmHg)

75 Pulse rate (bpm) 50 baseline1 3 6 12 18 24 30 36

Treated SBP ≥ 140 mmHg n 136 71 113 140 119 96 87 86 72 TreatedSBP < 140 mmHg n 176 74 149 169 161 145 129 116 109 Months

Figure 1. Changes over time in blood pressure (BP) and pulse rate during treatment with benidipine (values are mean ± SD). SBP, systolic blood pressure; DBP, diastolic blood pressure; PR, pulse rate. *p < 0.0001 compared with baseline.

Cardiovascular events Cerebrovascularevents Cardiac events 70

30 patient-5 years) Incidence (/1000 20

0 Treated SBP < 140 mmHg Treated SBP ≥ 140 mmHg

Cardiovascular events 3 4 Cerebrovascular events 3 2 Cardiac events 0 2

Figure 2. Primary outcomes according to treated systolic blood pressure threshold 140 mmHg. In all patients, the results were adjusted for sex, age, diabetes mellitus, cerebrovascular disease, heart disease, smoking habit, and alcohol drinking.

200

150

100

0 Incidence (/1000 patient–5 years) <130 ≥ 130–140 ≥ 140–150 ≥ 150–160 ≥ 160 (mmHg)

Cardiovascular events 0 3 3 0 1 No. of patients 80 150 116 47 22

Figure 3. Relationship between cardiovascular events and systolic blood pressure during antihypertensive treatment. The results were adjusted for sex, diabetes mellitus, cerebrovascular disease, heart disease, smoking habit, and alcohol drinking.

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