Journal of Human Hypertension (2001) 15, 643–648  2001 Nature Publishing Group All rights reserved 0950-9240/01 $15.00 www.nature.com/jhh ORIGINAL ARTICLE Effects of long-acting ACE inhibitor (temocapril) and long-acting Ca channel blocker (amlodipine) on 24-h ambulatory BP in elderly hypertensive patients

K Eguchi1,2, K Kario2 and K Shimada2 1Department of Internal Medicine, Nishiarita Kyoritu Hospital, Saga, Japan; 2Department of Cardiology, Jichi Medical School, Tochigi, Japan

In a prospective randomised cross-over study, we com- ferences in the office, 24-h or daytime BPs between the pared the effects of ACE inhibitor temocapril and cal- two groups (dippers and non-dippers). Though the cium channel blocker (CCB) amlodipine on ambulatory office BPs and daytime BPs were successfully con- blood pressure in 59 asymptomatic elderly hypertensive trolled to the same levels with both treatments and in patients (mean age 69 years). This study was performed both dipping groups, the antihypertensive effects were in a cross-over fashion after a 2-week placebo period stronger with the CCB than with the ACE inhibitor in the and 4 to 8 weeks each of treatment with temocapril and night time and morning, especially in non-dippers. We amlodipine. Of those 59 hypertensive patients, three conclude that even though office BPs were controlled patients with side effects and 10 patients whose office successfully to almost the same levels, there is a possi- BPs did not achieve the target BPs were excluded, and bility that these long-acting drugs have differential anti- the remaining 46 were analysed in this study: they con- hypertensive effects on night time and morning BPs sisted of 30 dippers, with a night time reduction in sys- among hypertensive patients with different night time tolic BP (SBP) у10% and 16 non-dippers, with reduction BP dipping statuses. by Ͻ10%. At the baseline, there were no significant dif- Journal of Human Hypertension (2001) 15, 643–648

Keywords: long-acting ACE inhibitor; calcium channel blocker; non-dipper; night time BP

Introduction well controlled by a calcium channel blocker (CCB) or ACE inhibitor, and we assessed diurnal BP vari- In recent years, the usefulness of non-invasive ation. ambulatory blood pressure monitoring (ABPM) as a Long-acting CCBs and long-acting ACE inhibitors method for evaluating diurnal blood pressure (BP) are most popular antihypertensive drugs in Japan, variations in addition to the BP level per se has been 1 and are recommended for use once daily. However, reported. Non-dippers (blunted night time BP fall), there are few reports assessing the efficacy of these in particular, have been reported to have greater drugs throughout 24 h, and we do not know how hypertensive target organ damage1–5 and poorer car- 4 long the drugs remain at a therapeutic level after diovascular prognosis. This indicates that con- administration or how potent these drugs are. And trolling night time and morning BPs may be essen- there are few reports comparing these drugs in terms 6 tial for antihypertensive treatment. Even when of diurnal BP variations.7 We conducted this study office BPs are well controlled, it is uncertain to evaluate the effects of temocapril (a long-acting whether the BPs are controlled all day in clinical ACE inhibitor), and amlodipine (a long-acting CCB) practice. Using ABPM, we noted that office BPs were on 24-h ambulatory BP under successful office BP control.

Correspondence: Kazuo Eguchi, MD, Department of Internal Medicine, Nishiarita Kyoritu Hospital, 2485–3, Ogiotsu, Nishiar- Patients and methods ita, Nishimatsuura, Saga, 849–4193, Japan. Fax: +81 955 41 2036 or Kazuomi Kario, MD, PhD, Jichi Medical School, Department Study design of Cardiology, 3311–1, Yakushiji, Minamikawachi, Kawachi, Tochigi, 329–0498, Japan. Fax: +81 285 44 5317 The study was a randomised prospective cross-over Received 12 January 2001; revised 29 March 2001; accepted 1 study. After a 2-week washout and run-in period, May 2001 baseline ABPM was performed. The patients were Effects of temocapril and amlodipine on 24-h ABP K Eguchi et al 644 then randomised to temocapril (2–8 mg) or amlodip- variation). Written, informed consent was obtained ine (2.5–10 mg) for 4 to 8 weeks, and a second from all subjects. This study was approved by the ABPM was performed. Then the drug used for treat- Research Ethics Committee, Department of Cardi- ment was changed from temocapril to amlodipine or ology, Jichi Medical School, Japan. from amlodipine to temocapril, and 4 to 8 weeks later a third ABPM was performed. The dose was Measurement of blood pressure and heart rate adjusted according to the BP response to achieve successful BP control. Successful BP control was Measurement of office SBPs and DBPs were made defined as a reduction to Ͻ150/90 mm Hg by a single physician with a standard mercury systolic/diastolic BP (SBP/DBP) and if the BP was sphygmomanometer at each clinical visit, 24 ± 4h higher than 150/90 mm Hg after treatment, a after the previous intake of medication (ie, at reduction of у20/10 mm Hg was considered suc- trough). Pulse rate (PR) was measured by pulse pal- cessful. Initially, all patients were treated with tem- pation for 30 seconds immediately after the BP ocapril (2 to 4 mg) or amlodipine (2.5 to 5 mg) once measurement. These measurement were made in the daily. Then, the temocapril dose was increased by seated position after patients had rested in the 2 mg or amlodipine by 2.5 mg or by 4 mg or 5 mg, seated position for 5 min. We used the left arm for respectively for 2 weeks up to twice the maximum measurements with an appropriate-sized cuff reference dose recommended in Japan (ie, to 8 mg because the left arm is ordinarily used for ABPM for temocapril and 10 mg for amlodipine). For measurements. Automatic ABPM with electric-pow- patients in whom BP was not controlled success- ered cuff inflation (TM2421, A&D, Tokyo, Japan), fully within 8 weeks, ABPM was carried out after 8 which recorded BP and PR every 30 min for 24 h, weeks of each therapy. was performed. The ABPM device was attached in the morning. The accuracy of this device was pre- viously validated.8 The ambulatory data used in the Patients present study were obtained using the oscillometric We studied 59 consecutive asymptomatic (never method. Each subject recorded his or her own daily treated) elderly hypertensive outpatients, each of activities. Patients with documented disturbed sleep whom had visited our office more than three times (frequent waking during sleep) were not included in during 14 to 28 days and showed a mean office SBP the present study. The night time BP was defined as Ͼ150 mm Hg or mean office DBP Ͼ90 mm Hg on the mean BP for the interval from the time the two or more occasions during this run-in period. We patient went to bed until he or she awoke. The did not use a placebo. All patients were uncompli- morning BP was defined as the mean BP during the cated and ambulant. Exclusion criteria included first 2 h after waking (5 points), and daytime BP as possible diabetes mellitus (fasting glucose the mean BP from waking until he or she went to Ͼ100 mg/dl and/or haemoglobin A1c Ͼ6.2%), sec- bed. The night lowest BP was the mean BP of three ondary or malignant hypertension, history of myo- consecutive measurements, including as the middle cardial infarction, angina pectoris, stroke, transient value the lowest BP recorded during the night. The ischaemic attack or other severe concomitant dis- night–day ratio of BP was calculated as the ratio of ease before the study. Secondary hypertension was night time BP to daytime BP. The night time SBP ruled out based on history of hypertension, physical fall was calculated using the formula (daytime SBP examination, blood and urine tests. When secondary − night time SBP)/daytime SBP and was also hypertension was suspected, we performed expressed as a percentage. additional tests, including hormonal profile. Of the 59 consecutive hypertensive patients enrolled in Other measurements this study, three cases did not complete the protocol because of side effects (one case had general fatigue, The body mass index was calculated as weight one case had facial oedema due to temocapril, and (kg)/height (m)2. The left ventricular (LV) wall thick- one case developed weakness due to excessive low- ness and LV end diastolic and systolic diameters ering of BP during amlodipine therapy; the patient were measured with an ultrasonic echocardiograph who developed general fatigue was a 58-year-old (ALOKA, SSD500CV, Tokyo, Japan). LV mass index man receiving amlodipine (10 mg) therapy. His (LVMI) was calculated using the formula introduced clinic BP was 124/66 mm Hg, and his baseline BP by Devereux et al.9 was 176/88 mm Hg. Because he wanted to quit the study, we excluded him. Ten patients did not achi- Statistical considerations eve successful BP control with only temocapril, and were excluded. Finally, the data from 46 patients The SAS statistical program (SAS Institute, Cary, who achieved successful BP control were analysed. NC, USA) was used to perform all statistical analy- Thirty were classified as dippers (night time SBP fall ses. Student’s t-test was used to compare the mean у10%, considered normal diurnal BP variation) and values between dippers and non-dippers. A two- 16 were classified as non-dippers (night time SBP tailed paired t-test was used to compare the mean fall Ͻ10%, considered abnormal diurnal BP values before and after each drug therapy within the

Journal of Human Hypertension Effects of temocapril and amlodipine on 24-h ABP K Eguchi et al 645 same subgroup (dippers or non-dippers). Pearson’s correlation coefficients were calculated to test the relationships among baseline BPs and changes in daytime, night time and morning BPs after each drug therapy. The chi-squared test was applied to exam- ine difference between the prevalence in the two groups. P Ͻ 0.05 was considered significant. Data are expressed as the mean (s.d.) or prevalence.

Results Patients Table 1 shows the characteristics of the 46 patients who achieved successful BP control as assessed by office BP. There were 30 dippers and 16 non-dip- pers. At the baseline, there was no difference in the office BP, 24-h BP, daytime BP or clinical character- istics between the two groups. Night time BP and LVMI were significantly higher in the non-dippers than in the dippers.

Office BP and ambulatory BP Figure 1 shows the differences in BPs after antihy- pertensive therapy using temocapril and amlodipine in dippers and non-dippers. In both dipping groups, there were no significant differences in the office or

Figure 1 Differences between BP after amlodipine treatment and Table 1 Characteristics and ambulatory blood pressure (BP) pro- BP after temocapril treatment, evaluated for office BPs and ambu- file of the studied patients latory BPs of dippers (n = 30) and non-dippers (n = 16), are shown. SBP, systolic blood pressure; DBP, diastolic blood press- Dippers Non-dippers ure. *P Ͻ 0.05; **P Ͻ 0.01; ***P Ͻ 0.001; ****P Ͻ 0.0001: amlod- (n = 30) (n = 16) ipine vs temocapril within each dipping group. †P Ͻ 0.05: Dip- pers vs non-dippers for each difference. Dotted bars: dippers, Age (y) 68.5 (7.6) 70.8 (9.3) solid bars: non-dippers. Male (%) 16.7 25 Body mass index (kg/m2) 24.9 (3.2) 23.5 (3.6) Duration of hypertension 4.2 (2.0) 4.2 (1.8) daytime BP reduction between the amlodipine and (years) temocapril therapy. However, 24-h BP, night time Smoker (%) 10 25 Left ventricular mass index 107 (21) 146 (29)*** BP and morning BP were significantly lower with (g/m2) amlodipine therapy than with temocapril therapy. The differences of morning SBP, DBP and night– Systolic BP (mm Hg) Office 171 (11) 173 (12) lowest SBP between temocapril and amlodipine 24 h 145 (12) 151 (17) therapy in non-dippers were significantly greater Daytime 157 (13) 163 (17) than those in dippers. This indicates a significant Night time 124 (14) 147 (17)*** difference between amlodipine and temocapril with Night lowest 114 (13) 133 (14)*** respect to BP reduction. Morning 157 (17) 156 (22) There were significant negative correlations Diastolic BP (mm Hg) between the baseline BP level and the degree of SBP Office 94 (13) 90 (13) 24 h 82 (8.4) 81 (9.0) changes following temocapril and amlodipine ther- Daytime 89 (9.5) 83 (9.3) apy in daytime SBP, night time SBP, and morning Night time 71 (9.8) 78 (8.5)* SBP (Figure 2). There were no significant differences Night lowest 65 (8.8) 72 (6.6)** in the relationships among baseline BP and BP Morning 87 (10) 86 (11) changes in daytime SBP, night time SBP, or morning Pulse rate (bpm) SBP between dippers and non-dippers. Even with Office 73 (16) 67 (5.5) successful treatment as assessed by the office BP, the 24 h 66 (8.4) 64 (4.0) 24-h BP profiles were still higher than the normal Daytime 69 (9.5) 68 (4.6) Night time 59 (6.9) 57 (4.2) value described in the Joint National Committee VI (JNC VD).10 Concerning daytime BP, the broken line Data are expressed as mean (s.d.) or prevalence. shows the normal SBP of 135 mm Hg (daytime nor- * P Ͻ 0.05; **P Ͻ 0.01; ***P Ͻ 0.0001: non-dippers vs dippers. mal BP level described in JNC VI) after antihyperten-

Journal of Human Hypertension Effects of temocapril and amlodipine on 24-h ABP K Eguchi et al 646

Figure 2 The relationship between baseline BP values and BP changes after temocapril and amlodipine therapy. Broken lines show the normal daytime SBP (Ͻ135 mm Hg) and normal night time SBP levels (Ͻ120 mm Hg) recommended by the Joint National Committee (JNC) VI. Solid lines are linear regression lines. (᭺) Dippers (×) Non-dippers

Journal of Human Hypertension Effects of temocapril and amlodipine on 24-h ABP K Eguchi et al 647 sive therapy. Fifteen (33%) of 46 subjects treated ocapril was shown to be 17.5 mg in a previous with temocapril and 17 (40%) of 46 patients treated report, and in a few people even a 40 mg dosage was with amlodipine were below this line. As for night used.13 However, the recommended dose of temoca- time BP, the broken line shows normal SBP of 120 pril in Japan is 4 mg, and we used a maximum dose mm Hg (night time normal BP level described in JNC of 8 mg. Therefore, an inadequate dose of temocapril VI) after antihypertensive therapy; 17 of 46 (40%) was not the problem. Third, our study population patients treated with temocapril and 27 of 46 (59%) lives in a small island and has a tendency to have patients treated with amlodipine were below this high salt intake. Therefore, it is possible that the line (␹2 = 4.43, P = 0.035). On the other hand, among insufficient efficacy of temocapril for night time and patients with baseline SBP less than 120 mm Hg, morning BP in non-dippers was due not only to the there were only two patients treated with temocap- characteristics of the drug, but also to the character- ril, and none treated with amlodipine, whose BP istics of our population. decreased more than 10 mm Hg. Regarding morning Concerning excessive BP reduction, one previous hypertension (defined as a morning SBP of 140 report showed that an ACE inhibitor (enalapril) mm Hg or higher), 20 of 46 (43%) patients treated decreased normal BP further in white-coat hyperten- with temocapril did not reduce morning BP more sive patients, while a CCB (nifedipine SR) did not than 10 mm Hg, and nine of 46 (20%) patients decrease normal BP further in such patients.14 On treated with amlodipine did not (␹2 = 5.04, P = the other hand, under conditions of successful office 0.025). BP control using temocapril, excessive night time BP reduction seems to be rare, as shown in our study Discussion by the fact that when baseline SBPs were less than 120 mm Hg, there were only two patients whose BP We performed a prospective study of the effects of decreased more than 10 mm Hg in response to treat- temocapril (a long-acting ACE inhibitor) and amlod- ment with temocapril. ipine (a CCB) on diurnal BP variation in uncompli- Several reports on ambulatory BP found that CCBs cated hypertensive elderly patients. There are few had powerful effects on night time and morning reports comparing the effects of these drugs on diur- BP.7,14 In our study, amlodipine once daily in the nal BP under successful control of office BP. Our morning reduced the BP level throughout the day aim in this study was to clarify the changes in night and night in both dippers and non-dippers. In non- time and morning BP levels during antihypertensive dippers, night time and morning high BP were well therapy using an ACE inhibitor and a CCB, under reduced by amlodipine. In dippers, the amlodipine successful office BP control with each drug in hyper- treatment reduced not only the daytime BP, but also tensive patients with different night time BP significantly further reduced the lower baseline dipping statuses (dippers and non-dippers). We night time BP. However, the decrease in night time excluded from the analysis 10 cases that were not BP was possibly not harmful, because the post-treat- controlled by temocapril alone, even after using ment BP levels were not excessively low. When the twice the maximum recommended dose (8 mg). The baseline night time SBP was less than 120 mm Hg, office and daytime BPs decreased to a similar degree no further reduction in night time BP was observed after treatment with each drug in both dippers and with amlodipine (Figure 2). This finding is consist- non-dippers. ent with our previous finding that no further night Several previous reports concluded that ACE time BP reduction was observed in extreme-dippers inhibitors reduced ambulatory BP levels throughout with marked falls in night time BP.14 a 24-h period while maintaining diurnal BP vari- It remains unclear whether or not these different ation.11 In this study, we confirmed this finding in antihypertensive effects on ambulatory BPs between dippers. However, the antihypertensive effects of CCBs and ACE inhibitors contribute to the prognosis temocapril did not persist for 24-h in non-dippers, of hypertensive patients. Two recent trials disclosed ie, the reductions in night time BPs and morning that the degree of office BP control was equal or bet- BPs were smaller than those caused by amlodipine. ter with CCBs, but the rate of major cardiovascular The same phenomenon was observed in a report complications was higher with CCBs than with ACE comparing amlodipine and lisinopril.7 We suggest inhibitors,15,16 Further studies are required to clarify three possible explanations for this phenomenon. this issue. First, the plasma half-life of temocapril (14.5–21.5 h) In conclusion, a once-daily dose of a long-acting is shorter than that of amlodipine (35–48 h). How- CCB can control ambulatory BP throughout a 24-h ever, once-daily administration is recommended for period in elderly uncomplicated hypertensive temocapril, as for other long-acting ACE inhibitors. patients with different night time BP dipping In fact, other ACE inhibitors with plasma half-lives statuses, depending on the baseline BP level. On the shorter than that of temocapril have been shown to other hand, with a long-acting ACE inhibitor, the BP act for more than 24 h.12 Although the plasma half- reductions in the night time BPs of both dippers and life of these drugs is not so long, their high affinity non-dippers, in addition to the morning BPs of non- for tissue ACE makes it possible for the drug efficacy dippers, were less than the reductions with a CCB. to persist. Second, the average effective dose of tem- These characteristic effects of ACE inhibitors and

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