Abstract
Early morning hypertension and a high heart rate are risk factors for cardiovascular disease. The DOHSAM study was designed to evaluate the effect of candesartan on early morning blood pressure (BP) and heart rate in hypertensives. We used a prospective, randomized, open-label design. Protocol 1: Patients with early morning BP more than 135/85 mmHg who were not on any antihypertensive drug or on candesartan were given amlodipine 2.5 mg/day (amlodipine group, n = 22) or added candesartan 4 mg/day (candesartan group, n = 36). Candesartan or amlodipine was added when BP did not fall lower than 135/85 mmHg. Protocol 2: Early morning hypertensives who were on other angiotensin receptor blockers (ARBs) (n = 50) such as valsartan, losartan, telmisartan and olmesartan were switched to candesartan. Early morning BP significantly decreased in the candesartan group compared with the amlodipine group 9 and 12 months after treatment. Switching other ARBs except for olmesartan to candesartan significantly decreased early morning systolic and diastolic BP 3, 6, 9 and 12 months after treatment. Heart rate in the office significantly decreased by switching to candesartan 6, 9 and 12 months after treatment. In conclusion, candesartan significantly decreased early morning hypertension more than amlodipine or other ARBs except olmesartan in early morning hypertensives.
Introduction
Hypertension is one of the most important risk factors for cerebrovascular and cardiovascular diseases (Citation1,Citation2). Home-measured blood pressure (BP) has been reported to be a better prognostic factor than office BP (Citation3). By measuring home BP, early morning hypertension including masked hypertension can easily be detected. Early morning hypertension and the morning surge have been suggested to be accompanied with cardiovascular and cerebrovascular events (Citation4–6). In contrast, higher heart rate has also been reported to be an independent risk factor of cardiovascular diseases (Citation7–9); therefore, the usage of drugs that decreases both early morning hypertension and the heart rate may be more useful in reducing the risk of cardiovascular and cerebrovascular diseases. Among anti-hypertensive drugs, Ca-channel blockers and angiotensin receptor blockers (ARBs) are currently most frequently used for the treatment of hypertension. In the present study, we assessed the effect of candesartan on early morning hypertension and the heart rate comparing the effect of a Ca-channel blocker amlodipine and ARBs other than candesartan. The DOHSAM study (Domestic Observation of Heart rate and Systemic Arterial blood pressure in the Morning) was designed to investigate the efficacy of candesartan in patients with early morning hypertension.
Subjects and methods
Subjects
Patients with early morning hypertension whose home-measured early morning BP was more than 135/85 mmHg were enrolled in the present study. The following subjects were excluded: (i) patients with a past history of allergy to candesartan; (ii) pregnant and possible pregnant patients; (iii) patients already receiving the maximal dose of candesartan or amlodipine; (iv) patients receiving a Ca-channel blocker other than amlodipine; (v) patients with and/or a past history of atrial fibrillation.
Measurement of home BP
Home BP was measured by a digital home BP measurement device according to the guidelines for self-monitoring BP at home (Citation10), twice a day in the morning within 1 h after waking before taking medications and in the evening immediately before sleeping.
Study design
The DOHSAM study was a multicenter, prospective and open label study. The study name (Protocol 1 and Protocol 2), number of cases and institutes in the present study are shown in .
Table I. Study name and number of cases and institutes.
Protocol 1: Comparison study between candesartan and amlodipine.
The trial profile is shown in . In Protocol 1, patients with early morning BP more than 135/85 mmHg who were not on any antihypertensive drugs or on candesartan were given amlodipine 2.5 mg/day (amlodipine group, n = 22) or candesartan 4 mg/day (candesartan group, n = 36). Patients were recruited to each group according to birth month odd (candesartan) and even (amlodipine). If BP did not fall lower than 135/85 mmHg, candesartan or amlodipine was further added appropriately. shows the characteristics of patients included in Protocol 1.
Figure 1. Profile of Protocol 1 and Protocol 2.
Protocol 2: Switch to candesartan study.
The trial profile is shown in . In Protocol 2, patients with early morning BP more than 135/85 mmHg who were given ARBs other than candesartan were switched to candesartan. In each study, early morning BP and heart rate before and 3, 6, 9 and 12 months after treatment were evaluated. shows patients who were receiving other ARBs and were switched to candesartan and the doses used. The doses of candesartan were equipotent doses to other ARBs.
Table II. Characteristics of patients in Protocol 1.
Statistical analysis
Data are expressed as the mean± SE. To assess the changes in BP, one-way analysis of variance was used. Scheffe's analysis was used for intergroup comparisons at the end of the trial. p-values less than 0.05 were considered significant. The statistical software package Stat View, J5.0 version, was used for all analysis.
Results
Protocol 1: Comparison study between candesartan and amlodipine
Both early morning BP and office BP significantly decreased after treatment compared with those at the entry point both in the candesartan and amlodipine groups. Target morning early morning BP (early morning BP < 135/85 mmHg) achievement rate was 47.8% and 53.3% in the candesartan group and amlodipine group, respectively. As shown in , early morning systolic (SBP) and diastolic BP (DBP) decreased 3, 6, 9 and 12 months after treatment in both the candesartan and amlodipine groups. Concerning the office BP, as shown in , SBP significantly decreased 3, 6, 9 and 12 months after treatment in both groups, but DBP significantly decreased only at 6 months in the amlodipine group and decreased at 9 and 12 months in the candesartan group. When comparing the candesartan and amlodipine groups, the decrement of both early morning SBP and DBP was greater 9 and 12 months after treatment in the candesartan group than in the amlodipine group, as shown in ; however, there was no difference in the decrease in office SBP and DBP between the candesartan and amlodipine groups, as shown in . As shown in , there was no significant difference in heart rate in the early morning and at the office between amlodipine and candesartan groups.
Figure 2. (A) Changes in early morning blood pressure; (B) changes in office blood pressure. SBP, systolic blood pressure; DBP, diastolic blood pressure.
Figure 3. (A) Decrease in early morning blood pressure; (B) decrease in office blood pressure.
Figure 4. Changes in heart rate in the early morning and at the office.
Protocol 2: Switch from other ARBs to candesartan study
shows ARBs before switching to candesartan. Losartan, valsartan, telmisartan and olmesartan were switched to an equipotent dose of candesartan.
Table III. ARBs switched to candesartan and doses of candesartan switched.
As shown in , switching all other ARBs to candesartan significantly decreased early morning SBP and DBP and those at the office 3, 6, 9 and 12 months after treatment. When each ARB was evaluated, switching from valsartan, losartan and telmisartan but not from olmesartan showed a significant decrease in early morning BP, as shown in . Switching from valsartan, telmisartan and olmesartan but not from losartan showed a significant decrease in office BP, as shown in . Heart rate in the early morning after switching ARBs to candesartan tended to decrease but not significantly 3, 9 and 12 months after treatment, but significantly decreased 6 months after treatment, as shown in . Switching from other ARBs to candesartan significantly decreased the office heart rate 6, 9 and 12 months after treatment, as shown in .
Figure 5. Changes in systolic and diastolic blood pressure after switching from other angiotensin receptor blockers (ARBs) to candesartan.
Figure 6. (A) Changes in early morning blood pressure after switching from each angiotensin receptor blocker (ARB) to candesartan; (B) changes in office blood pressure after switching from each ARB to candesartan.
Figure 7. Changes in heart rate after switching from other angiotensin receptor blockers (ARBs) to candesartan.
Discussion
The DOHSAM study was designed to evaluate the effect of candesartan on early morning hypertension and heart rate in patients with morning hypertension. The DOHSAM study demonstrated that: (i) early morning SBP and DBP significantly decreased in the candesartan group compared with the amlodipine group 9 and 12 months after treatment; (ii) switching from other ARBs to candesartan significantly decreased early morning SBP and DBP 3, 6, 9 and 12 months after treatment; and (iii) heart rate at the office significantly decreased by switching from other ARBs to candesartan.
Early morning hypertension is one of the risk factors for cardiovascular and cerebrovascular diseases (Citation4–6). Recently, in Japan, measurement of home BP has become popular among hypertensive patients because both doctors and patients know that not only office BP but also home BP is important to predict the prognosis of hypertension. Recently, many hypertensive patients have acquired their own digital home BP measurement devices. Currently, Ca-channel blockers and ARBs are most frequently used for the treatment of hypertension as first-line antihypertensive drugs. These drugs sufficiently decrease the office BP; however, whether these drugs sufficiently decrease the early morning high BP and heart rate is still not fully clarified. In the present study, in protocol 1, patients with early morning BP more than 135/85 mmHg who were not on any antihypertensive drugs or on candesartan were given amlodipine 2.5 mg/day (amlodipine group) or candesartan 4 mg/day (candesartan group). The early morning BP and heart rate, and office BP and heart rate were measured before and 3, 6, 9 and 12 months after treatment. Both groups showed a significant decrease in early morning SBP and DBP 3, 6, 9 and 12 months after treatment; however, compared with the amlodipine group, the candesartan group showed a more significant decrease in the early morning SBP and DBP 9 and 12 months after treatment. These results suggest that candesartan is more effective in decreasing early morning BP than amlodipine. Concerning the office BP, both groups showed significantly decreased SBP 3, 6, 9 and 12 months after treatment; however, DBP was significantly decreased at 6 months in the amlodipine group and at 9 and 12 months in the candesartan group. Amlodipine is a long-acting Ca-channel blocker and its half-life is 30–50 h (Citation11), while candesartan is also a long-acting ARB but its half-life is 9 h (Citation12). Candesartan with a shorter half-life than amlodipine showed an even longer hypotensive effect and more strongly decreased early morning hypertension than amlodipine with a longer half-life. This seems strange and suggests that the difference in half-life between amlodipine and candesartan does not necessarily explain the different effects on early morning hypertension between amlodipine and candesartan. What is the mechanism by which candesartan shows a longer hypotensive effect? Candesartan binds with AT1 receptor very tightly and the dissociation half-life of the AT1 receptor for candesartan is long (Citation13), i.e. candesartan very slowly dissociates from AT1 receptor (Citation14). Further, candesartan has the ability to impair angiotensin II-induced AT1 receptor activation even after washout (Citation15). Therefore, this may explain the longer antihypertensive effect of candesartan in respect to its half-life.
There is a diurnal variation in the onset time of cardiovascular events (Citation16). The onset time of cardiovascular events peaks in the first 4–6 h after awaking (Citation17). This may be related to increased sympathetic nervous system activity in the morning (Citation18). It has been reported that treatment with a Ca-channel blocker increases sympathetic nervous system activity (Citation19) through baroreceptor reflex mechanism caused by a decrease in BP, while candesartan inhibits the increase in sympathetic nervous system activity through the blockade of presynaptic angiotensin II AT1 receptor at the sympathetic nerve endings (Citation20). This may have also contributed to the difference in the effect on early morning hypertension between amlodipine and candesartan. In the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial, candesartan and amlodipine lowered the office BP to the same extent and there was no difference in the morbidity and mortality between the groups (Citation21). In the subanalysis of the CASE-J trial, candesartan and amlodipine also lowered the home-measured BP (morning and night) to the same extent (Citation22). The result of the present study was inconsistent with the result of the CASE-J substudy. The difference between the present study and the CASE-J substudy may be due to the difference in the study design, subjects recruited or the doses of candesartan and amlodipine used. However, the main reason may be due to the different subjects investigated in the two studies. The subjects in the present study were patients with early morning hypertension and those in CASE-J were high-risk hypertensive patients with high office BP. Concerning the heart rate, there was no significant difference in heart rate both in the early morning and at the office between amlodipine and candesartan groups, suggesting that amlodipine and candesartan had the same effect on heart rate.
In Protocol 2, patients with early morning BP more than 135/85 mmHg who were on ARBs other than candesartan were switched to receive candesartan. Switching from valsartan, losartan and telmisartan to candesartan showed a significant decrease in early morning BP, but switching from olmesartan to candesartan did not affect early morning hypertension. Switching from valsartan, telmisartan and olmesartan but not from losartan showed a significant decrease in office BP, as shown in (B). The half-life of candesartan, losartan, valsartan, telmisartan and olmesartan is 9, 2, 6, 24 and 12–18 h, respectively (Citation12,Citation23–26). Candesartan has four binding sites on the AT1 receptor but valsartan has three binding sites and losartan has only two binding sites (Citation27). ARBs have different strengths to bind with AT1 receptor and the binding potency or dissociation half-life is as follows: candesartan > olmesartan > telmisartan > valsartan > losartan (Citation28). Therefore, the greater strength of binding with AT1 receptor and slower dissociation from AT1 receptor of candesartan and olmesartan may have contributed to the longer hypotensive effects and more powerful decrease of early morning hypertension.
In Japan, the Ohasama Study demonstrated that morning hypertension was associated with hemorrhagic stroke (Citation29). Cardiovascular events have also been reported to be related to early morning hypertension in a large and heterogenous population of patients (Citation30). Therefore, it is important to evaluate the effect of drugs on early morning hypertension. The DOHSAM study is unique since it compared the effect on early morning hypertension between candesartan and amlodipine, and between candesartan and other ARBs. The results of the present study suggest that candesartan may be a more useful and powerful drug to control early morning hypertension than amlodipine or other ARBs. Concerning the heart rate, office heart rate significantly decreased by switching from other ARBs to candesartan 6, 9 and 12 months after treatment as shown in . However, switching from other ARBs to candesartan tended to decrease the heart rate in the early morning but a significant decrease was only present 6 months after treatment. Greater strength of binding with the presynaptic angiotensin II AT1 receptor of candesartan may have contributed to the decreased heart rate at the office through inhibiting the release of noradrenaline from sympathetic nerve endings. The mechanism by which switching from other ARBs to candesartan decreased the heart rate at the office remains to be elucidated.
Study limitation
A limitation of the present study was the small number of subjects.
Conclusions
Candesartan significantly decreased BP in the early morning more than amlodipine or other ARBs in patients with early morning hypertension. Larger-scale trials are needed to confirm the beneficial effect of candesartan on early morning hypertension.
Appendix
Members of the DOHSAM study are as follows:
Naoki Kawai (Kawai Clinic, Gifu), Mitsunori Iwasa (Iwasa Clinic, Hashima, Gifu), Masayuki Oda (Oda Clinic, Hashima, Gifu), Keiji Kida (Kida Clinic, Kakamigahara, Gifu), Syojiro Kojima (Kojima Clinic, Ogaki, Gifu), Naomi Goto (Goto Clinic, Gifu), Masahiro Goto (Goto Clinic, Gifu), Fusayoshi Sugishita (Sugishita Clinic, Gujyo, Gifu), Kuniyuki Takai (Takai Clinic, Gifu), Ryuhei Tanaka (Tanaka, Hagiwara, Gifu), Keiji Hiei (Hiei Clinic, Minogamo, Gifu), Taro Minagawa (Minagawa Clinic, Gifu), Noritaka Yamamoto (Yamamoto Clinic, Gifu), Ikuo Watanabe (Watanabe Clinic, Ogaki, Gifu), Takao Yasue (Yasue Clinic, Gifu), Hiroshi Kobayashi (Konayashi Clinic, Kakamigahara, Gifu)
Acknowledgement
We thank all participants, physicians, medical staff and other contributors to the DOHSAM study.
Declaration of interest:
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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