Clinical and Experimental Hypertension, 2012; 34(2): 86–91Copyright © Informa Healthcare USA, Inc.ISSN 1064-1963 print /1525-6006 onlineDOI: 10.3109/10641963.2011.628729

Effect of Switching from Telmisartan, Valsartan, Olmesartan,or Losartan to Candesartan on Morning Hypertension

Hiroshi Hasegawa,1 Hiroyuki Takano,1 Yoshihito Kameda,1 Akihiko Kubota,1 YoshioKobayashi,1 Issei Komuro2

1Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chuo-ku, Chiba,Japan, 2Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

Abstract

The Candesartan Cooperative Research of Therapy Design for Early Morning Hypertension in CHIBA was designed toinvestigate whether switching from angiotensin II receptor blockers (ARBs) except candesartan to candesartan mightbe effective in Japanese patients with morning hypertension. Seventy-eight mild to moderate hypertensive patients,who were treated with the standard doses of ARBs except candesartan (losartan, 50 mg; valsartan, 80 mg; telmisartan,40 mg; or olmesartan, 20 mg), were entered into 12-week treatment period with candesartan 8 mg according to amulticenter, open-label design. Morning and office blood pressures (BPs) were significantly reduced (morning, −10.1± 10.5/−4.5 ± 8.4 mm Hg; office, −13.1 ± 17.3/−6.2 ± 11.3 mm Hg) after medication change. Target BPs (morningBPs ≤ 135/85 mm Hg and office BPs ≤ 140/90 mm Hg) achievement rates were 42.9% in the morning and 64.3%at office. No adverse events were recognized in all patients. Candesartan treatment significantly reduced the morningand office BPs compared with other ARBs in Japanese patients with morning hypertension.

Keywords: angiotensin II receptor blocker, clinical trial, hypertension, candesartan

INTRODUCTION

Hypertension is the most powerful risk factor for thecardiovascular diseases and the final purpose of antihy-pertensive treatment is to reduce morbidity and mor-tality of cardiovascular disease associated with hyper-tension. Blood pressures (BPs) usually follow a distinctcircadian rhythm, characterized by a nocturnal declineduring sleep of 10%–30%, followed by a moderate-to-marked increase coinciding with the time of awakening(1,2). Morning hypertension is an important clinicalcondition that is closely related to cardiovascular dis-ease and is a significant predictor of target organ damage(3,4). To control morning BPs, well-tolerated antihy-pertensive agents with long durations of action arerequired.

Renin–angiotensin system (RAS) is a cascade ofenzymatic reactions leading to the formation ofits primary effective molecule, angiotensin II (AII).Angiotensin II plays an important role in the regulationof BPs and progresses the development of hypertension,atherosclerosis, heart failure, type 2 diabetes mellitus,and renal disease (5). In addition to their BP-loweringeffects, angiotensin II receptor blockers (ARBs), which

Address correspondence to Hiroyuki Takano, MD, PhD, Department of Cardiovascular Science and Medicine, Chiba UniversityGraduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail: htakano-cib@umin.ac.jp

Received 6 July 2011; revised 10 August 2011; accepted 11 August 2011.

inhibit RAS, have been shown to promote regressionof left ventricular hypertrophy and decrease cardiovas-cular morbidity and mortality in patients with heartfailure, stroke, or hypertensive diabetic nephropathy(6–11). Among various ARBs, candesartan has cer-tain properties of a highly potent, long-acting, andselective AII receptor type 1 (AT1) receptor blockade(12–15). Candesartan provides a dose-related and long-lasting antihypertensive effect due to candesartan’s tightbinding and slow dissociation from AT1 receptors (16).

Since ARBs have effective BP-lowering effects andare widely used as first-line antihypertensive agents inJapan, it is important to investigate the differences ineffects of ARBs to determine the optimal treatmentin the patients with hypertension. It was hypothesizedthat in patients who had been prescribed ARBs, thetreatment with candesartan might be more effectiveand tolerated in reducing morning BPs compared withother ARBs. The Candesartan Cooperative Researchof Therapy Design for Early Morning Hypertensionin CHIBA (COORDINATE) was designed to inves-tigate the efficacy and safety of switching from otherARBs to candesartan in Japanese patients with morninghypertension.

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SUBJECTS AND METHODS

Study PopulationThe inclusion criteria were (1) age 20–70 years; (2)hypertensive patients without blood pressure adequatelycontrolled (≥ 135/85 mm Hg in the morning); and(3) treated with the standard doses of ARBs exceptcandesartan (losartan, 50 mg; valsartan, 80 mg; telmis-artan, 40 mg; or olmesartan, 20 mg). Patients wereexcluded if they had (1) severe hypertension (≥ 180/110mm Hg); (2) malignant disease; (3) serious renal dys-function (serum creatinine ≥ 2.0 mg/dL); and (4) sec-ondary hypertension. Eighty patients were enrolled withmild to moderate hypertension between April 2009 andDecember 2010. The COORDINATE was closed onMarch 2011. Written informed consent was obtainedfrom all patients prior to their inclusion into this study.The Ethics Committee at Chiba University GraduateSchool of Medicine approved the COORDINATE pro-tocol which adhered according to the principles of theHelsinki Declaration.

Study DesignThe COORDINATE was a multicenter, prospective,and open-label design. Patients were switched fromother ARBs to the standard dose (8 mg) of candesar-tan that lowers BPs equally as other ARBs. If thepatients were already receiving antihypertensive treat-ment except ARBs prior to enrollment, those treatmentswere fixed throughout this study. Data entry and datacollection were performed at the center for the COOR-DINATE. The blood pressures of each patient weremeasured in a sitting position with a validated mer-cury sphygmomanometer at a clinic and with a validatedoscillometric device (HEM-6011; Omron Healthcare,Kyoto, Japan) at home. The morning BPs were mea-sured within 30 minutes after wake-up. The mean oftwo measurements was calculated and recorded. Allpatients were followed up for 12 weeks.

Outcome MeasurementsThe primary end point was the achievement rate of tar-get BPs (≤ 135/85 mm Hg in the morning and ≤ 140/90mm Hg at office). The secondary end point was theextent of changes in values of morning and office BPs.

Statistical AnalysisQuantitative data are expressed as mean ± SD. Toanalyze changes in BPs, single element of analysis ofvariance was used. P values were computed by the Bon-ferroni test for intergroup comparisons at the end ofthe trial. All of the statistical tests were two-sided, andP < .05 was considered to be statistically signifi-cant. The statistical software package SPSS version18.0 (SPSS Inc., Chicago, IL, USA) was used for allanalyses.

RESULTS

A total of 80 patients were screened as eligible forCOORDINATE and were assigned to this study. Twopatients were excluded because of the changes of medi-cations during the follow-up period (Figure 1). Seventy-eight patients were successfully switched to candesartantherapy and followed up for 12 weeks. Table 1 showsthe baseline characteristics of the patients. Thirty-threesubjects were female, and the mean age was 65.1 ±11.7 years. Among patients, 7.0% had angina pectoris,1.8% had old myocardial infarction (MI), 3.5% hadheart failure, 1.8% had left ventricular hypertrophy,43.9% had diabetes mellitus, and 54.4% had dyslipi-demia. Mean office BPs were 147.6 ± 15.8/83.8 ±11.9 mm Hg. Other additional agents were mainly

Assessed for eligibilityN = 80

Excludedchange of medications during

follow-up period N = 2

Included N = 78

Figure 1. Trial profile.

Table 1. Clinical characteristics of patients at baseline

Age (y) 65.1 ± 11.7Female 33 (34.9%)BMI (kg/m2) 23.6 ± 2.6Height (cm) 161.5 ± 8.8Weight (kg) 61.8 ± 10.3SBP (mm Hg) 147.6 ± 15.8DBP (mm Hg) 83.8 ± 11.9Angina pectoris (%) 7.0MI (%) 1.8Heart failure (%) 3.5Left ventricular hypertrophy (%) 1.8Diabetes mellitus (%) 43.9Dyslipidemia (%) 54.4Smoker (%) 9.5Concomitant medication

Calcium channel blockers (%) 64.9β-Blockers (%) 5.3α-Blockers (%) 10.5Diuretics (%) 15.8ACE inhibitor (%) 0Oral antidiabetics (%) 12.3Statins (%) 28.1

ARBs before enrollmentLosartan (%) 12.8Telmisartan (%) 11.5Olmesartan (%) 35.9Valsartan (%) 39.7

Abbreviations: BMI – body mass index; SBP – systolic bloodpressure; DBP – diastolic blood pressure; ARBs – angiotensin IIreceptor blockers; MI – myocardial infarction; ACE – angiotensinconverting enzyme.Data are expressed as mean ± SD or number and percentage.

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calcium channel blockers (64.9%), diuretics (15.8%),β-blockers (5.3%), and α-blockers (10.5%). The pre-treated ARBs before enrollment were valsartan (39.7%),olmesartan (35.9%), telmisartan (11.5%), and losartan(12.8%), respectively. The mean duration of the treat-ment with ARB before switching to candesartan was106.3 ± 90.0 weeks in the COORDINATE. The aver-age number of antihypertensive agents taken during thisstudy was 1.9 ± 0.8. Table 2 shows the biochemical andechocardiographic parameters at baseline.

Target BPs (morning BPs < 135/85 mm Hg andoffice BPs < 140/90 mm Hg) achievement rates were42.9% in the morning and 64.3% at office. Figure 2shows the changes in BPs in the morning and at officefrom baseline to 12 weeks. Morning and office BPs weresignificantly reduced by −10.1 ± 10.5/−4.5 ± 8.4 mm

Table 2. Biochemical parameters at baseline

Total cholesterol (mg/dL) 199.9 ± 26.4LDL-cholesterol (mg/dL) 110.9 ± 32.7Triglyceride (mg/dL) 130.6 ± 86.3Serum creatinine (mg/dL) 0.83 ± 0.31Fasting blood sugar (mg/dL) 107.8 ± 32.4HbA1c (%) 5.5 ± 0.5

Abbreviations: LDL – low-density lipoprotein; HbA1c –hemoglobin A1c.Data are expressed as mean ± SD.

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Hg (149.2 ± 11.5/85.7 ± 8.9 at baseline to 138.8 ±13.0/81.1 ± 9.8 at 12 weeks) and −13.1 ± 17.3/−6.2± 11.3 mm Hg (147.6 ± 15.8/83.8 ± 12.0 at baselineto 135.1 ± 14.5/77.1 ± 11.9 at 12 weeks), respec-tively (Figure 3). The differences in reductions in BPsbetween morning BPs and office BPs were not signifi-cant in this study (systolic BP; P = .256, diastolic BP;P = .346). The BP-lowering effects were observed in allsubgroups which had been previously treated with losar-tan, valsartan, telmisartan, or olmesartan (Table 3).There were no significant differences in the BP-loweringeffects among the subgroups. The switching was gener-ally tolerated and the drug-related clinical and labora-tory adverse effects were not recognized in all patients.

DISCUSSION

The COORDINATE was designed to evaluate the anti-hypertensive effects of candesartan on morning hyper-tension in Japanese mild to moderate hypertensivepatients. Target BPs achievement rates were 42.9% inthe morning and 64.3% at office at 12 weeks afterswitching. The changes in BPs were −10.1 ± 10.5/−4.5± 8.4 mm Hg in the morning and −13.1 ± 17.3/−6.2± 11.3 mm Hg at office at 12 weeks.

Hypertension is the major risk factor of cardiovas-cular clinical events such as cardiovascular death, MI,heart failure, and stroke in Japan. Strict control ofBPs is required to decrease the risk of cardiovascu-lar events. The renin–angiotensin system is a majorregulatory system of cardiovascular and renal func-tion (17). Angiotensin II, a potent vasoconstrictor, isa key effective peptide and its known pressor effectis mediated by AT1 receptor (18). The effects of AIIcan be directly blocked by selective ARBs at the AT1receptor. Since various studies and clinical trials havedemonstrated their effectiveness in lowering BPs withan excellent tolerability and safety profile, ARBs arewidely used as first-line antihypertensive agents. Can-desartan has an affinity for the AT1 receptor 80 times

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Effect of Candesartan on Morning Hypertension 89

Table 3. The changes in morning and office BPs after switching in each group which had been previously treatedwith losartan, valsartan, telmisartan, or olmesartan

Previous ARBs Baseline 4 wk 8 wk 12 wk

Morning BPsLosartan, 50 mg SBP 145.5 ± 7.3 143.8 ± 7.6 137.8 ± 12.0 135.5 ± 8.2

DBP 83.3 ± 8.0 88.8 ± 12.9 81.6 ± 10.1* 79.3 ± 6.5*Valsartan, 80 mg SBP 152.1 ± 13.4 142.6 ± 10.8 141.1 ± 9.1 142.5 ± 14.6*

DBP 86.8 ± 9.6 83.9 ± 7.7 82.6 ± 7.3 80.9 ± 13.2*Telmisartan, 40 mg SBP 144.2 ± 6.9 139.0 ± 2.6 132.8 ± 11.9 130.8 ± 11.7*

DBP 86.8 ± 12.6 84.6 ± 16.3 82.2 ± 12.9 81.4 ± 8.3Olmesartan, 20 mg SBP 148.8 ± 11.1 140.0 ± 8.0* 139.9 ± 10.3 138.6 ± 11.4*

DBP 85.3 ± 7.5 82.6 ± 6.0* 81.9 ± 5.6* 81.9 ± 5.5Office BPs

Losartan, 50 mg SBP 142.3 ± 11.9 142.4 ± 18.9 132.3 ± 13.5 136.8 ± 20.2DBP 80.1 ± 14.2 78.4 ± 14.3 78.0 ± 17.6 78.3 ± 16.5

Valsartan, 80 mg SBP 149.4 ± 17.2 138.2 ± 16.7 140.3 ± 18.3 133.7 ± 12.8*DBP 86.5 ± 11.8 82.2 ± 11.7 77.7 ± 10.3* 77.3 ± 12.7*

Telmisartan, 40 mg SBP 137.8 ± 11.9 131.3 ± 11.0 126.2 ± 11.4 128.6 ± 9.5*DBP 78.0 ± 9.7 73.5 ± 9.6 74.8 ± 8.4 73.8 ± 8.5

Olmesartan, 20 mg SBP 150.7 ± 15.4 133.8 ± 25.7 140.0 ± 12.5 138.8 ± 15.2*DBP 83.9 ± 11.5 81.2 ± 7.0 79.7 ± 6.1 77.7 ± 10.4

Abbreviations: SBP – systolic blood pressure; DBP – diastolic blood pressure; ARBs – angiotensin II receptorblockers; BPs – blood pressures.*Indicates P < .05 compared with baseline.

greater than that of losartan (19). Candesartan has fourbinding sites on the AT1 receptor, meanwhile losartanhas two and valsartan has three binding sites (20). Thedissociation half-life of the AT1 receptor is 152 min-utes for candesartan, and 5 minutes for losartan (21).Due to its tight binding and slow dissociation fromAT1 receptors, candesartan provides a dose-related andlong-lasting antihypertensive effects (16,22). It was pre-viously reported that, upon mechanical stretching ofcultured rat neonatal myocytes, the AT1 receptors couldbe activated without the AII stimulation and those acti-vations were blocked by candesartan (23). Candesartanis a potent, AT1 selective antagonist without agonistactivity (24). Most ARBs including irbesartan, valsar-tan, and telmisartan also produced a partial depressionof the maximal response and some like olmesartan andcandesartan even an almost complete depression. Thislatter behavior is qualified as “insurmountable” and,because of the competitive nature of the ARBs (withrespect to AII), it is related to their ability to slowlydissociate from the AT1 receptor (24,25). Several clin-ical trials have indicated that 8 mg once daily is asuitable maintenance dosage of candesartan for man-agement of hypertension in Japan. In the CandesartanAntihypertensive Survival Evaluation in Japan trial, can-desartan was as effective as calcium channel blocker,amlodipine, to lower BPs and prevent cardiovascularevents including sudden death and cerebrovascular, car-diac, renal, and vascular events in high-risk Japanesehypertensive patients (26,27). In patients with heart fail-ure, candesartan significantly reduced the risk of thecomposite outcome of cardiovascular death or nonfa-tal MI (8,9,11,28). Recently, Eklind-Cervenka et al.(29) reported that candesartan is superior to losartan in5-year all-cause mortality in patients with heart failure.

It is well known that there is a diurnal variationin the onset time of cardiovascular events (1,30). Theonset of acute events, including sudden death, MI, andstroke, peaks in the first 4–6 hours post-awakening (31).Increased sympathetic nervous system activity and acti-vation of the RAS are possible contributors to increasesin vascular resistance and morning hypertension. Morn-ing hypertension is an independent risk factor for stroke(32), vascular disease (33), and cardiac hypertrophy(34). In Ohasama Study that had a 10-year medianfollow-up period in Japan (3), morning hypertensionwas associated with the development of hemorrhagicstroke. Recently, Yi et al. (35) demonstrated the signif-icant relations between early morning hypertension andcardiovascular outcomes by analysis of large and het-erogenous population using the International Databaseon Ambulatory Blood Pressure in relation to Cardio-vascular Outcome (5645 people from eight countrieson three continents, and more than half were women)for 11.4 years of median follow-up. Renin–angiotensinsystem blocking agents that maintain pharmacodynamiceffects into the early morning period have been shownto have a significant effect on the morning hypertension(32,36–38).

To date, many trials have been designed to evalu-ate the beneficial effects of antihypertensive agents inhigh-risk hypertensive patients. Although it is importantto find the optimal treatment for high-risk hypertensivepatients, it is also necessary to examine the appropriatetreatment for low-risk patients with mild to moder-ate hypertension. The COORDINATE seems to be aunique study in that it compared the depressor responseof candesartan with other ARBs. Although patients withuncontrolled morning hypertension were enrolled inthis study, office BPs of them were also a little high.

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Switching to candesartan was effective on office BPs aswell as morning BPs. Our results suggest that candesar-tan may be a more useful agent to control not only officeBPs but also morning BPs than other ARBs.

LIMITATIONS

The small number of subjects was the most importantlimitation of this study. There were no control patientswho continued same ARB in the COORDINATE.However, because the mean duration of the treatmentwith ARB before switching to candesartan was 106.3± 90.0 weeks in the COORDINATE, it was thoughtthat the changes in BPs after switching were the effect ofcandesartan. In this study, the office BP measurementswere determined by using a mercury sphygmomanome-ter, and the morning BP measurements were made byan oscillometric device. So the absolute value of BPsbetween office BPs and morning BPs is not comparable.

CONCLUSIONS

Change of medication from other ARBs to candesar-tan could be considered as effective and safe to treatmorning BPs and office BPs in Japanese patients withmorning hypertension. Further large trials are neededto examine the beneficial effects of candesartan oncardiovascular events.

ACKNOWLEDGMENTS

We thank all participants, physicians, medical staff,and other contributors to the COORDINATE.

Declaration of interest: The authors report no con-flicts of interest. The authors alone are responsible forthe content and writing of the paper.

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APPENDIX

Members of the COORDINATE are the following:

Michio Azuma (Azuma Clinic, Tomisato, Chiba,Japan); Tomonori Fujishima (Fujishima Clinic, Chiba,Japan); Gyouetsu Kudo (Kudo Clinic, Sakura, Chiba,Japan); Tadahiko Mizuguchi (Chiba Social InsuranceHospital, Chiba, Japan); Taeko Motoyama (Motoyamaclinic, Chiba, Japan); Yuichiro Ozeki (Saegusa Clinic,Chiba, Japan); Yuichi Shinoda (Misato GeneralHospital, Misato, Saitama, Japan); Daigaku Uchida(Hotaruno Central Medical Clinic, Kisarazu, Chiba,Japan); and Kenji Usui (Usui Clinic, Ichihara, Chiba,Japan).

© 2012 Informa Healthcare USA, Inc.

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