Hypertension Research (2014) 37, 225–231 & 2014 The Japanese Society of Hypertension All rights reserved 0916-9636/14 www.nature.com/hr ORIGINAL ARTICLE Comparative effects of telmisartan and valsartan as add-on agents for hypertensive patients with morning blood pressure insufficiently controlled by amlodipine monotherapy Hideaki Yoshida1, Hiroshi Akasaka1, Shigeyuki Saitoh1, Kazuaki Shimamoto1 and Tetsuji Miura1 on behalf of the SPEED investigators2 The aim of this study was to determine the efficacies of valsartan and telmisartan as add-on agents for the control of morning blood pressure (BP) in patients already on amlodipine monotherapy. A total of 414 hypertensive patients were prospectively enrolled in a 4-week run-in period when they were treated with amlodipine (5 mg/day), and home BP was measured in the morning and evening. Patients with home systolic BP (SBP) being 135–159 mm Hg in the morning at the end of the run-in period were randomized to additional treatment with valsartan (80 mg/day) or with telmisartan (40 mg/day) for 8 weeks. The primary endpoint was the change in morning home BP, and secondary endpoints included variability of morning home BP. Of the 282 patients randomized, 262 patients (n ¼ 131, in each treatment) completed the protocols. Demographic parameters and baseline morning SBP/diastolic BP (DBP) (146.3±7.1/84.8±9.3 vs. 146.0±7.1/84.2±9.1 mm Hg) were comparable in the valsartan group and telmisartan group, and changes in SBP/DBP after 8-week treatment were not significantly different between the two groups ( À7.4±10.6/ À3.9±6.1 vs. À8.3±9.9/ À5.0±5.9 mm Hg). Valsartan significantly increased individual standard deviation and variation coefficient of morning SBP, but telmisartan did not change either of these indices of SBP variation. In subgroups with baseline SBP being above the median (145.2 mm Hg), change in DBP was significantly larger by telmisartan than by valsartan ( À6.3±5.6 vs. À3.9±6.7 mm Hg, Po0.05). These results suggest that telmisartan is more useful than valsartan as an add-on agent for reducing the level and variability of morning BP in patients on amlodipine monotherapy. Hypertension Research (2014) 37, 225–231; doi:10.1038/hr.2013.141; published online 10 October 2013 Keywords: blood pressure variation; telmisartan; valsaratan INTRODUCTION in a large number of hypertensive patients on treatment.13–15 Accumulating evidence indicates that levels of blood pressure (BP) Furthermore, inter-individual variation in BP response differs determined by ambulatory BP monitoring and home BP monitors are between classes of anti-hypertensive agents,16 and it is likely that better predictors than office BP of cardiovascular events.1–3 In such inter-individual variation is also present within a class of agents addition to the BP level, variability of BP has been shown to owing to different pharmacokinetic features of each specific agent. significantly influence the clinical outcomes of hypertensive patients. Thus, it has not been established which combination of anti- Not only circadian variation of BP but also visit-to-visit variation in hypertensive drugs is suitable to sufficiently control both average BP and day-by-day variation in home BP were shown to be associated and variation of BP during a day. with an increased risk of cardiovascular mortality in studies In the present study, we compared the effects of valsartan and using ambulatory BP monitoring and home BP monitoring,4–9 telmisartan as add-on agents on morning BP and variation in BP for although the impact of ‘morning surge’ of BP on prognosis remains control of BP in hypertensive patients already being treated with a controversial.1–12 Currently, long-acting antihypertensive agents are calcium channel blocker (CCB). The rationale for this study is widely used for 24-h control of BP. However, recent studies have threefold. First, a long-acting CCB is an anti-hypertensive agent for disclosed that BP during the early-morning hours remains high which inter-individual variation in SBP is smaller than that of other 1Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University, School of Medicine, Sapporo, Japan 2See Appendix. Correspondence: Dr T Miura, Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, 060-8556, Japan. E-mail: [email protected] Received 20 May 2013; revised 2 August 2013; accepted 22 August 2013; published online 10 October 2013 Telmisartan vs. valsartan as an add-on agent H Yoshida et al 226 agents and is thus a good choice as a baseline treatment.16 Second, an enrollment in the run-in period, as CCB is not the first choice for angiotensin receptor antagonist (ARB) is preferable to diuretics as an these patients in Treatment Guidelines of the Japanese Society of agent to combine with CCB from a metabolic point of view. Third, Hypertension 2009 (The Japanese Society of Hypertension:guidelines plasma half-lives of valsartan and telmisartan are different (6–10 h vs. for the management of hypertension, http://www.jpnsh.org/guide- 21–38 h),17 which possibly results in difference in levels of morning line.html). The primary endpoint was change in home SBP in the BP control. Although head-to-head comparison of telmisartan and early morning, and secondary endpoints were variability of home SBP valsartan as monotherapy has been reported previously,18–20 in the early morning and home BP before sleep. comparative effects of these ARBs as agents in combination with a On the basis of the results of a previous study showing that CCB have not been examined. We addressed this issue by a morning home BP differed by 2.3 mm Hg in patients treated with 40– prospective randomized open-label blinded-endpoint (PROBE) 80 mg/day of telmisartan and those treated with 80–160 mg/day of study design with morning home BP as a primary endpoint. valsartan21 and the assumption that standard deviation of home BP is approximately 6 mm Hg, we estimated that a sample size of 125 METHODS patients per treatment arm would be necessary to detect a 2.3 mm Hg The present study was conducted at 36 clinical sites that participated difference between the two treatment groups with 80% power. in the SPEED (Sapporo study to prove efficacies of telmisartan and valsartan for early-morning blood pressure as add-on therapy) study. Determination of BP and its variability The protocol of this study was approved by the Clinical Investigation After enrollment, study subjects were requested to measure BP by the Ethics Committee of Sapporo Medical University Hospital and was HEM-7080IC within 1 h after waking up and before sleeping every registered in the UMIN Clinical Trials Registry (UMIN 000003922). day, and BP data were automatically stored in the HEM-7080IC with We conducted this study in strict adherence with the principles of the a14.6Â 44.6-cm arm cuff. The method of BP measurement (that is, Declaration of Helsinki. Written informed consent was obtained from BP measurement by use of the HEM-7080IC placed at the level of the all study participants. heart in a sitting position with feet on the floor after a 2-min rest following urination) was explained to all study participants using Study design and subjects written instructions with illustrations. BP data were retrieved at the This study was designed as a PROBE trial. As shown in Figure 1, time of randomization and at 8 weeks after ARB treatments, and the hypertensive patients at the age of 40–79 years were enrolled in a 4- first BP data and the last BP data within a day were used as morning week run-in period when amlodipine (5 mg/day) was administered, home BP and home BP before sleep, respectively, for that day. BP and home BP was determined in the early morning (within 1 h after values within 5 days before randomization and those within 5 days waking up) and in the evening (within 1 h before sleeping) with a before the end of the ARB treatment period were used for calculation semi-automated sphygmomanometer (HEM-7080IC, OMRON of BP and its variability. Standard deviation (s.d.) of BP during a HEALTHCARE, Kyoto, Japan). Patients whose home SBP in the 5-day period and coefficient of variation (CV, s.d. divided by mean morning was 135 mm Hg or higher but lower than 160 mm Hg were BP) were used as indices of BP variability. Office BP data at baseline randomized to a valsartan (80 mg/day) group or to a telmisartan and 8 weeks after ARB treatments were collected from each clinic (40 mg/day) group for an 8-week add-on therapy. Randomization of together with the data for demographic parameters. all subjects was performed by a central registration office. Exclusion criteria were allergy to telmisartan or valsartan, pregnancy, severe liver Biochemical evaluation dysfunction, serum creatinine X3.0 mg dl À1, malignant hypertension Blood and urine samples were obtained at the time of randomization and secondary hypertension. Patients with chronic heart failure, atrial for biochemical analyses in a central laboratory (Daiichi-Kishimoto fibrillation, history of myocardial infarction, proteinuria, diabetes Clinical Laboratory, Sapporo, Japan). The estimated glomerular mellitus or metabolic syndrome were also excluded from the filtration rate was calculated from the data for serum creatinine, age and sex by the use of equations for Japanese.22 Statistical analysis Data were analyzed by intention-to-treat analysis. Group mean data are expressed as means±s.d. Differences between means of para- meters in treatment groups and differences between means within a group were tested by Student’s t-test and by Student’s paired t-test, respectively.