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Abstract
It has not been fully examined whether angiotensin II receptor blocker is superior to calcium channel blocker to reduce cardiovascular events in hypertensive patients with glucose intolerance. A prospective, open-labeled, randomized, controlled trial was conducted for Japanese hypertensive patients with type 2 diabetes mellitus or impaired glucose tolerance. A total of 1150 patients (women: 34%; mean age: 63 years; diabetes mellitus: 82%) were randomly assigned to receive either valsartan- or amlodipine-based antihypertensive treatment. Primary outcome was a composite of acute myocardial infarction, stroke, coronary revascularization, admission attributed to heart failure, or sudden cardiac death. Blood pressure was 145/82 and 144/81 mm Hg, and glycosylated hemoglobin was 7.0% and 6.9% at baseline in the valsartan group and the amlodipine group, respectively. Both of them were equally controlled between the 2 groups during the study. The median follow-up period was 3.2 years, and primary outcome had occurred in 54 patients in the valsartan group and 56 in the amlodipine group (hazard ratio: 0.97 [95% CI: 0.66–1.40]; P=0.85). Patients in the valsartan group had a significantly lower incidence of heart failure than in the amlodipine group (hazard ratio: 0.20 [95% CI: 0.06–0.69]; P=0.01). Other components and all-cause mortality were not significantly different between the 2 groups. Composite cardiovascular outcomes were comparable between the valsartan- and amlodipine-based treatments in Japanese hypertensive patients with glucose intolerance. Admission because of heart failure was significantly less in the valsartan group.
- angiotensin II type 1 receptor blocker
- calcium channel blocker
- cardiovascular disease
- diabetes mellitus
- hypertension
- impaired glucose tolerance
Introduction
Hypertension and type 2 diabetes mellitus (T2DM) are major risk factors for cardiovascular diseases (CVDs), and a combination of those further increases CVD.1–3 Activation of the renin-angiotensin system exacerbates not only hypertension but also insulin resistance and diabetic vascular complications.4–6 Indeed, various renin-angiotensin system blockers (ie, angiotensin-converting enzyme inhibitor [ACEI] or angiotensin II type 1 receptor blocker [ARB]) have been shown to suppress new onset of T2DM and to reduce the progression of diabetic nephropathy.7–10 Hence, many guidelines worldwide recommend ACEI/ARB as the first-line antihypertensive medications for diabetic hypertensive patients.3,11–14
Several clinical trials previously assessed head-to-head comparisons between ACEI/ARB and calcium channel blocker (CCB) regarding the efficacies on CVD.15–21 In diabetic hypertensive patients, some small-sample trials showed that ACEI significantly reduced the risk of CVD compared with CCB,15,16 whereas another large-scale trial showed no difference.17 The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) and Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trials, which recruited 5250 (34%) and 2018 patients (43%) with T2DM, respectively,18,19 showed that ARB significantly reduced new onset of T2DM but failed to reduce total CVD compared with CCB. The Irbesartan Diabetic Nephropathy Trial (IDNT) also compared ARB and CCB in diabetic patients with nephropathy.20,21 Although the IDNT revealed better renal protection by ARB than CCB as a primary outcome,20 ARB and CCB had similar efficacies on composite CVD as a secondary outcome.21 Among the components, ARB was more protective against heart failure (HF), whereas CCB tended to be more protective against myocardial infarction (MI) and stroke.
Epidemiologically, CV events in East Asia are different from those in Western countries. Age-adjusted incidence of ischemic heart disease is ≈80% lower, but cerebrovascular mortality is 2- to 3-fold higher in Japan compared with those in the United States.22,23 In addition, mean body mass indices in East Asians are lower than that of Western population.24 ARB is less protective against new onset of T2DM in lean patients compared with the obese,25 and CCB has a beneficial property for preventing stroke.26 Thus, CCBs are still frequently used in hypertensive patients with T2DM in East Asia.
Taken together, it is still unknown whether ACEI/ARB should be the first-line medication for diabetic hypertensive patients in East Asia for the CVD protection. Accordingly, we carried out the NAGOYA HEART Study (NHS) to compare the efficacies of an ARB valsartan and a CCB amlodipine on cardiovascular morbidity and mortality as a primary outcome in Japanese hypertensive patients with glucose intolerance.
Materials and Methods
Study Design
The rationale and design of the NHS have been described previously.27 The NHS is an investigator-initiated trial which used a prospective, randomized, open-labeled, blinded endpoints design.28 Participants were recruited by 171 cardiologists only from 46 board-certified medical centers and hospitals. All of the patients provided their written informed consent. This study was approved by the ethical review committee of the Nagoya University School of Medicine and of participating institutions.
Inclusion Criteria
Eligible participants were men and women aged between 30 and 75 years with both hypertension and glucose intolerance (ie, T2DM or impaired glucose tolerance [IGT]). We enrolled hypertensive patients with not only T2DM but also IGT, because IGT has a similarly elevated risk for CVD compared with T2DM.29,30 Hypertension was defined as having received any antihypertensive drugs already or blood pressure ≥140/90 mm Hg. T2DM was defined as having received any antidiabetic agents or plasma glucose level ≥7.0 mmol/L in fasting state, ≥11.1 mmol/L in nonfasting state, or 2 hours after glycemic load in an oral glucose tolerance test. IGT was defined by plasma glucose level <7.0 mmol/L in fasting state and 7.8 to 11.0 mmol/L as the 2-hour value in an oral glucose tolerance test.31 For exclusion criteria, please see the online-only Data Supplement.
Study Outcomes Measure
Primary outcome was a composite of acute MI (ECG changes, elevation of cardiac enzymes more than twice as high as upper limit of normal levels, and culprit lesion detected by coronary angiogram), stroke (neurological deficit persisting for >24 hours and relevant findings in computed tomography or MRI), admission because of HF (new or worsening typical clinical symptoms including dyspnea, shortness of breath, and peripheral edema, together with pulmonary congestion in chest roentgenogram, echocardiographic left ventricular dysfunction according to the guidelines of the American Heart Association/American College of Cardiology, and increased plasma brain natriuretic peptide levels), coronary revascularization (percutaneous coronary intervention or coronary bypass graft surgery unplanned at randomization), or sudden cardiac death (unexpected intrinsic death within 24 hours after the onset of symptoms). All-cause mortality was included as the secondary outcome. All of the reported adverse events were analyzed, and outcomes were strictly adjudicated by an independent End point Evaluation Committee in a blinded manner as for the assigned treatments.
Procedures and Follow-Up
Patients were randomly assigned to the valsartan- or the amlodipine-based treatment group. Random allocation was performed by a minimization method with 5 factors of baseline characteristics, such as age, sex, medication for dyslipidemia, current smoking status, and the T2DM/IGT ratio.
As an initial dose, either valsartan 80 mg or amlodipine 5 mg once daily was administered to patients in a respective group. For patients already taking antihypertensive drugs at the enrollment, all of the ACEI/ARB and CCB were once discontinued and the allocated drug was started without a run-in period. During the follow-up, target blood pressure was ≤130/80 mm Hg.3,11–14 Physicians could increase the respective dose until 160 mg or 10 mg daily after 4 weeks, and other antihypertensive drugs, such as diuretics, β-blockers, or α-blockers could be added after 8 weeks as needed. Blood glucose control was performed according to the treatment guidelines issued from the Japan Diabetes Society.32 For additional information, please see the online-only Data Supplement.
Sample
Sample size calculation was described previously.27 Patient enrollment began in October 2004 on the assumption that 1500 patients for each group were enrolled and anticipated to be finished by the end of 2006. Finally, we recruited total 1168 patients by the end of January 2009, when the Data and Safety Monitoring Board suggested stopping the recruitment because a longer recruitment period might be required to complete the enrollment. Consequently, the steering committee decided not to recruit patients thereafter. Follow-up was continued until July 31, 2010, and available data were fixed on November 5, 2010.
Interim Analyses and Data Monitoring
The interim analyses were assessed immediately after closing the enrollment and every 6 months (4 times in total). For additional information, please see the online-only Data Supplement.
Statistical Analysis
Data were analyzed on the basis of the intention-to-treat principle. Only the first cardiovascular event was analyzed as a primary outcome in case of multiple events observed in a single patient. Cumulative incidence of cardiovascular events was estimated by the Kaplan-Meier method. The crude hazard ratios (HRs) and 95% CIs were calculated by the Cox proportional hazard model to compare the treatment group differences. The Levene test and repeated-measure ANOVA were used to compare the changes of blood pressure and glycosylated hemoglobin (HbA1c) levels throughout the follow-up. All of the statistical analyses were performed by an independent statistical analysis board, and a P value <0.05 was considered statistically significant.
Results
Patient Characteristics
A total of 1168 patients were considered to be eligible for the present study, but 6 patients who met exclusion criteria and 12 patients who withdrew their consent were excluded. Consequently, 1150 patients were randomly assigned to the valsartan group (n=575) or the amlodipine group (n=575), and a total of 1117 patients (97%) completed the follow-up throughout the study (Figure S1). Please see the online-only Data Supplement.
Baseline characteristics of enrolled patients are shown in Table 1. All of the patients were diagnosed as hypertensive, and 82% and 18% had T2DM and IGT, respectively. In overall samples, mean age was 63 years, and 66% were men. Mean blood pressure and HbA1c were 145/82 mm Hg and 7.0%, respectively. There were no significant differences in baseline characteristics between the 2 groups. Table 2 shows the prescribed medications during the follow-up. Immediately after the random allocation, 77% of patients in both groups were prescribed only the assigned regimen as an antihypertensive medication. The concomitant antihypertensive drugs were mainly β-blockers in both groups. Antihypertensive and hypoglycemic agents showed no differences in use between the 2 groups.
Baseline Characteristics of Enrolled Patients
Prescribed Medications During the Follow-Up
Blood Pressure Changes and HbA1c Levels During the Study
Changes in blood pressure and HbA1c levels are shown in Figure 1. Blood pressure was reduced to 131/73 mm Hg in the valsartan group and 132/74 mm Hg in the amlodipine group at 54 months. The Levene test for equality of variances showed no differences between the 2 groups. Blood pressure did not differ between the 2 groups throughout the trial (P=0.653 in systolic BP and P=0.658 in diastolic BP by repeated-measure ANOVA). HbA1c levels were shown to decrease steadily to 6.7% in both groups, and the changes did not differ between the 2 groups.
Changes in blood pressure and glycemic control throughout the study. SBP indicates systolic blood pressure; DBP, diastolic blood pressure.
Clinical Outcomes
The median follow-up period reached 3.2 years (interquartile range: 2.6–4.7 years), and the Data and Safety Monitoring Board suggested finishing the follow-up at that point. A total of 202 clinical adverse events from 148 patients (26%) in the valsartan group and 204 events from 162 patients (28%) in amlodipine group were reported to the end point evaluation committee.
Figure 2 shows the incidence of adjudicated primary composite cardiovascular outcomes. A total of 56 events from 54 patients (9.4%) in the valsartan group and 64 events from 56 patients (9.7%) in the amlodipine group were adjudicated as primary outcomes, and time-to-event curves did not significantly differ between the 2 groups (HR: 0.97 [95% CI: 0.66–1.40]; P=0.85). Table 3 shows HRs for each component ascertained in this study, and there were no significant differences in the risk of MI, stroke, coronary revascularization, or sudden cardiac death between the 2 groups. However, incidence of admission because of HF was significantly less in the valsartan group than in the amlodipine group (3 versus 15 patients; HR: 0.20 [95% CI: 0.06–0.69]; P=0.012). Figure S2 shows the time-dependent curves of the incidence of admission attributed to worsening of HF. Please see the online-only Data Supplement. All-cause mortality, as a secondary outcome, did not significantly differ between the 2 groups (22 versus 16 patients; HR: 1.37 [95% CI: 0.72–2.61]; P=0.34; Table 3).
Kaplan-Meier curves for the incidence of primary composite outcome. Time to the first cardiovascular event was used for the analysis.
Primary Outcome and Overall Cardiovascular Event
Adverse Events
With respect to the safety outcome, we confirmed 106 adverse events of 94 patients in the valsartan group and 112 events of 94 patients in the amlodipine group during the follow-up (Table S1). However, any serious adverse events were not observed. There were no significant differences in the incidence of each adverse event, including the definite solid cancer (22 in the valsartan group and 23 in the amlodipine group) between the 2 groups. Please see the online-only Data Supplement.
Discussion
The NHS is a randomized, prospective clinical trial comparing the efficacies on cardiovascular outcomes between ARB and CCB in hypertensive patients with glucose intolerance. The present study has a novelty to evaluate the cardiovascular events as a primary outcome exclusively in non-Western patients with glucose intolerance. East Asians are generally less obese than Western population, although they had similar prevalence of T2DM.24 This epidemiological data suggest that East Asians could have some different substrates in glucose intolerance. Furthermore, the incidence of CVD in East Asia is much different from Western countries. However, there was little clinical evidence that supports therapeutic guidelines for the treatment of diabetic hypertensive patients in East Asia. In this study, both blood pressure and glycemic status were equally controlled between the 2 treatment groups, and there was no difference in a primary composite cardiovascular outcome. Our result was generally in line with the data of the Western IDNT Trial for which the number of patients were almost similar to ours, whereas the cardiovascular outcome was measured as a secondary outcome.21 The VALUE and CASE-J trials enrolled a larger number of diabetic patients than ours, but they also showed no difference in composite cardiovascular outcomes between the ARB- and CCB-based treatments.18,19 Consequently, any evidence in clinical advantage of ARB against CCB regarding composite CVD has not been yielded regardless of the race.
In the present study, the valsartan-based treatment significantly reduced the risk of HF as compared with the amlodipine-based treatment. One may argue that more frequent use of thiazides in the valsartan group possibly attributed to better protection against HF. However, this effect on HF in valsartan-based treatment was statistically significant even in those who never received thiazides throughout the study (n=967; HR: 0.21; [95% CI: 0.05–0.96]; P=0.04), and test of heterogeneity in thiazides use showed no statistical significance (P=0.50). Thus, our study suggested the more protective efficacy of valsartan against HF regardless of the use of thiazides, and our findings confirm the results of the IDNT Trial, as well as a meta-analysis in diabetic patients in Western countries.21,33 In contrast, both the original VALUE Trial and CASE-J Trial showed significant difference of blood pressure throughout the follow-up and no difference in the risk of HF.18,19 However, a modified analysis of the VALUE Trial indicated that, when blood pressure effects of valsartan and amlodipine were adjusted equally, the only difference in outcomes between the 2 groups was a lower incidence of HF in the valsartan group.34 Our study showed considerably lower HR (0.20) for HF than previous trials because of the small number of cases, whereas there may be several possible explanations for this finding. First, given the fact that T2DM leads to renal damage and sodium retention, our patients could be more likely to develop HF than those with hypertension only.5 Indeed, a subanalysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial suggested that ACEI was more protective against HF compared with CCB in diabetic patients,17 and a meta-analysis in diabetic patients showed that ARB showed a greater protection against HF than other antihypertensive drugs.33 In addition, the progression of insulin resistance and diabetic vascular complications are enhanced by the renin-angiotensin system.5 It is then conceivable that the complicated glucose intolerance unmasked the beneficial effect of ARB compared with hypertension alone. Second, our study patients are all Japanese. A subanalysis of the Reduction of Endpoints in Non–Insulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan Study showed that ARB was particularly effective against diabetic nephropathy in Japanese patients compared with other ethnicities.35 Taken together, ARB may have a greater potential to reduce the risk of HF compared with CCB, especially in Japanese hypertensive patients with glucose intolerance.
We showed that CCB had a tendency to reduce the risk of MI compared with ARB similar to the IDNT findings.21 The VALUE Trial demonstrated that MI was significantly lower in the CCB group compared with the ARB group.18 However, it requires careful interpretation, because this finding might be yielded by the difference in blood pressure control (≈4/2 mm Hg) during the follow-up in the VALUE Trial. However, when the effect of blood pressure was adjusted, the difference of MI risk disappeared.34 Furthermore, an updated meta-analysis demonstrated that ARB and CCB showed equivalent MI risk.36
In the risk of stroke, we found no difference between ARB and CCB. This finding is also in line with a previous meta-analysis in diabetic patients33 and head-to-head comparison trials not only in Asians19 but also in whites.18,21 However, it is quite in contrast to the 2 recent Japanese trials, the JIKEI HEART and KYOTO HEART Studies that clearly showed reduced risk of stroke in the add-on group with valsartan compared with the non-ARB group, who mainly received CCB.37,38 In these 2 trials, >50% of patients in the ARB add-on group also received CCB, so that these trials might suggest the superiority of combined therapy with ARB and CCB against the control group (mainly CCB-based without ARB). Thus, the discrepancy between the NHS and the JIKEI/KYOTO HEART Studies may partially be explained by the difference in the concomitant medications and the study design.
We applied the prospective, randomized, open-labeled, blinded endpoints method to assess outcomes. The prospective, randomized, open-labeled, blinded endpoints design is relatively vulnerable to reporting bias, because allocated drugs are open to both patients and physicians. In this regard, softer end points should be adjudicated with a special care. In the present study, an independent clinical research nurse coordinator group managed to follow up patient records and to collect the data in >90% of patients, and all of the reported adverse events were strictly adjudicated by an independent end point evaluation committee under a blinded manner as to the drug assignment. In fact, among 386 provisional reports, only 120 (31.1%) were adjudicated as the primary end point by the committee. Therefore, we believe that the bias would be highly unlikely to account for the differences. Rather, prospective, randomized, open-labeled, blinded endpoints design is close to daily clinical practice and less stressful to patients.28
Our patients were relatively well controlled in both blood pressure and glycemic status. A recent international cohort study reconfirmed that the incidence of CVD was significantly lower in Japan compared with other countries.39 These underlying conditions might result in quite lower incidence of primary outcomes (3.1% per year) than we anticipated. In addition, the sample size (n=1150) was less than the initially planned number of samples (n=3000), and that the present study was underpowered to determine our initial hypothesis that ARB might be more effective in preventing major CV events than CCB. However, postcensored analysis indicated acceptable statistical power (84.9%), the risk of primary outcome in each group was almost even (HR: 0.97), and our results were consistent with previous clinical evidence.18,19,21,33,34
Perspectives
The NHS is the first randomized, controlled trial comparing the clinical efficacies of ARB and CCB in Japanese hypertensive patients with glucose intolerance. Composite major CV events were similarly observed between ARB-based and CCB-based antihypertensive treatment. However, HF was more significantly reduced by ARB regimen. The NHS results echo those of the IDNT CV event trial and confirm the efficacy of ARB in this patient population in diabetic hypertensive patients in East Asia. Our results will highlight the safety and efficacy of ARB and support the current therapeutic guidelines for the treatment of diabetic hypertensive patients.
Sources of Funding
The NAGOYA HEART Study was funded by Nagoya University Graduate School of Medicine. The Department of Cardiology, Nagoya University Graduate School of Medicine, reported receiving research promotion grants (Shougaku Kifukin) from Actelion, Astellas, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Fuji Film RI, Kaken, Kowa, Kureha, Medtronic, Mitsubishi Tanabe, Mochida, MSD, Novartis, Pfizer, Sanofi-Aventis, Schering-Plough, and Takeda. However, the research topics of these donation grants are not restricted.
Disclosures
To.M. received lecturer's fees from Daiichi Sankyo, Novartis Pharma, Pfizer, and Takeda.
Acknowledgments
We thank Dr Hiroshi Yatsuya (the Department of Public Health, Nagoya University Graduate School of Medicine) for useful comments. We dedicate special recognition to Dr Takao Nishizawa, who passed away on August 2, 2009, after making a significant contribution to the study.
The NAGOYA HEART Study investigators include the following researchers: Principal Investigator: Toyoaki Murohara; Executive Committee: Toyoaki Murohara (chair), Takahisa Kondo, Satoshi Shintani, Kengo Maeda, Kunihiro Matsushita, Takashi Muramatsu, and Kentaro Yamashita; Steering Committee: Toyoaki Murohara (chair), Takahisa Kondo, Satoshi Shintani, Kengo Maeda, Kunihiro Matsushita, Takashi Muramatsu, Kentaro Yamashita, Makoto Akahoshi, Haruo Hirayama, Satoshi Ichimiya, Masato Iida, Yoshio Iwama, Shinji Kaneko, Taizo Kondo, Nobuyuki Marui, Toshihiro Obayashi, Miyoshi Ohno, Osamu Ohno, Toshiyuki Osaka, Takahito Sone, Yasunobu Takada, Chiei Takanaka, and Masato Watarai; Endpoints Evaluation Committee: Tatsuaki Matsubara (chair), Kimihiro Komori, and Manabu Doyu; Data and Safety Monitoring Board: Hideaki Toyoshima (chair), Yutaka Oiso, and Makoto Hirai; Statistical Analysis Board: Nobuo Shirahashi; Writing and Subanalysis Study Committee: Toyoaki Murohara (chair), Takahisa Kondo, Satoshi Shintani, Kengo Maeda, Kunihiro Matsushita, Takashi Muramatsu, and Kentaro Yamashita; Clinical Research Coordinator and Data Management Group: Kumi Sasaki, Emiko Watanabe, and Yoko Inoue; and Investigators Participating in the NAGOYA HEART Study: Masayoshi Ajioka, Tetsuya Amano, Toru Aoyama, Yutaka Aoyama, Hiroshi Asano, Yoshizumi Asano, Tokiko Fuchino, Takaharu Fujimura, Ryoji Fukui, Yoshihiro Futamura, Yukihisa Hamaguchi, Yoshihiro Hanaki, Ken Harada, Mitsunori Harada, Shuji Harata, Hiroaki Harayama, Kazuyuki Haruta, Kazuki Hattori, Kazunori Hayashi, Yuzo Hayashi, Michitaka Hibino, Akihiro Hirashiki, Yoshio Ichihara, Shigeo Iino, Hajime Imai, Haruo Inagaki, Yasuya Inden, Natsuo Inoue, Atsushi Iseki, Hideki Ishii, Kyosuke Ishikawa, Shinichi Ishikawa, Shinji Ishikawa, Ryoji Ishiki, Satoshi Isobe, Atsushi Ito, Hirokazu Iwata, Hideo Izawa, Kenji Kada, Masahiro Kajiguchi, Haruo Kamiya, Hiroki Kamiya, Masaaki Kanashiro, Hitoshi Kanayama, Yoshiyuki Kataoka, Masataka Kato, Kimihiko Kato, Rinya Kato, Katsuhiro Kawaguchi, Hideki Kawai, Kei Kawakami, Toshiki Kawamiya, Shohei Kikuchi, Akira Kimura, Keita Kondo, Teruo Kondo, Masayoshi Koyasu, Nobutake Kurebayashi, Yasuko Kureishi-Bando, Yasunori Kushiyama, Seifuku Kyo, Mitsutaka Makino, Haruo Matsui, Yoshichika Matsui, Tatsuyuki Matsunami, Kazuhiro Matsuo, Satoshi Matsuyama, Sachio Mitani, Hirotsugu Mitsuhashi, Hiroshi Miyake, Shinji Mokuno, Shuji Morikawa, Ryuta Morimoto, Yasutsugu Morimoto, Yasuhiro Morita, Hisashi Murakami, Yoshihiro Murata, Masahiro Muto, Kazuyoshi Nagao, Kozo Nagata, Harumichi Nakagawa, Eishin Nakamura, Yoshihito Nakashima, Mamoru Nanasato, Yasuhiro Nishimoto, Hideya Nishimura, Yasuto Nishinaka, Takuya Nishiura, Takao Nishizawa, Manabu Niwa, Shoji Noda, Yasushi Numaguchi, Yasuhiro Ogawa, Shozo Ogawa, Yasuhiro Ogura, Mitsutoshi Oguri, Taiki Ohashi, Jun Ohno, Takashi Okashiro, Kenji Okumura, Kei Oshima, Naohiro Osugi, Masahiro Oya, Yoshihiro Saburi, Makoto Saito, Kazuyoshi Sakai, Shinichi Sakai, Hiroaki Sano, Bummei Sato, Ken Sawada, Kohei Sawasaki, Tetsuo Shibata, Yukio Shiga, Toshimasa Shigeta, Masayuki Shimano, Atsuya Shimizu, Kiyokazu Shimizu, Masanori Shinoda, Toshikazu Sobue, Mikio Sugino, Shigeo Sugino, Hiroki Sugiura, Hirohiko Suzuki, Noriyuki Suzuki, Tomoyuki Suzuki, Toru Tajika, Katsumasa Takagi, Kensuke Takagi, Ryotaro Takahashi, Hiroki Takanari, Kenji Takemoto, Yoshio Takemoto, Kyosuke Takeshita, Susumu Takeuchi, Toyonari Takeuchi, Atsushi Tanaka, Toshikazu Tanaka, Toshiro Tanaka, Yasushi Tatematsu, Akihiro Terasawa, Mamoru Tokuda, Masayuki Torigoe, Toshio Torii, Takanobu Toriyama, Hideyuki Tsuboi, Naoya Tsuboi, Hideto Tsukamoto, Issei Uchida, Tomohiro Uchikawa, Yusuke Uemura, Tadayuki Uetani, Hisashi Umeda, Hiroki Watanabe, Michiharu Yamada, Minoru Yamada, Takashi Yamada, Takashi Yamamoto, Masaki Yamauchi, Kenichiro Yokoi, Kiminobu Yokoi, Kiyoshi Yokoi, Eriko Yokoyama, Tomohiro Yoshida, Yukihiko Yoshida, and Mari Yoshikane.
The affiliation of Mr. Nobuo Shirahashi is Novartis Pharma KK, Tokyo, Japan, and Department of Preventive Medicine and Environmental Health, Osaka City University Medical School, Osaka, Japan.
Footnotes
This trial has been registered at www.clinicaltrials.gov (identifier NCT00129233).
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.111.184226/-/DC1.
- Received September 29, 2011.
- Revision received October 26, 2011.
- Accepted December 17, 2011.
- © 2012 American Heart Association, Inc.
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