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Angiotensin System Has a Renal-Protective Effect in Hypertensive Patients: High-Dose ARB with ACE Inhibitor (Hawaii) Study

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Angiotensin System Has a Renal-Protective Effect in Hypertensive Patients: High-Dose ARB with ACE Inhibitor (Hawaii) Study Hypertension Research (2010) 33, 1150–1154 & 2010 The Japanese Society of Hypertension All rights reserved 0916-9636/10 $32.00 www.nature.com/hr ORIGINAL ARTICLE Strong suppression of the renin–angiotensin system has a renal-protective effect in hypertensive patients: High-dose ARB with ACE inhibitor (Hawaii) study Mitsuru Ohishi, Yasushi Takeya, Yuji Tatara, Koichi Yamamoto, Miyuki Onishi, Yoshihiro Maekawa, Kei Kamide and Hiromi Rakugi The principal means for reducing proteinuria in patients with chronic kidney disease are strong blockade of the renin– angiotensin system and strict regulation of blood pressure (BP). This study compared the efficacy of the maximum permissible doses of two common angiotensin receptor blockers (ARBs), namely valsartan (maximum dose¼160 mg per day) and olmesartan (maximum dose¼40 mg per day). We also investigated whether a high-dose ARB or the combination of an angiotensin-converting enzyme inhibitor with a high-dose ARB would be more renal protective. We recruited 87 poorly controlled hypertensive patients. In the first study, 50 patients without proteinuria were switched from valsartan (160 mg per day) to olmesartan (40 mg per day) for 4 months. In the second study, 37 patients with proteinuria were randomized to either switch from valsartan 160 mg per day to 40 mg per day olmesartan (n¼19; Olm-G) or addition of 2.5–10 mg per day imidapril (stepped up by 2.5 mg per month) to valsartan at 160 mg per day (n¼18; Imi-G). After 4 months, the BP level decreased (first study) from 157/88 mm Hg to 145/ 82 mm Hg (Po0.001) and (second study) from 149/86 mm Hg to 135/77 mm Hg and 145/82 mm Hg for Olm-G and Imi-G, respectively. Furthermore, in the second study, urinary protein/creatinine excretion was reduced from 2.0±1.8 g gÀ1 to 0.8±0.8 g gÀ1 (P¼0.0242) in Olm-G and from 1.4±1.3 g gÀ1 to 0.9±1.0 g gÀ1 (P¼0.0398) in Imi-G. The significance persisted after adjustment for BP or other risk factors. Our results suggested that the maximum dose of olmesartan was more effective than that of valsartan and comparable with the combination of valsartan and imidapril for reducing BP and proteinuria in poorly controlled hypertensive patients. Hypertension Research (2010) 33, 1150–1154; doi:10.1038/hr.2010.145; published online 12 August 2010 Keywords: high dosage; JSH2009 guidelines; olmesaratan; urinary protein excretion INTRODUCTION 2009). The recommended BP for patients with CKD is lower than Chronic kidney disease (CKD) has received considerable attention in that for older patients with hypertension alone with no complications. the management of hypertension,1 and it is an independent risk factor We hypothesized that patients with hypertension and CKD would for cardiovascular disease in patients with hypertension.2 Proteinuria benefit from treatment with an ARB that sufficiently reduced BP, on is one of the clinical parameters for diagnosing renal damage, the basis of previous results obtained from meta-analyses and the particularly glomerular hypertension, and it is a risk factor and IRMA2 multicenter clinical trial.9 However, the initial, standard and predictor for cardiovascular events.3 Reducing glomerular pressure is maximum doses for ARBs are under government regulation in Japan. a principal strategy for reducing proteinuria in patients with hyper- We previously reported that the administration of valsartan at 160 mg tension.4 To reduce glomerular pressure, blood pressure (BP) must be per day was more effective for reducing BP and proteinuria than the decreased, typically by reducing arteriolar resistance in the efferent administration of candesartan at 12 mg per day in patients with renal arterioles.5–6 Angiotensin II type 1 receptors are localized to both hypertension.10 The Val-HeFT11 and VALIANT12 trials demonstrated afferent and efferent renal arterioles.5–6 Several multicenter rando- that 320 mg per day of valsartan had beneficial effects on the prog- mized clinical trials have shown that both angiotensin II receptor noses for chronic heart failure and ischemic heart disease. However, blockers (ARBs)7 and angiotensin-converting enzyme inhibitors in Japan, the permitted maximum doses of candesartan and valsartan (ACEIs)8 can reduce proteinuria. On the basis of those results, ARBs are lower than the doses used in those clinical trials. No studies and ACEIs are the drugs of choice for managing hypertensive have compared the BP-lowering and renal-protective effects of the patients with CKD, according to JSH2009 (Japanese Society of permitted maximum doses of ARBs. Head-to-head comparisons Hypertension Guidelines for the Management of Hypertension, of olmesartan with each of the other ARBs, administered at the Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Suita, Japan Correspondence: Dr M Ohishi, Department of Geriatric Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Japan. E-mail: [email protected] Received 24 May 2010; revised 3 June 2010; accepted 8 June 2010; published online 12 August 2010 Effects of ARB and ACEI on renal protection MOhishiet al 1151 label-recommended doses, showed that olmesartan was most effective equation: glomerular filtration rate (ml minÀ1 per 1.73 m2)¼175Â(serum at decreasing BP.13 This study focused on hypertensive patients who creatinine)À1.154Â(age)À0.203Â0.741 (Â0.742 for females).14 had not achieved optimal BP after at least 3 months of treatment with the maximum permitted valsartan dose. We had two aims: (1) to Statistical analysis determine whether BP would be better controlled by switching from Data were analyzed using commercially available statistical software (JMP valsartan to the maximum permitted olmesartan dose; and (2) to version 5.1.1; SAS Institute, Cary, NC, USA). Differences in responses to treatment with olmesartan and valsartan were assessed with paired t-tests. determine, in patients with hypertension and CKD, whether BP and Differences in low and high UPEs were assessed by one-factor ANOVA (analysis urinary protein excretion (UPE) would be better controlled by switch- of variance) and Fisher’s test. We used multiple regression analysis to evaluate ing from valsartan to the maximum permitted olmesartan dose or by influential factors for reducing UPE. P-values o0.05 were considered statisti- adding an ACEI to valsartan. Thus, we called this study the high-dose cally significant. ARB with ACEI study (Hawaii) study. RESULTS METHODS Results are expressed as mean±s.d. Study population We recruited 90 hypertensive outpatients of the Osaka University Hospital who Patient characteristics had received 160 mg valsartan per day for at least 3 months. At the onset of this Table 1 summarizes the characteristics of the 87 patients who study, patients had not achieved optimal BP recommended by the JSH2009. completed studies 1 and 2. In study 2, the frequency of male patients According to the JSH2009, optimal BP was o130/80 mm Hg for managing was high (86%) and the mean age was slightly low compared with hypertensive patients with diabetes or CKD; o130/85 mm Hg for patients o65 patients in study 1; however, these were not different between the years of age without major complications; o140/90 mm Hg for patients 465 Olm-G and Imi-G groups. Before entering this study, 68 participants years of age; and 125/75 mm Hg for patients with proteinuria or 41.0 g per o had been taking anti-hypertensive drugs in addition to valsartan at day UPE. Patients were excluded from the study when they had experienced a stroke or cardiovascular event during the previous year; had grade 2 or higher 160 mg per day. These included calcium channel blockers (n¼62, congestive heart failure, according to the New York Heart Association scale; had 71%), b-blockers (n¼27, 31%), diuretics (n¼21, 24%) and a-blockers 43.0 mg per 100 ml serum creatinine; and/or had a history of dry cough when (n¼6, 7%). These ‘other hypertensive drugs’ were continued without taking ACEIs. The use of other antihypertensive drugs was permitted, except change throughout the study. The mean number of concurrent anti- ACEIs. The doses of concurrent drugs remained unchanged throughout the hypertensive drugs taken per patient was 2.3±1.0. Common serum study. The protocol for this study was approved by the hospital ethics factors that indicate liver function (Table 1) did not change during the committee, and informed consent was obtained from all patients before study. There were no significant differences between the Olm-G and switching from valsartan to olmesartan or before adding imidapril. Imi-G groups. Study protocol for study 1 BP and PR changes in study 1 A total of 53 patients without CKD who had been taking 160 mg per day Both BP and PR measurements were comparable 1 month before and valsartan were recruited for study 1. Two patients were excluded because their on the day of switching from valsartan to olmesartan (Table 2). average BP level was lower than optimal on the day of switching to olmesartan. However, after the switch to olmesartan, systolic blood pressure Thus, 51 hypertensive patients were switched to 40 mg per day olmesartan. One (SBP), diastolic blood pressure (DBP) and mean BP (MBP) levels month before the switch, we measured the cholesterol profile, uric acid, fasting were significantly lower (+1 month, +2 months; Table 2). After blood glucose, as well as renal and liver functions. BP and pulse rate (PR) were switching to olmesartan, the mean (averaged +1 and +2 month evaluated 1 month before, the day of and 1 and 2 months after the switch. One ± patient left the study because of unpleasant side effects; thus, a total of 50 values) SBP was 144.7 13.8 mm Hg and the mean DBP was ± hypertensive patients were analyzed.
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