An angiotensin II receptor blocker–calcium channel blocker combination prevents cardiovascular events in elderly high-risk hypertensive patients with chronic kidney disease better than high-dose angiotensin II receptor blockade alone
Authors: Shokei Kim-Mitsuyama, Hisao Ogawa, Kunihiko Matsui, Tomio Jinnouchi, Hideaki Jinnouchi, Kikuo Arakawa, None for the OSCAR Study Group
Journal: Kidney International (2012)

The OSCAR study was a multicenter, prospective randomized open-label blinded end-point study of 1164 Japanese elderly hypertensive patients comparing the efficacy of angiotensin II receptor blocker (ARB) uptitration to an ARB plus calcium channel blocker (CCB) combination. In this prospective study, we performed prespecified subgroup analysis according to baseline estimated glomerular filtration rate (eGFR) with chronic kidney disease (CKD) defined as an eGFR <60ml/min per 1.73m2. Blood pressure was lower in the combined therapy than in the high-dose ARB cohort in both groups with and without CKD. In patients with CKD, significantly more primary events (a composite of cardiovascular events and noncardiovascular death) occurred in the high-dose ARB group than in the combination group (30 vs. 16, respectively, hazard ratio 2.25). Significantly more cerebrovascular and more heart failure events occurred in the high-dose ARB group than in the combination group. In patients without CKD, however, the incidence of primary events was similar between the two treatments. The treatment-by-subgroup interaction was significant. Allocation to the high-dose ARB was a significant independent prognostic factor for primary events in patients with CKD. Thus, the ARB plus CCB combination conferred greater benefit in prevention of cardiovascular events in patients with CKD compared with high-dose ARB alone. Our findings provide new insight into the antihypertensive strategy for elderly hypertensive patients with CKD. The OSCAR study was a multicenter, prospective randomized open-label blinded end-point study of 1164 Japanese elderly hypertensive patients comparing the efficacy of angiotensin II receptor blocker (ARB) uptitration to an ARB plus calcium channel blocker (CCB) combination. In this prospective study, we performed prespecified subgroup analysis according to baseline estimated glomerular filtration rate (eGFR) with chronic kidney disease (CKD) defined as an eGFR <60ml/min per 1.73m2. Blood pressure was lower in the combined therapy than in the high-dose ARB cohort in both groups with and without CKD. In patients with CKD, significantly more primary events (a composite of cardiovascular events and noncardiovascular death) occurred in the high-dose ARB group than in the combination group (30 vs. 16, respectively, hazard ratio 2.25). Significantly more cerebrovascular and more heart failure events occurred in the high-dose ARB group than in the combination group. In patients without CKD, however, the incidence of primary events was similar between the two treatments. The treatment-by-subgroup interaction was significant. Allocation to the high-dose ARB was a significant independent prognostic factor for primary events in patients with CKD. Thus, the ARB plus CCB combination conferred greater benefit in prevention of cardiovascular events in patients with CKD compared with high-dose ARB alone. Our findings provide new insight into the antihypertensive strategy for elderly hypertensive patients with CKD. Chronic kidney disease (CKD), manifested by decreased glomerular filtration rate (GFR), is a worldwide public health problem, and an older population has a higher prevalence of CKD.1.Go A.S. Chertow G.M. Fan D. et al.Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.N Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (8984) Google Scholar, 2.Irie F. Iso H. Sairenchi T. et al.The relationships of proteinuria, serum creatinine, glomerular filtration rate with cardiovascular disease mortality in Japanese general population.Kidney Int. 2006; 69: 1264-1271Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar, 3.Manjunath G. Tighiouart H. 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Gullion C.M. et al.Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization.Arch Intern Med. 2004; 164: 659-663Crossref PubMed Scopus (1366) Google Scholar and high-risk populations such as the elderly,3.Manjunath G. Tighiouart H. Coresh J. et al.Level of kidney function as a risk factor for cardiovascular outcomes in the elderly.Kidney Int. 2003; 63: 1121-1129Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar as well as in patients with hypertension,7.Ruilope L.M. Salvetti A. Jamerson K. et al.Renal function and intensive lowering of blood pressure in hypertensive participants of the hypertension optimal treatment (HOT) study.J Am Soc Nephrol. 2001; 12: 218-225PubMed Google Scholar diabetes,8.Mann J.F. Gerstein H.C. 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K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.Am J Kidney Dis. 2002; 39: S1-S266Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar and a statement from the American Heart Association Councils12.Sarnak M.J. Levey A.S. Schoolwerth A.C. et al.Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention.Circulation. 2003; 108: 2154-2169Crossref PubMed Scopus (2874) Google Scholar have recommended that patients with CKD should be considered as a high-risk group for subsequent cardiovascular events and that treatment recommendation based on cardiovascular risk stratification should take into account the highest-risk status of patients with CKD. It has been established that the renin–angiotensin system (RAS) has a pivotal role in the pathophysiology of CKD and cardiovascular disease. Inhibition of RAS by angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors confers cardiovascular protection in both diabetic13.Brenner B.M. Cooper M.E. de Zeeuw D. et al.Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med. 2001; 345: 861-869Crossref PubMed Scopus (6147) Google Scholar,14.Lewis E.J. Hunsicker L.G. Clarke W.R. et al.Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.N Engl J Med. 2001; 345: 851-860Crossref PubMed Scopus (5040) Google Scholar and nondiabetic hypertensive patients with CKD,7.Ruilope L.M. Salvetti A. Jamerson K. et al.Renal function and intensive lowering of blood pressure in hypertensive participants of the hypertension optimal treatment (HOT) study.J Am Soc Nephrol. 2001; 12: 218-225PubMed Google Scholar,15.Solomon S.D. Rice M.M. AJ K. et al.Renal function and effectiveness of angiotensin-converting enzyme inhibitor therapy in patients with chronic stable coronary disease in the Prevention of Events with ACE inhibition (PEACE) trial.Circulation. 2006; 114: 26-31Crossref PubMed Scopus (150) Google Scholar and is regarded as the first-line therapeutic strategy for CKD in Western countries16.Chobanian A.V. Bakris G.L. Black H.R. et al.Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure.Hypertension. 2003; 42: 1206-1252Crossref PubMed Scopus (10557) Google Scholar,17.Mancia G. De Backer G. Dominiczak A. et al.Guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of hypertension (ESH) and of the European Society of cardiology (ESC).Eur Heart J. 2007; 28 (2007): 1462-1536PubMed Google Scholar and Japan.18.Ogihara T. Kikuchi K. Matsuoka H. et al.The Japanese Society of Hypertension Guidelines for the management of hypertension (JSH 2009).Hypertens Res. 2009; 32: 3-107Crossref PubMed Scopus (4) Google Scholar Furthermore, previous evidence indicates that uptitration of an ARB provides greater suppression of renal events in hypertensive patients with diabetic nephropathy19.Parving H.H. Lehnert H. Brochner-Mortensen J. et al.The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes.N Engl J Med. 2001; 345: 870-878Crossref PubMed Scopus (2938) Google Scholar and greater reduction of cardiovascular events in heart failure patients20.Konstam M.A. Neaton J.D. Dickstein K. et al.Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial.Lancet. 2009; 374: 1840-1848Abstract Full Text Full Text PDF PubMed Scopus (493) Google Scholar compared with lower dose of ARB, thereby showing the benefit of high-dose ARB therapy in prevention of cardiovascular and renal events. On the other hand, the combination of ARB and calcium channel blocker (CCB) is recommended as one of the preferred combination therapies for the general hypertensive population.16.Chobanian A.V. Bakris G.L. Black H.R. et al.Seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure.Hypertension. 2003; 42: 1206-1252Crossref PubMed Scopus (10557) Google Scholar, 17.Mancia G. De Backer G. Dominiczak A. et al.Guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of hypertension (ESH) and of the European Society of cardiology (ESC).Eur Heart J. 2007; 28 (2007): 1462-1536PubMed Google Scholar, 18.Ogihara T. Kikuchi K. Matsuoka H. et al.The Japanese Society of Hypertension Guidelines for the management of hypertension (JSH 2009).Hypertens Res. 2009; 32: 3-107Crossref PubMed Scopus (4) Google Scholar However, it remains to be elucidated which antihypertensive strategy is more effective for the prevention of cardiovascular morbidity and mortality in high-risk subjects with CKD compared with those without CKD at baseline; that is, is ARB plus CCB combination therapy or high-dose ARB therapy more effective? We conducted the OlmeSartan and Calcium Antagonists Randomized (OSCAR) study comparing the preventive effect of ARB plus CCB combination therapy versus high-dose ARB therapy on cardiovascular morbidity and mortality in Japanese elderly hypertensive patients with baseline cardiovascular disease and/or type 2 diabetes, and have recently reported the principal results of the OSCAR study.21.Ogawa H. Kim-Mitsuyama S. Matsui K. et al.Angiotensin II receptor blocker-based therapy in Japanese elderly high-risk hypertensive patients.Am J Med. 2012Abstract Full Text Full Text PDF Scopus (45) Google Scholar In the present study, to determine whether CKD might influence the relative effectiveness of ARB plus CCB combination versus high-dose ARB in the prevention of cardiovascular morbidity and mortality, we performed a subgroup analysis of the OSCAR study according to baseline estimated GFR (eGFR), which we had prespecified as described in our protocol paper.22.Ogawa H. Kim-Mitsuyama S. Jinnouchi T. et al.Rationale, design and patient baseline characteristics of OlmeSartan and calcium antagonists randomized (OSCAR) study: a study comparing the incidence of cardiovascular events between high-dose angiotensin II receptor blocker (ARB) monotherapy and combination therapy of ARB with calcium channel blocker in Japanese elderly high-risk hypertensive patients (ClinicalTrials. gov no. NCT00134160).Hypertens Res. 2009; 32: 575-580Crossref PubMed Scopus (16) Google Scholar Eighty-six patients were excluded from the present analysis because no serum creatinine value at baseline was available. As a result, 1078 patients of a total of 1164 patients originally enrolled in the OSCAR study were included in the present analysis (Table 1). The number of patients with an eGFR of <60ml/min per 1.73mm2 (defined as patients with CKD) was 353; of these, 334 (94.6%) patients had an eGFR of 30–59ml/min per 1.73mm2 and 19 patients (5.4%) had an eGFR <30ml/min per 1.73mm2. The number of patients having an eGFR ≥60ml/min per 1.73mm2 (patients without CKD) was 725; of these, 629 (86.8%) patients had an eGFR of 60–89ml/min per 1.73mm2 and 96 patients (13.2%) had an eGFR ≥90ml/min per 1.73mm2.Table 1Baseline characteristicsOverallCKD (+)CKD (-)Total patients(n=1078)CKD (+)(n=353)CKD (-)(n=725)P-valueHigh-dose ARB(n=181)ARB+CCB(n=172)High-dose ARB(n=354)ARB+CCB(n=371)eGFR (ml/min per 1.73m2)67.2±18.747.8±9.176.7±14.4<0.000147.3±8.948.3±9.376.4±13.976.9±14.8Age (years)73.7±5.475.5±5.272.8±5.3<0.000175.2±5.175.8±5.473.0±5.472.7±5.3Male, n (%)477 (44.3)167 (47.3)310 (42.8)0.1680 (44.2)87 (50.6)157 (44.4)153 (41.2)BMI (kg/m2)24.1±3.623.9±3.224.2±3.70.1724.2±3.423.5±3.0aP=0.03 versus high-dose ARB.24.3±3.824.1±3.7BMI ≥25kg/m2, n (%)403 (37.5)118 (33.4)285 (39.4)0.0667 (37.0)51 (29.7)144 (40.8)141 (38.1)Systolic BP (mmHg)158.0±11.9158.9±12.0157.5±11.80.07158.9±12.8158.9±11.2158.3±12.3156.7±11.3Diastolic BP (mmHg)84.6±9.884.8±9.784.6±9.80.7985.0±9.884.5±9.784.8±9.884.4±9.8Heart rate (b.p.m)73±1073±1073±100.7674±1073±1074±1073±9Hyperlipidemia, n (%)528 (49.0)177 (50.1)351 (48.4)0.5996 (53.0)81 (47.1)173 (48.9)178 (48.0)Current smoker, n (%)107 (9.9)26 (7.4)81 (11.2)0.0516 (8.9)10 (5.8)43 (12.2)38 (10.2)Current alcohol intake, n (%)350 (32.6)125 (35.7)225 (31.0)0.1255 (30.7)70 (40.9)114 (32.2)111 (29.9)Serum values Creatinine (mg/dl)0.8±0.31.1±0.30.7±0.1<0.00011.1±0.31.1±0.30.7±0.10.7±0.1 Potassium (mmol/l)4.3±0.54.4±0.54.3±0.4<0.00014.4±0.44.5±0.54.3±0.44.3±0.4 Total cholesterol (mg/dl)199±35195±35200±350.03196±36194±35198±34203±36 HDL cholesterol (mg/dl)56.6±15.253.9±15.257.9±15.0<0.000154.9±17.052.9±13.056.8±14.658.9±15.3 Fasting plasma glucose (mg/dl)117±44116±46117±430.72119±48113±45120±48115±38 Casual plasma glucose (mg/dl)145±59140±56147±600.25138±54144±59144±55150±64Previous antihypertensive treatment, n (%) No. of agents 0300 (27.8)66 (18.7)234 (32.3)<0.000133 (18.2)33 (19.2)115 (32.5)119 (32.1) 1473 (43.9)163 (46.2)310 (42.8)83 (45.9)80 (46.5)150 (42.4)160 (43.1) 2253 (23.5)104 (29.5)149 (20.6)52 (28.7)52 (30.2)72 (20.3)77 (20.8) ≥352 (4.8)20 (5.7)32 (4.4)13 (7.2)7 (4.1)17 (4.8)15 (4.0) Oral glucose-lowering agents, n (%)417 (38.7)134 (38.0)283 (39.0)0.7371 (39.2)63 (36.6)144 (40.7)139 (37.5) Insulin treatment, n (%)68 (6.3)24 (6.8)44 (6.1)0.6412 (6.6)12 (7.0)19 (5.4)25 (6.7) Lipid-lowering agents, n (%)399 (37.0)133 (37.7)266 (36.7)0.7566 (36.5)67 (39.0)134 (37.9)132 (35.6) Antiplatelet agents, n (%)343 (31.8)142 (40.2)201 (27.7)<0.000165 (35.9)77 (44.8)103 (29.1)98 (26.4)Abbreviations: ARB, angiotensin II receptor blocker; BMI, body mass index; BP, blood pressure; CCB, calcium channel blocker; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein.Data are mean±s.d. for continuous variables and number (%) for categorical variables. P-value was calculated using t-tests for continuous variables and χ2 tests for categorical variables. CKD (+), patients with CKD (with eGFR of <60 ml/min per 1.73m2) at baseline; CKD (-), patients without CKD (with eGFR of ≥60 ml/min per 1.73m2) at baseline; High-dose ARB, patients allocated to high-dose ARB therapy; ARB+CCB, patients allocated to ARB+CCB combination therapy.a P=0.03 versus high-dose ARB. Open table in a new tab Abbreviations: ARB, angiotensin II receptor blocker; BMI, body mass index; BP, blood pressure; CCB, calcium channel blocker; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein. Data are mean±s.d. for continuous variables and number (%) for categorical variables. P-value was calculated using t-tests for continuous variables and χ2 tests for categorical variables. CKD (+), patients with CKD (with eGFR of <60 ml/min per 1.73m2) at baseline; CKD (-), patients without CKD (with eGFR of ≥60 ml/min per 1.73m2) at baseline; High-dose ARB, patients allocated to high-dose ARB therapy; ARB+CCB, patients allocated to ARB+CCB combination therapy. Importantly, there was no significant difference regarding any of the baseline characteristics between the patients (n=1078) included in the present analysis and total patients (n=1164)21.Ogawa H. Kim-Mitsuyama S. Matsui K. et al.Angiotensin II receptor blocker-based therapy in Japanese elderly high-risk hypertensive patients.Am J Med. 2012Abstract Full Text Full Text PDF Scopus (45) Google Scholar,22.Ogawa H. Kim-Mitsuyama S. Jinnouchi T. et al.Rationale, design and patient baseline characteristics of OlmeSartan and calcium antagonists randomized (OSCAR) study: a study comparing the incidence of cardiovascular events between high-dose angiotensin II receptor blocker (ARB) monotherapy and combination therapy of ARB with calcium channel blocker in Japanese elderly high-risk hypertensive patients (ClinicalTrials. gov no. NCT00134160).Hypertens Res. 2009; 32: 575-580Crossref PubMed Scopus (16) Google Scholar originally enrolled in the OSCAR study. As shown in Table 1, eGFR (mean±s.d.) in patients with and without CKD was 47.8±9.1 and 76.7±14.4ml/min per 1.73mm2, respectively (P<0.0001 between the two groups). Compared with patients without CKD, patients with CKD were older, had higher serum creatinine, and lower serum high-density lipoprotein cholesterol; a lower proportion of them had a history of previous antihypertensive agents and a higher proportion had a history of antiplatelet agents. In patients with CKD (Table 1), baseline characteristics were well balanced between high-dose ARB and ARB plus CCB treatment groups, except for a slight difference in body mass index between the two groups (24.2±3.4 vs. 23.5±3.0kg/m2, P=0.03). In patients without CKD (Table 1), there was no significant difference between the two treatment groups in any of the baseline characteristics. Table 2 shows that a higher proportion of patients with CKD had cardiovascular disease at baseline compared with those without CKD (80.5 vs. 66.9%, P<0.0001), whereas a slightly lower proportion of them had type 2 diabetes at baseline (49.0 vs. 55.9%, P=0.03).Table 2Baseline cardiovascular disease and type 2 diabetes of overall patients and patients with or without CKDOverallCKD (+)CKD (-)Total patients(n=1078)CKD (+)(n=353)CKD (-)(n=725)P-valueHigh-dose ARB(n=181)ARB+CCB(n=172)High-dose ARB(n=354)ARB+CCB(n=371)Previous cardiovascular disease, n (%)769 (71.3)284 (80.5)485 (66.9)<0.0001149 (82.3)135 (78.5)238 (67.2)247 (66.6)Stroke193 (17.9)74 (21.0)119 (16.4)0.0737 (20.4)37 (21.5)69 (19.5)50 (13.5)aP=0.03 versus high-dose ARB.Transient ischemic attack52 (4.8)27 (7.7)25 (3.5)0.00316 (8.8)11 (6.4)9 (2.5)16 (4.3)Asymptomatic cerebrovascular disease196 (18.2)58 (16.4)138 (19.0)0.333 (18.2)25 (14.5)68 (19.2)70 (18.9)Myocardial infarction35 (3.3)22 (6.2)13 (1.8)0.000111 (6.1)11 (6.4)5 (1.4)8 (2.2)Angina pectoris121 (11.2)44 (12.5)77 (10.6)0.3723 (12.7)21 (12.2)39 (11.0)38 (10.2)Heart failure83 (7.7)34 (9.6)49 (6.8)0.117 (9.4)17 (9.9)21 (5.9)28 (7.6)Left ventricular hypertrophy189 (17.5)56 (15.9)133 (18.3)0.3132 (17.7)24 (14.0)64 (18.1)69 (18.6)Aortic aneurysm4 (0.4)3 (0.9)1 (0.1)0.071 (0.6)2 (1.2)0 (0)1 (0.3)Arteriosclerotic peripheral arterial occlusive disease24 (2.2)10 (2.8)14 (1.9)0.355 (2.8)5 (2.9)4 (1.1)10 (2.7)Serum creatinine outside normal range73 (6.8)68 (19.3)5 (0.7)<0.000134 (18.8)34 (19.8)3 (0.9)2 (0.5)Proteinuria126 (11.7)69 (19.6)57 (7.9)<0.000139 (21.6)30 (17.4)26 (7.3)31 (8.4)Previous type 2 diabetes, n (%)578 (53.6)173 (49.0)405 (55.9)0.0385 (47.0)88 (51.2)197 (55.7)208 (56.1)Abbreviations: ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; CKD, chronic kidney disease.Data are number (%). P-value was calculated using χ2 tests. CKD (+), patients with CKD at baseline; CKD (-), patients without CKD at baseline; high-dose ARB, patients allocated to high-dose ARB therapy; ARB+CCB, patients allocated to ARB+CCB combination therapy.a P=0.03 versus high-dose ARB. Open table in a new tab Abbreviations: ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; CKD, chronic kidney disease. Data are number (%). P-value was calculated using χ2 tests. CKD (+), patients with CKD at baseline; CKD (-), patients without CKD at baseline; high-dose ARB, patients allocated to high-dose ARB therapy; ARB+CCB, patients allocated to ARB+CCB combination therapy. As shown in Table 2, in patients with CKD and without CKD, no significant difference was found between the two treatment groups in proportion of patients with previously existing cardiovascular disease or type 2 diabetes, except for a slight difference between the treatment groups in the percentage of previous stroke in patients without CKD. Table 3 shows the number and percentage of patients who received additional antihypertensive drug(s) in the two treatment groups in the subgroups with CKD or without CKD, throughout the follow-up period. In all groups, diuretics, β-blockers, and α-blockers were mainly prescribed as additional antihypertensive medications, and diuretics were the most prescribed among all additional antihypertensive drugs. The percentage of patients who received these additional antihypertensive drugs was greater in the high-dose ARB group than in the ARB plus CCB combination group, in both the subgroups with CKD and that without CKD.Table 3Number of patients who received additional antihypertensive drug(s) throughout the follow-up periodCKD (+)CKD (-)High-dose ARBARB+CCBHigh-dose ARBARB+CCBAfter allocationNNoneDβαNNoneDβαNNoneDβαNNoneDβα6 mos180112 (62)34 (19)21 (12)18 (10)170138 (81)13 (7)6 (4)6 (4)350246 (70)55 (16)30 (9)32 (9)371292 (79)34 (9)10 (3)6 (2)12 mos17191 (53)44 (26)28 (16)15 (9)165130 (79)16 (10)6 (4)9 (5)336211 (63)74 (22)39 (12)38 (11)361280 (78)38 (11)17 (5)11 (3)18 mos16386 (53)49 (30)28 (17)17 (10)158119 (75)17 (11)8 (5)6 (4)325204 (63)77 (24)38 (12)36 (11)341262 (77)42 (12)22 (6)11 (3)24 mos15677 (49)55 (35)30 (19)19 (12)156114 (73)20 (13)11 (7)9 (6)311184 (59)80 (26)39 (13)42 (14)327242 (74)43 (13)24 (7)11 (3)30 mos15265 (43)57 (38)30 (20)16 (11)154113 (73)20 (13)10 (6)6 (4)302163 (54)83 (27)41 (14)39 (13)321229 (71)44 (14)24 (7)10 (3)36 mos14865 (44)52 (35)30 (20)15 (10)147103 (70)22 (15)9 (6)9 (6)297163 (55)92 (31)42 (14)38 (13)315218 (69)50 (16)27 (9)9 (3)Abbreviations: ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; CKD, chronic kidney disease; D, diuretics; mos, months; none, no additional drug; β, β-blockers; α, α-blockers.Data represent number (%) of patients. CKD (+), patients with CKD at baseline; CKD (-), patients without CKD at baseline; high-dose ARB, patients allocated to high-dose ARB therapy; ARB+CCB, patients allocated to ARB+CCB combination therapy. Open table in a new tab Abbreviations: ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; CKD, chronic kidney disease; D, diuretics; mos, months; none, no additional drug; β, β-blockers; α, α-blockers. Data represent number (%) of patients. CKD (+), patients with CKD at baseline; CKD (-), patients without CKD at baseline; high-dose ARB, patients allocated to high-dose ARB therapy; ARB+CCB, patients allocated to ARB+CCB combination therapy. In patients with CKD (Figure 1a), systolic BP of the ARB plus CCB combination group was lower than that of the high-dose ARB group throughout the follow-up period, and the mean difference in systolic BP between the groups during follow-up period was 3.7mmHg (P=0.0051). In patients without CKD (Figure 1b), both systolic BP and diastolic BP were lower in the ARB plus CCB combination group than in the high-dose ARB group, and the mean difference in systolic BP and diastolic BP between the groups was 2.2mmHg (P=0.0039) and 1.8mmHg (P=0.0013), respectively. The proportion of patients who achieved target BP of <140/90mmHg was significantly higher in the ARB plus CCB combination group than in the high-dose ARB group, both in patients with CKD (77.3 vs. 60.2%, P=0.0005) and those without CKD (75.7 vs. 67.8%, P=0.0174). Figure 2 indicates the incidence of primary outcome events in the high-dose ARB and ARB plus CCB combination groups in patients with CKD and without CKD. There was a significant interaction between the subgroup of patients with CKD and those without CKD for the incidence of primary outcome events, and the treatment-by-subgroup interaction was statistically significant (P=0.0293 for interaction). In patients with CKD (Figure 2a), 30 patients (16.6%; 63.7 per 1000 patient-years) of 181 patients assigned to high-dose ARB and 16 patients (9.3%; 33.9 per 1000 patient-years) of 172 patients assigned to ARB plus CCB combination experienced primary events: the difference (56.1%) in relative risk between the two groups was significant (hazard ratio (HR)=2.25; 95% confidence interval (CI)=1.20–4.20; P=0.0096). On the other hand, in patients without CKD (Figure 2b), there was no significant difference between high-dose ARB and ARB plus CCB combination groups regarding the incidence of primary events (27 (7.6%) vs. 32 (8.6%) events: 28.8 per 1000 patient-years vs. 31.9 per 1000 patient-years): HR=0.89: 95% CI=0.53–1.50; P=0.6671. In patients with CKD (Figure 3a), the ARB plus CCB combination group had a lower incidence of cerebrovascular disease (HR=3.45; 95% CI=1.20–9.92; P=0.0151) and heart failure (HR=9.27; 95% CI=1.11–77.29; P=0.0148) than the high-dose ARB group. On the other hand, in patients without CKD (Figure 3b), there was no significant difference between the two treatment groups with regard to any secondary end point. Figure 4 depicts the time course of eGFR changes in the subgroups with CKD or without CKD. In the subgroup with CKD, compared with baseline eGFR, eGFR slightly declined in both the high-dose ARB group and ARB plus CCB combination group during the follow-up period. eGFR (mean±s.d.) at the end of the study tended to be lower in the high-dose ARB group than in the ARB plus CCB combination group (44.6±11.4 vs. 48.1±16.5ml/min per 1.73m2; P=0.291), although the difference did not reach statistical significance. In the subgroup without CKD, eGFR at the end of the study did not significantly differ between high-dose ARB and ARB plus CCB combination groups (66.5±19.9 vs. 70.0±16.1ml/min per 1.73m2; P=0.12), although eGFR in the high-dose ARB group was significantly lower than that in the ARB plus CCB combination group at 24 months (66.8±13.4 vs. 70.6±15.0ml/min per 1.73m2; P=0.01) and 30 months (65.2±14.2 vs. 69.9±15.9ml/min per 1.73m2; P=0.002). Table 4 shows the results of multivariable Cox regression analysis for overall patients, the subgroup with CKD, and the subgroup without CKD. For overall patients, high-dose ARB treatment was not significantly associated with primary outcome events (P=0.239), whereas sex (P=0.004), age (P=0.001), and baseline cardiovascular disease (P=0.042) were significantly associated with primary outcome events.Table 4Adjusted hazard ratios of prognostic factor for primary outcome eventsOverall patientsCKD (+)CKD (-)HR (95% CI)P-valueHR (95% CI)P-valueHR (95% CI)P-valueHigh-dose ARB1.26 (0.86–1.86)0.2392.27 (1.22–4.23)0.0100.86 (0.51–1.44)0.561Male gender1.79 (1.21–2.64)0.0041.66 (0.92–3.01)0.0921.96 (1.15–3.34)0.013Age≥75 years2.00 (1.35–2.97)0.0012.76 (1.40–5.43)0.0031.61 (0.96–2.71)0.072Previous CV disease1.76 (1.02–3.04)0.0421.60 (0.65–3.95)0.3041.93 (0.96–3.85)0.064Previous diabetes1.26 (0.81–1.94)0.3101.31 (0.68–2.52)0.4221.33