Efficacy of the combination of amlodipine and candesartan in hypertensive patients with coronary artery disease: A subanalysis of the HIJ-CREATE study

Journal of Cardiology 62 (2013) 217–223

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Original article

Efficacy of the combination of amlodipine and candesartan in hypertensive patients with coronary artery disease: A subanalysis of the HIJ-CREATE study Ryo Koyanagi (MD, PhD), Nobuhisa Hagiwara (MD, PhD), Jun-ichi Yamaguchi (MD, PhD), Erisa Kawada-Watanabe (MD), Shoji Haruta (MD, PhD), Atsushi Takagi (MD, PhD, FJCC), Hiroshi Ogawa (MD, PhD) ∗ , the HIJ-CREATE Investigators The Heart Institute of Japan, Tokyo Women’s Medical University, Tokyo, Japan

a r t i c l e

i n f o

Article history: Received 16 July 2012 Received in revised form 13 April 2013 Accepted 22 April 2013 Available online 16 June 2013 Keywords: Coronary artery disease Hypertension Combination therapy Amlodipine Candesartan

a b s t r a c t Background: The effects of the combination of angiotensin II receptor blocker (ARB) plus dihydropyridine calcium channel blockers (DHP-CCBs), which is known as a potent antihypertensive drug regimen, on cardiovascular events remain unclear. Objective: The purpose of this post hoc subgroup analysis was to compare the incidence of major adverse cardiovascular events (MACE) of patients treated with candesartan and amlodipine with that of those with candesartan and non-amlodipine CCBs in hypertensive patients with coronary artery disease (CAD). Methods: HIJ-CREATE was a multicenter, prospective, randomized, controlled study that compared the effects of candesartan-based with those of non-ARB-based standard therapy on MACE in 2049 hypertensive patients with CAD. In the candesartan group, a total of 335 patients were treated with DHP-CCBs (amlodipine: 170 and non-amlodipine-CCBs: 165) at the baseline. In this sub-analysis, we compared, among the participants allocated to candesartan regimen, the long-term effects of amlodipine and non-amlodipine CCBs that were concomitantly given with ARB, although the choice of CCB was not randomized. Results: The median follow-up was 3.9 years. Treatment using amlodipine with candesartan reduced the risk of MACE by 38% (hazard ratio, 0.62; 95% confidence interval, 0.41–0.94, p = 0.025), as compared to patients treated with non-amlodipine-CCBs and candesartan. In a multivariate analysis, combination therapy of candesartan with amlodipine was an independent predictor of reduced risk of MACE. Conclusions: The results suggest that the combination of amlodipine and candesartan is more beneficial in reducing MACE in hypertensive patients with CAD compared to non-amlodipine-DHP-CCBs in combination therapy with candesartan. Further investigation in larger-scale prospective randomized studies is required to reach any conclusion as to the superiority of combination therapy of candesartan with amlodipine. © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Introduction Hypertension is highly prevalent, affecting approximately one billion individuals worldwide [1,2]. Approximately 26.4% of the adult population worldwide had hypertension in 2000, and this is expected to increase to 29.2% by 2025 [1]. Hypertension is a potent, independent risk factor for myocardial infarction [3,4]. Despite the variety of treatment modalities available, hypertension remains undertreated and, subsequently, poorly controlled. The average ∗ Corresponding author at: Department of Cardiology, The Heart Institute of Japan, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. Tel.: +81 3 3353 8111; fax: +81 3 3356 0441. E-mail address: [email protected] (H. Ogawa).

number of drugs used to reach target blood-pressure levels in recent clinical trials was about 2.0 [5,6]. The aggregate of previous studies suggests that at least 75% of patients will require combination therapy to achieve contemporary blood pressure targets [7,8]. Consequently, initial therapy for hypertension with a combination of drugs is recommended by both the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and European guidelines for patients whose blood pressures are 20/10 mm Hg or more above the goal [9,10]. An experimental study demonstrated that the calcium-channel blocker (CCB) amlodipine effectively increases the availability of vascular endothelial nitric oxide [11]. Another study showed that the combined effects of amlodipine and an angiotensin-converting enzyme inhibitor (ACEI), benazepril, on

0914-5087/$ – see front matter © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jjcc.2013.04.004

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nitric oxide are greater than the effect with either drug alone, and combination therapy of CCB and an ACEI is beneficial for managing cardiac ischemia [12]. In the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial [13], a recent randomized trial, the investigators clearly demonstrated the ACEI-CCB combination significantly reduced cardiovascular events in high-risk hypertensive patients. Angiotensin II receptor blockers (ARBs) are well-tolerated in patients unable to tolerate ACEIs [14]. The vasodilatory action of CCBs stimulates counterregulatory mechanisms such as sympathetic activation and activation of the renin-angiotensin-aldosterone system. These mechanisms reduce the blood pressure-lowering effects of CCBs [15–17]. ARBs act by blocking the vasoconstriction effect of angiotensin II at angiotensin receptor type-1, thus complementing CCB use for effective blood pressure-lowering [18]. In the OlmeSartan and Calcium Antagonists Randomized (OSCAR) Study, a recent randomized trial, the investigators demonstrated that the ARB and CCB combination reduced the incidence of cardiovascular events in elderly hypertensive patients with cardiovascular disease [19]. Previous studies [20–22] demonstrated that there is an inconsistency for the renoprotective effect among several dihydropyridine CCBs. Among dihydropyridine CCBs, amlodipine is a well-studied one. To our knowledge, the impact of combination therapy of an ARB and amlodipine on the long-term outcome in hypertensive patients with coronary artery disease (CAD) has not been studied. The purpose of this post hoc subgroup analysis was to compare the incidence of major adverse cardiovascular events (MACE) of patients treated with candesartan and amlodipine with that of those with candesartan and non-amlodipine CCBs in hypertensive patients with CAD. Patients and methods Study population and treatment In the Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease (HIJ-CREATE) study, a multicenter, prospective, randomized, open-label, blinded-endpoint trial conducted in Japan, the effects of ARB (candesartan)-based therapy on MACE were compared with those of non-ARB-based standard therapy in hypertensive patients with CAD, which was detected by angiography. The study methods and principal results have previously been published [23]. Briefly, 2049 patients with hypertension in whom angiography revealed CAD were randomly assigned to receive ARB (candesartan)-based (n = 1024) or nonARB-based drug therapy (n = 1025). Among the total of 2049 hypertensive patients with CAD, 1024 participants were allocated to the candesartan-based treatment arm. Among them, 335 received combination therapy with candesartan and DHP-CCB. In the HIJ-CREATE study, combination therapy was prescribed at the discretion of the attending physician to reach the target blood pressure. Of these 335 participants, candesartan was combined with amlodipine in 170, and with non-amlodipine-DHP-CCBs in 165 (Fig. 1). Periodic follow-up was performed 6, 12, 24, 36, 48, and 60 months after assignment to confirm the onset of events as endpoints and the safety of agents. All patients were followed for 36 months or more. The appearance of MACE, including cardiovascular death, nonfatal myocardial infarction, unstable angina, heart failure, stroke, and other cardiovascular events requiring hospitalization was established as a primary endpoint. In this sub-group analysis, we evaluated the usefulness of the combination therapy of candesartan with amlodipine in comparison with the combination therapy of candesartan with non-amlodipine-DHP-CCBs.

Statistical analysis The background data are expressed as the mean ± SD and percentage. The p-values were calculated using the two-tailed Student’s t-test or Fisher’s exact test. To compare the two treatment groups, we employed the log-rank test and Cox’s proportional hazard model. Kaplan–Meier survival curves were generated by the product-limit method. Intergroup differences were evaluated with the use of the log-rank test. Predictors of subsequent MACE were analyzed using Cox regression models. It was desirable to include the traditional risk factors that were determined by reference to previous studies [24–26] in the proportional hazard model. Multivariate analysis using the Cox proportional hazards model was performed to assess the relationship of the following baseline characteristics to subsequent MACE: age ≥ 65 years, male gender, previous percutaneous coronary intervention, aspirin use, creatinine clearance > 60 ml/min, and combination therapy of amlodipine with candesartan. The interaction of hypertension with the effect of anti-hypertensive medical therapy was analyzed using a likelihood ratio test. Adjusted hazard ratios (HRs) with 95% CIs were calculated for MACE. Statistical analysis was conducted at an independent statistical data center (Medical TOUKEI Corporation, Tokyo, Japan) employing SPSS 15.0 (SPSS Inc., Chicago, Il, USA) and SAS 9.1.3 (SAS Institute Inc., Cary, NC, USA). Results Among the total of 2049 hypertensive patients with CAD, 1024 participants were allocated to the candesartan-based treatment arm. Among them, 335 received combination therapy with candesartan and DHP-CCB. Of these, candesartan was combined with amlodipine besylate in 170, and with non-amlodipine-DHP-CCBs, which were restricted to three CCBs, nifedipine CR, benidipine hydrochloride, and cilnidipine in 165 (Fig. 1). Although the DHPCCBs were restricted to these four agents, the design of our database did not allow a quantitative assessment of such medications. The median follow-up period was 3.9 years. The backgrounds of the subjects are presented in Table 1. There were no significant differences between the two groups in background factors except the female ratio, proportion of patients with acute coronary syndrome, those undergoing percutaneous coronary intervention, systolic blood pressure, and proportion of patients receiving aspirin.

Fig. 1. Flow of patients through the study. ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; DHP, dihydropyridine.

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Table 1 Baseline characteristics. Variables Women Age (years) Acute coronary syndrome Number of diseased vessels ≤1 ≥2 Revascularization Percutaneous coronary intervension During enrolment hospitalization Coronary artery bypass grafting During enrolment hospitalization Dyslipidaemia Diabetes mellitus Current smoker Family history Cerebrovascular disease Peripheral vascular disease Artrial fibrillation NYHA functional class I II III IV Body mass index (kg/m2 ) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Left ventricular ejection fraction (%) Total cholesterol (mg/dL) Triglyceride (mg/dL) HDL-cholesterol (mg/dL) Fasting blood sugar(mg/dL) HbA1c (%) Serum creatinine (mg/dL) C-reactive protein (mg/dL) Medications before randomization ACE-Is Diuretics Calcium-channel blockers ␤-Blockers ARBs Medications at discharge ACE-Is Diuretics ␤-Blockers Aspirin Antiplatelet agents Nitrates Statins

Non-amlodipine–DHP–CCB + candesartan (n = 165)

Amlodipine + candesartan (n = 170)

p-Value

24 (14.1%) 65.5 ± 8.7 35 (20.6%)

42 (25.5%) 65 ± 9.5 46 (27.9%)

88 (51.8%) 82 (48.2%)

95 (57.6%) 70 (42.4%)

146 (85.9%) 85 (50.0%) 19 (11.2%) 0 (0.0%) 104 (61.2%) 77 (45.3%) 63 (37.1%) 40 (23.5%) 17 (10.0%) 8 (4.7%) 9 (5.3%)

125 (75.8%) 82 (49.7%) 14 (8.5%) 4 (2.4%) 105 (63.6%) 69 (41.8%) 54 (32.7%) 36 (21.8%) 23 (13.9%) 11 (6.7%) 3 (1.8%)

139 (81.8%) 25 (14.7%) 3 (1.8%) 3 (1.8%) 25.1 ± 2.7 135.2 ± 16.7 75.1 ± 11.8 55.8 ± 10.6 191.5 ± 29.8 143 (108.5–190.5) 44.3 ± 13.5 133.3 ± 59.1 6.2 ± 1.3 0.9 ± 0.3 0.17 (0.1–0.3)

131 (79.4%) 28 (17.0%) 6 (3.6%) 0 (0%) 24.8 ± 3.1 139.0 ± 18.6 75.0 ± 11.9 55.3 ± 10.3 197.2 ± 36.8 131 (93.0–200.0) 44.3 ± 11.9 122.8 ± 38.4 6.1 ± 1.3 0.9 ± 0.3 0.2 (0.1–0.4)

0.332 0.046 0.953 0.700 0.124 0.514 0.967 0.057 0.843 0.778 0.196

61 (35.9%) 11 (6.5%) 158 (92.9%) 78 (45.9%) 42 (24.7%)

57 (34.5%) 17 (10.3%) 143 (86.7%) 64 (38.8%) 38 (23.0%)

0.820 0.239 0.070 0.224 0.798

2 (1.2%) 9 (5.3%) 87 (51.2%) 165 (97.1%) 89 (53.0%) 80 (47.1%) 80 (47.1%)

1 (0.6%) 18 (10.9%) 71 (43.0%) 143 (86.7%) 76 (46.1%) 86 (52.1%) 79 (47.9%)

1.000 0.071 0.155 0.0005 0.229 0.383 0.913

The mean office systolic blood pressure at the baseline in the candesartan + amlodipine group was lower than in the candesartan + non-amlodipine-CCBs group (135 ± 17 mmHg and 139 ± 19 mmHg, respectively, p = 0.046). However, after 6 months of treatment, there were no further significant differences between the two groups. The mean office systolic blood pressures after 36 months of treatment in the candesartan + amlodipine and candesartan + non-amlodipine-CCBs groups were 132 ± 17 mmHg and 133 ± 17 mmHg, respectively. The values after 48 months were 133 ± 16 mmHg and 133 ± 15 mmHg, respectively (Fig. 2). The mean heart rate at the baseline in the candesartan + amlodipine group was lower than that in the candesartan + non-amlodipine-CCBs group (67.3 ± 9.7 bpm vs. 69.6 ± 11.2 bpm, respectively, p = 0.043). However, after 6 months of treatment, there were no further significant differences between the two groups (Fig. 3). There were no significant differences in any parameter of lipid/glucose metabolism between the two groups, excluding the HbA1c value after 48 months and the HDL-cholesterol level after 60 months of treatment (Fig. 4).

0.013 0.604 0.127 0.699

0.026 1.000 0.466 0.058 0.654 0.582 0.424 0.794 0.313 0.485 0.139 0.228

(mmHg)

180

AML(-) n=165 AML(+) n=170

160 140

p=0.927

120 100 80

p=0.696

60 40 number

mean± ± SD

baseline6

12

24

36

48 months

AML(-)

165 154 146

141

140

97

AML(+)

170 164 161

156

149

105

Fig. 2. Mean patient blood pressure at baseline and during follow-up. AML, amlodipine.

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Fig. 3. Mean heart rate at baseline and during follow-up. AML, amlodipine.

MACE, as a primary endpoint, occurred in 37 patients (21.8%) in the ARB + amlodipine group and 52 (31.5%) in the ARB + nonamlodipine-CCBs group. In the former, the risk of MACE decreased by 38% in comparison with the latter. The hazard ratio was 0.62, and the 95% confidence interval ranged from 0.41 to 0.94 (p = 0.025) (Fig. 5). In the former, the risk of myocardial infarction and unstable angina significantly decreased (Table 2). The incidences of myocardial infarction and unstable angina were 1.8% and 11.2%, respectively (HR: 0.27 and 0.52, 95% CI: 0.76–0.998 and 0.29–0.91, p = 0.049 and 0.022, respectively), lower than in the control group (6.1% and 20.0%, respectively). In addition, when reviewing the hazard ratio after corrected factor adjustment using Cox’s regression analysis, the risk of MACE

Fig. 5. Cumulative event rates for primary endpoints in both treatment groups. DHPCCB, dihydropyridine calcium channel blocker; MACE, major adverse cardiovascular event.

in the ARB + amlodipine group was significantly lower than in the ARB + non-amlodipine-CCBs group (Table 2). Table 3 shows relative risks and 95% confidence intervals for the primary endpoint according to selected demographics. Most point estimates demonstrated similar hazard ratios, and no statistical heterogeneity was identified among subgroups. Among them, male gender, age younger than 65 years, and a lower level of C-reactive protein (<2 mg/L) were associated with a significant reduction in MACEs, without any significant interactions among patient characteristics. It was desirable to include the traditional risk factors

Fig. 4. Changes in metabolic parameters in both groups: (A) total cholesterol level, (B) HDL cholesterol level, (C) LDL cholesterol level, and (D) hemoglobin A1c level, AML, amlodipine; HDL, high-density lipoprotein; LDL, low-density lipoprotein; Hb, hemoglobin.

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Table 2 Hazard ratio for major adverse cardiovascular events. Events

Adjusted*

Unadjusted

Non-fatal MI Unstable angina Heart failure Stroke Other cardiovascular Cardiovascular death MACE

Amlodipine (+)

Amlodipine (−)

Hazard ratio (95%CI)

p-Value

Hazard ratio (95%CI)

p-Value

3 (1.8%) 19 (11.2%) 4 (2.4%) 7 (4.1%) 9 (5.3%) 2 (1.2%) 37 (21.8%)

10 (6.1%) 33 (20.0%) 6 (3.6%) 9 (5.5%) 5 (3.0%) 6 (3.6%) 52 (31.5%)

0.27 (0.76–0.998) 0.52 (0.29–0.91) 0.63 (0.18–2.24) 0.74 (0.28–1.98) 1.71 (0.57–5.11) 0.31 (0.06–1.55) 0.62 (0.41–0.94)

0.049 0.022 0.478 0.547 0.335 0.155 0.025

0.32 (0.08–1.21) 0.52 (0.29–0.93) 0.66 (0.18–2.45) 0.72 (0.26–2.01) 1.88 (0.59–6.01) 0.55 (0.10–3.06) 0.63 (0.41–0.98)

0.093 0.026 0.532 0.535 0.287 0.497 0.040

MACE: major adverse cardiovascular events, MI: myocardial infarction * The hazard ratio was adjusted for gender, percutaneous coronary intervension, systolic blood pressure, aspirin usage

Table 3 Adverse cardiovascular events with amlodipine(+) compared to non-amlodipine-CCBs by subgroup. Adverse cardiovascular events (%) Amlodipine Sex 4 (16.7%) Female 33 (22.6%) Male Age 70 (17.1%) <65yr ≥65yr 100 (25.0%) Body mass index (kg/m2 ) 86 (17.4%) <25 78 (25.6%) 25–30 ≥30 6 (33.3%) Acute coronary syndrome 135 (22.2%) No 35 (20.0%) Yes C-reactive protein 163 (21.5%) <2 mg/L 7 (28.6%) ≥2 mg/L Estimated GFR (ml/min./1.73m2 ) ≥60 110 (19.1%) 60 (26.7%) <60 All patients 170 (21.8%)

Hazard ratio (95%CI)

p-Value

p-Value for interaction

12 (28.6%) 40 (32.5%)

0.573 (0.184–1.782) 0.603 (0.380–0.956)

0.336 0.031

0.919

70 (31.4%) 95 (31.6%)

0.470 (0.233–0.950) 0.726 (0.427–1.236)

0.036 0.238

0.348

86 (29.1%) 71 (35.2%) 8 (25.0%)

0.533 (0.281–1.012) 0.638 (0.354–1.149) 1.538 (0.216–10.947)

0.054 0.134 0.667

0.299

119 (30.3%) 46 (34.8%)

0.654 (0.403–1.062) 0.514 (0.211–1.252)

0.086 0.143

0.703

156 (31.4%) 9 (33.3%)

0.610 (0.395–0.941) 0.750 (0.124–4.535)

0.026 0.754

0.767

95 (26.3%) 69 (37.7%) 165 (31.5%)

0.666 (0.373–1.190) 0.610 (0.327–1.138) 0.617 (0.405–0.941)

0.170 0.120 0.025

0.846

Non-amlodipine-CCBs

CCB, calcium channel blocker; CI, confidence interval; GFR, glomerular filtration rate.

which were determined by reference to previous studies in the proportional hazard model. Furthermore several factors showed significant differences in the prevalence between the two groups in the present subanalysis should also be included in the proportional hazard model. The results are shown in Table 4. Multivariable analysis for predictors of subsequent MACE showed the combination therapy of ARB with amlodipine as an independent predictor (HR 0.626, 95% CI 0.402–0.975). Discussion The sub-analysis of the HIJ-CREATE study showed that combination therapy with candesartan and amlodipine more markedly reduced the incidence of MACE compared to that with candesartan and non-amlodipine-DHP-CCBs in hypertensive patients with CAD. Table 4 Results of multivariate analysis for predictors of MACE shown as adjusted HRs and 95%CIs.

Candesartan + amlodipine Age ≥ 65 years Male gender Previous PCI Aspirin use Creatinine clearance ≥ 60

Adjusted hazard ratios (95%CI)

p-Value

0.626 1.319 0.655 1.049 0.715 0.814

0.038 0.239 0.146 0.870 0.385 0.369

(0.402–0.975) (0.832–2.091) (0.370 –1.159) (0.593–1.854) (0.336–1.522) (0.519–1.276)

MACE: major adverse cardiovascular events, PCI: percutaneous coronary intervention.

In particular, this therapeutic regimen decreased the incidence of myocardial infarction and unstable angina, although there was no significant difference in the blood pressure at any point other than the baseline during the study period, suggesting that the combination of candesartan and amlodipine exhibits vasoprotective actions independent from blood pressure lowering effects, differing from combination regimens with other CCBs. In the recently published Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, the investigators clearly demonstrated the potential synergistic effect of amlodipine plus ACEI compared with hydrochlorothiazide plus ACEI in high-risk patients with hypertension [13]. In a recently published case–control study of relatively low-risk patients with hypertension, treatment with diuretics plus CCBs was associated with a higher risk of myocardial infarction than treatment with diuretics plus ␤ blockers or diuretics plus ACEIs or ARBs [27]. Subsequently, the optimal combination therapy for the prevention of cardiovascular events among hypertensive patients who require additional treatment for blood pressure control is not known. We have recently suggested that the combination of amlodipine and candesartan had a more favorable effect on reducing cardiovascular events in patients with hypertension with CAD compared to amlodipine-based therapy without candesartan [28]. Since the HIJ-CREATE study was an open-label trial evaluating for hypertension and CAD, we could not exclude the possibility that we might overestimate the effects of candesartan-based therapy compared to non-ARB standard therapy. It was necessary to evaluate

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the usefulness of amlodipine therapy by comparison to other dihydropyridine calcium channel blockers (DHP-CCBs) in participants allocated to candesartan-based therapy in the HIJ-CREATE study. Amlodipine and candesartan have both been shown to be as effective as or sometimes better than other antihypertensive agents in terms of cardiovascular morbidity and mortality and associated adverse events. In the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT), amlodipine decreased the risk of cardiovascular events including angioplasty by 31% in comparison with the placebo group, and B-mode echography confirmed a significant decrease in the carotid intima-media thickness (IMT) [29]. The Comparison of Amlodipine vs. Enalapril to Limit Occurrences of Thrombosis study (CAMELOT) indicated that the risk of cardiovascular events in the amlodipine group was 31% lower than in the placebo group, and that amlodipine inhibited a progression of atherosclerosis observed on an intravascular ultrasound (IVUS)-guided procedure [30]. Furthermore, amlodipine significantly reduced the incidence of angina requiring hospitalization compared to enarapril, although there was no significant difference in the blood pressure-lowering effect. The vasoprotective actions of amlodipine may be associated with its chemical structure. Mason et al. suggested that unique features of amlodipine contribute to anti-arteriosclerotic effects such as antioxidant [31], anti-inflammatory [32], and vascular endothelium-protecting actions [33]. In addition, other studies indicated that amlodipine inhibited the proliferation of smooth muscle cells [34] and platelet aggregation [35], exhibiting anti-arteriosclerotic effects. In this study, amlodipine may have protected the blood vessels of CAD patients, reducing the risk of MACE. Furthermore, the beneficial effects of the combination of amlodipine and a renin-angiotensin-aldosterone system blocker on endothelial function have been found to be greater than the effect of either drug alone, likely due to additive effects on nitric oxide activity [36]. Furthermore, the difference of effect on the morning surge in blood pressure among CCBs might be considered for the results of the present study, as the diurnal blood pressure is supposed to be related with significant biomarkers [37]. The results of this study suggest that amlodipine complemented the less potent inhibitory effects of candesartan on vascular smooth muscle growth. It therefore is not unreasonable to suggest that a combination of amlodipine and candesartan that specifically target hypertension and CAD will potentially produce a more than additive benefit in terms of improvement of clinical outcomes and reduction in vascular risk. Due to a lack of direct comparison among DHP-CCBs in clinical studies [38–40], it is difficult to account for the results of the present study. The present intriguing possibility can be answered only by further study. Study strength and limitations Previous randomized, controlled trials have applied strict criteria to avoid heterogeneities of treatment effects [41]. Recently, it is increasingly common for clinical trials to have several hundred sites in operation in order to enroll the required number of participants [42]. As a result, baseline characteristics, protocol completion, and outcomes differed significantly among higher vs lower enrolling sites in a recent clinical trial [42]. In the HIJ-CREATE study, a total of 2049 patients were randomized in only 14 clinical centers in which mutual exchange of medical doctors are conducted annually. Consequently, above-mentioned inter-institutional differences must be negligible. The main limitation of this study was the fact that it was retrospective and based on subgroup analysis of the prospective study and we did not provide a post hoc power calculation. The results must therefore be interpreted with caution. A second limitation was that the number of study subjects was small. Because

the combination of amlodipine and candesartan may be expected to demonstrate a 20–30% reduction in the rate of cardiovascular events from previous studies [13,28], we estimated a cardiovascular event rate of 20% for the combination of amlodipine and candesartan, and 30% for the combination of non-amlodipine-DHPCCBs and candesartan. Sample calculations were based on 80% power with a 2-sided significance level of 0.05 to detect cardiovascular events using a log-rank test. It was estimated that 296 patients were required in each group. Thus, the relatively small number of patients in this sub-analysis was a limitation since it reduced the statistical power of the analysis. Although the results of the present sub-analysis demonstrated the beneficial effects of amlodipine + candesartan on reducing the incidence of MACE, these results should be confirmed in a larger and adequately powered sample size trial. Because this study was not predefined, a bias in the selection of patients cannot be excluded. Also, there might be a bias in the selection of CCBs in each medical center. In addition, the details on the non-amlodipine CCBs, the dose of prescribed CCBs, and their compliance were not fully investigated. As the effective doses of amlodipine and candesartan for their combination could not be clarified, further studies are necessary to clarify this point. Conclusions These data suggest that combination therapy with candesartan and amlodipine is useful for reducing the risk of MACE in CAD patients with hypertension. This therapeutic regimen is more useful than that with candesartan and non-amlodipine-CCBs, confirming amlodipine-specific vasoprotective actions. Because our sample size was small, further investigation in larger-scale prospective randomized studies is required to reach any conclusion as to the superiority of combination therapy with candesartan and amlodipine. Source of funding HIJ-CREATE was supported by Japan Research Promotion Society for Cardiovascular Diseases, which played no role in the study design, data collection, data interpretation, of writing of the report. Disclosures None. References [1] Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet 2005;365:217–23. [2] Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo Jr JL, Jones DW, Materson BJ, Oparil S, Wright Jr JT, Roccella EJ, Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, National Heart, Lung, and Blood Institute, National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42:1206–52. [3] Sakata Y, Nakatani D, Shimizu M, Suna S, Usami M, Matsumoto S, Hara M, Sumitsuji S, Kawano S, Iwakura K, Hamasaki T, Sato H, Nanto S, Hori M, Komuro I. Oral treatment with nicorandil at discharge is associated with reduced mortality after acute myocardial infarction. J Cardiol 2012;59:14–21. [4] Okura N, Ogawa H, Katoh J, Yamauchi T, Hagiwara N. Long-term prognosis of patients with acute myocardial infarction in the era of acute revascularization (from the Heart Institute of Japan Acute Myocardial Infarction [HIJAMI] registry). Int J Cardiol 2012;159:205–10. [5] ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981–97. [6] Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Ostergren J, ASCOT Investigators. Prevention of cardiovascular events with an

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