Comparison between valsartan and amlodipine regarding cardiovascular morbidity and mortality in hypertensive patients with glucose intolerance:
Toyoaki Murohara, Takashi Muramatsu, Kunihiro Matsushita,
Kentaro Yamashita, Takahisa Kondo, Kengo Maeda, Satoshi Shintani,
The NAGOYA HEART Study Investigators
Department of Cardiology
Nagoya University Graduate School of Medicine
ACC 2011, Late Breaking Clinical Trials IV. April 5th, 2011, New Orleans, LA

Presenter disclosure information
Toyoaki Murohara, MD, PhD.
Lecturer’s fee from Daiichi-Sankyo, Novartis Pharma,
Pfizer, and Takeda (Modest).
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• Funding / Support: The NAGOYA HEART Study was funded and supported by Nagoya University Graduate School of Medicine.
• Role of the Sponsor: The funding source had no role in the study design, data collection, analyses and interpretation, or in the preparation, review, or approval of the manuscript.
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Golden Shachi-hoko
= Symbol of Nagoya City
NAGOYA City
The NAGOYA Castle
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 Hypertensive patients are often complicated with type 2 diabetes (T2DM) and, combination of hypertension and T2DM markedly increases cardiovascular event risk.
 ACEIs / ARBs reduce the new onset of T2DM* and slowed-down the progression of diabetic nephropathy
†
.
* Yusuf S, et al. JAMA.
2001; 286: 1882-1885.
* McMurray JJ, et al. N Engl J Med. 2010; 362: 1477-1490.
† HOPE Investigators.
Lancet. 2000; 355: 253-259.
†
Brenner BM, et al. N Engl J Med. 2001; 345: 861-869.
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Many guidelines recommend ACEIs / ARBs as the first-line antihypertensive medications for diabetic hypertensive patients.
JNC7
2003
◎
ADA
2004
◎
ESC-ESH
2007
◎
JSH
2009
◎
◎ ◎ ◎ ◎
ACEIs
ARBs
CCBs ○ △ ○ ○
β-blockers ○ ○ ○ ○
α-blockers NA
○
△
○
△
○
NA
○ Diuretics
◎ Recommended as a First-Choice Agent, ○ Available as an Alternative Agent, △ Not Recommended
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Previous major trials comparing ARBs vs. other active treatments
Trials
LIFE
DM-subgroup
(2001)
IDNT
CV outcomes-analysis
(2003)
VALUE
(2004)
CASE-J
(2008) n
1195
1146
4728
DM
100%
100%
15245 34%
43%
Control
BB
CCB
CCB
CCB
CV outcomes
Composite
CV death
Acute MI
Stroke
Composite
CV death
Acute MI
PCI/CABG
Heart Failure
Stroke
Composite
CV death
Acute MI
Heart Failure
Composite
Sudden death
Acute MI
Stroke
Angina
Heart Failure
1.04
1.01
1.20
0.89
1.01
0.73
0.95
1.28
0.57
1.25
0.90
1.36
1.54
0.93
0.65
1.55
HRs (95% CIs)
0.76
0.63
0.83
0.79
(0.6-0.98)
(0.4-0.95)
(0.6-1.3)
(0.6-1.1)
(0.7-1.1)
(0.9-2.1)
(0.97-2.5)
(0.6-1.6)
(0.5-0.9)
(0.8-2.9)
(0.9-1.2)
(0.9-1.2)
(1.0-1.4)
(0.8-1.03)
(0.8-1.3)
(0.3-1.6)
(0.5-1.8)
(0.9-1.9)
(0.2-1.4)
(0.7-2.4)

Irbesartan Diabetic Nephropathy Trial (IDNT)
Secondary endpoint
Hazard ratio n = 1146
Cardiovascular composite
Favours ARB Favours CCB
Cardiovascular death
Myocardial infarction
Congestive heart failure
Cerebrovascular accident
Cardiac revascularization
0.25
0.5
1 2 4
Irbesartan Diabetic Nephropathy Trial Collaborative Study Group. Ann Intern Med 2003;138:542-9.
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To compare the efficacies of an ARB Valsartan versus a CCB Amlodipine regarding cardiovascular morbidity and mortality in Japanese hypertensive patients with T2DM or impaired glucose tolerance (IGT).
ClinicalTrials.gov: NCT00129233.
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• An investigator-initiated trial .
• A prospective randomized controlled trial .
• Allocated treatment was open-labeled .
• Outcomes were adjudicated in a blinded manner as for the drug assignment ( PROBE method ).
• Definition of outcomes in an Endpoint Evaluation
Committee had never be opened until this study was closed.
• Conducted in 46 JCS-certified medical centers (by 171 cardiologists) in Nagoya and vicinity.
• Began on Oct 2004 and closed on July 31, 2010.
(available data were fixed on November 5, 2010)
Matsushita K, et al. J Cardiol.
2010; 56:111-117.
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Trial scheme of the Nagoya Heart Study
30 to 75 y.o.
and Hypertension and T2DM or IGT *
Random allocation
Minimization factors ： age, gender, statin use, smoking, and T2DM/IGT
PROBE
Valsartan-based treatment
1 : 1
Amlodipine-based treatment
BP goal < 130/80 mmHg, median 3-years follow-up
Primary outcome: Composite CV events
Secondary outcome: All-cause mortality
*T2DM and IGT were diagnoses by *ADA 2004 criteria

Run-in
-4w
*excluding ACEIs/ARBs, and other CCBs
Amlodipine 10 mg + Other drugs*
Amlodipine 10 mg / day
Amlodipine 5 mg / day
Valsartan 80 mg / day
Valsartan 160 mg / day
Valsartan 160 mg + Other drugs*
0w 4w 8w
*excluding ACEIs/other ARBs, and CCBs
12w
Last
Visit
Randomization
Matsushita K, et al. J Cardiol.
2010; 56:111-117.
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• Prior cardiovascular diseases within 6 mo
• Taking CCBs continuously for angina pectoris
• Left ventricular ejection fraction (LVEF) < 40%
• Advanced atrioventricular block
• Secondary or severe hypertension ( ≥ 200/110 mmHg)
• Serum creatinine ≥ 221 μmol/L (2.5 mg/dL)
• Pregnant women
• Estimated prognosis within 3 years
• Other conditions by which physicians judged inappropriate to enroll
Matsushita K, et al. J Cardiol.
2010;56:111-117.
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Primary outcome
Composite of cardiovascular events
 Acute myocardial infarction
 Stroke
 Coronary revascularization (PCI or CABG)
 Admission due to heart failure
 Sudden cardiac death
Secondary outcome
All-cause mortality
Matsushita K, et al. J Cardiol.
2010;56:111-117.
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1168 Patients assessed for eligibility
18 Excluded
12 Withdrew consent
3 Prior cardiovascular diseases within 6 Mo
1 Aged >75 years
2 Judged inappropriate to be enrolled
1150 Patients randomized
575 Assigned to receive
Valsartan-based treatment
558 Completed follow-up
1 Withdrew consent
16 Lost to follow up
575 Included in efficacy analysis
575 Included in safety analysis
575 Assigned to receive
Amlodipine-based treatment
559 Completed follow-up
2 Withdrew consent
14 Lost to follow up
575 Included in efficacy analysis
575 Included in safety analysis
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Variables
Age, mean (SD), y
Women, n (%)
Body mass index, mean (SD), kg/m
2
Current smoker, n (%)
Dyslipidemia, n (%)
Prior cardiovascular diseases, n (%)
Prior cerebrovascular diseases, n (%)
Blood pressure
Systolic, mean (SD), mmHg
Diastolic, mean (SD), mmHg
Heart rates, mean (SD), /min
Status of glucose intolerance
Type 2 diabetes mellitus, n (%)
Impaired glucose tolerance, n (%)
Valsartan
(n = 575)
63 (8)
197 (34)
25 (4)
106 (18)
245 (43)
150 (26)
24 (4)
145 (18)
82 (13)
70 (11)
470 (82)
105 (18)
Amlodipine
(n = 575)
63 (8)
199 (35)
25 (4)
104 (18)
253 (44)
156 (27)
30 (5)
144 (19)
81 (13)
71 (12)
472 (82)
103 (18)

Variables, mean (SD)
Valsartan
(n = 575)
Amlodipine
(n = 575)
Glycosylated hemoglobin (HbA1c) *, % 7.0 (1.4) 6.9 (1.1)
Fasting plasma glucose, mmol/L
Triglycerides, mmol/L
HDL cholesterol, mmol/L
LDL cholesterol, mmol/L
Uric acid, μmol/L
Blood urea nitrogen, mmol/L
Serum creatinine, μmol/L
8.2 (3.0)
1.9 (1.2)
1.6 (0.4)
3.5 (1.0)
328 (83)
5.6 (1.5)
60 (18)
7.9 (2.6)
1.9 (1.2)
1.6 (0.4)
3.6 (1.0)
333 (84)
5.6 (1.6)
60 (17)
* Presented as National Glycohemoglobin Standardization Program (NGSP) value.

Variables, n (%)
Valsartan
(n = 575)
Amlodipine
(n = 575)
Treatment for hypertension
Angiotensin II type 1 receptor blockers
Angiotensin converting enzyme inhibitors
Calcium channel blockers
β-Blockers
α-Blockers
Anti-aldosterone agents
Thiazides
Other diuretics
Treatment for glucose intolerance
Sulfonylurea
Insulin
Other hypoglycemic agents
Other medication
Aspirin
Statins
171 (30)
54 (9)
258 (45)
125 (22)
12 (2)
15 (3)
17 (3)
20 (4)
141 (25)
40 (7)
196 (34)
157 (27)
227 (40)
168 (29)
44 (8)
275 (48)
147 (26)
17 (3)
10 (2)
13 (2)
25 (4)
134 (23)
36 (6)
198 (34)
162 (28)
217 (38)

100
80
60
40
20
0
0
(mmHg)
180
Changes in blood pressure and glycemic status
Valsartan Amlodipine
160
Systolic blood pressure (mmHg)
140
120
6 12 18 24 30
Diastolic blood pressure (mmHg)
(%)
10.0
Glycosylated hemoglobin (%)
8.0
6.0
36 42 48 54 60
4.0
Months

Primary composite CV outcome
Follow-up median 3.2 (2.6-4.7) years
Hazard ratio 0.97 (95% CI, 0.66-1.40)
No. at risk
Valsartan
Amlodipine
575 562 549 536 492 443 343 253 206 165
575 567 555 540 493 445 336 250 197 159
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Hazard ratios and 95% confidence intervals
Number of events (%)
0.25
0.5
1 2 4
Valsartan
(n = 575)
Amlodipine
(n = 575)
Primary outcome
Composite cardiovascular event
Components
Acute myocardial infarction
Stroke
Ischemic stroke
Intracerebral hemorrhage
Subarachnoid hemorrhage
Coronary revascularization
Congestive heart failure
Sudden cardiac death
Secondary outcome
All-cause death
54 (9.4%) 56 (9.7%)
7 (1.2%) 3 (0.5%)
13 (2.3%) 16 (2.8%)
10 (1.7%)
2 (0.3%)
11 (1.9%)
4 (0.7%)
1 (0.2%) 1 (0.2%)
29 (5.0%) 26 (4.5%)
3 (0.5%) 15 (2.6%)
4 (0.7%) 4 (0.7%)
22 (3.8%) 16 (2.8%)
HRs
0.97
2.33
0.81
0.90
0.50
1.00
1.12
0.20
1.00
1.37

Adverse events (n ≥3)
Valsartan Amlodipine
(n = 575) (n = 575)
Solid cancer
Dizziness
Liver dysfunction
Aortic aneurysm
Headache
Rashes / Zoster
Benign tumor
Fracture
Face flush
Fatigue
Hyperkalemia
Atrioventricular block
Gastric ulcer
Pruritis
3
2
1
1
3
4
22
14
4
4
0
0
3
0
3
2
3
3
5
2
23
10
5
4
3
3
0
3
Total 106 112

 A total of 54 patients (9.4%) in the valsartan group and 56 patients (9.7%) in the amlodipine group were determined to have primary outcomes during the median follow-up of 3.2 years.
 Time-to-event curves showed no difference between the two groups.
(HR 0.97 [95% CI, 0.66-1.40], p = 0.85)
 admission due to CHF was significantly less in the valsartan group (3 patients) than in the amlodipine group (15 patients).
(HR 0.20 [95% CI, 0.06-0.69], p = 0.01)
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n = 1146
Secondary outcome
Cardiovascular composite
Favours ARB
Cardiovascular death
Myocardial infarction
Congestive heart failure
Cerebrovascular accident
Cardiac revascularization
0.25
0.5
IDNT
Hazard ratio
1
Favours CCB
2 4
IDNT Collaborative Study Group. Ann Intern Med 2003;138:542-9.
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Kyoto Heart Study
Eur. Heart J. 2009;30:2461 –2469.
Kaplan
–Meier estimate and effect of treatment on all endpoints.
HR=0.55, p=0.00001
95% CI 0.42-0.72
Percent of CCB administered
Valsartan Group 51%
Non-ARB Group 63%
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 There were lower incidence of primary composite cardiovascular events as well as smaller sample size than anticipated.
 We assessed the CV outcomes by the PROBE method that may be vulnerable to treatment and reporting bias.
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Multivariable Predictors of CV death, MI, or Stroke
Favours 1st Favours 2nd Variables
Polyvascular disease vs. risk factors only
Congestive heart failure, yes vs. no
Ischemic event
≤
1y vs. no ischemic event
History of diabetes, yes vs. no
Ischemic event >1y vs. no ischemic event
Single vascular territory disease vs. risk factors only
Body mass index <20, yes vs. no
Current smoker vs. former or never
Eastern Europe and Middle East vs. other regions*
Atrial fibrillation/flutter, yes vs. no
Sex, male vs. female
Age, per 1-year increase
Aspirin, yes vs. no
Statins, yes vs. no
Japan vs. other regions *
HR 95% CI
1.99
(1.78-2.24)
1.71
(1.60-1.83)
1.71
(1.57-1.85)
1.44
(1.36-1.53)
1.41
(1.32-1.51)
1.39
(1.25-1.54)
1.30
(1.14-1.49)
1.30
(1.20-1.41)
1.28
(1.19-1.39)
1.28
(1.18-1.38)
1.14
(1.07-1.21)
1.04
(1.03-1.04)
0.93
(0.87-0.98)
0.73
(0.69-0.77)
0.70
(0.63-0.77)
• Other regions were North America, Latin America,
Western Europe, and Asia.
o.5
1 2
Bhatt DL, et al. JAMA 2010; 304(12): 1350-7.

 The NHS showed no difference between the valsartan-based and amlodipine-based antihypertensive treatment in terms of preventing composite major cardiovascular outcomes.
 Valsartan-based treatment significantly reduced the risk of CHF as compared to amlodipine-based treatment.
 Our results will highlight the safety and efficacy of an
ARB valsartan especially in preventing heart failure, and support the current therapeutic recommendations for diabetic hypertensive patients.
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 We wish to express sincere appreciation to all the patients, collaborating physicians, and other medical staffs for their important contribution to the NAGOYA
HEART Study (NHS).
 Special recognition is due to Dr. Takao Nishizawa who deceased in August 2, 2009 after making significant contribution to the NHS.
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