Transcript NAGOYA HEART Study

Comparison between valsartan and
amlodipine regarding cardiovascular
morbidity and mortality in hypertensive
patients with glucose intolerance:
NAGOYA HEART Study
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 information
• 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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NAGOYA City
The NAGOYA Castle
Golden Shachi-hoko
= Symbol of Nagoya City
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Background
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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Background
Previous major trials comparing ARBs vs. other active treatments
Trials
n
DM
Control
CV outcomes
LIFE
1195
100%
BB
Composite
CV death
Acute MI
Stroke
0.76
0.63
0.83
0.79
(0.6-0.98)
(0.4-0.95)
(0.6-1.3)
(0.6-1.1)
1146
100%
CCB
Composite
CV death
Acute MI
PCI/CABG
Heart Failure
Stroke
0.90
1.36
1.54
0.93
0.65
1.55
(0.7-1.1)
(0.9-2.1)
(0.97-2.5)
(0.6-1.6)
(0.5-0.9)
(0.8-2.9)
15245
34%
CCB
Composite
CV death
Acute MI
Heart Failure
1.04
1.01
1.20
0.89
(0.9-1.2)
(0.9-1.2)
(1.0-1.4)
(0.8-1.03)
4728
43%
CCB
Composite
Sudden death
Acute MI
Stroke
Angina
Heart Failure
1.01
0.73
0.95
1.28
0.57
1.25
(0.8-1.3)
(0.3-1.6)
(0.5-1.8)
(0.9-1.9)
(0.2-1.4)
(0.7-2.4)
DM-subgroup
(2001)
IDNT
CV outcomes-analysis
(2003)
VALUE
(2004)
CASE-J
(2008)
HRs (95% CIs)
Irbesartan Diabetic Nephropathy Trial (IDNT)
Secondary endpoint
Hazard ratio
n = 1146
Favours ARB
Favours CCB
Cardiovascular composite
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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Purpose
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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Study design of the NHS
•
•
•
•
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
Treatment schedule
*excluding ACEIs/ARBs, and other CCBs
Amlodipine 10 mg + Other drugs*
Amlodipine 10 mg / day
Run-in
Amlodipine 5 mg / day
Valsartan 80 mg / day
Valsartan 160 mg / day
Valsartan 160 mg + Other drugs*
*excluding ACEIs/other ARBs, and CCBs
-4w
0w
4w
8w
12w
Last
Visit
Randomization
Matsushita K, et al. J Cardiol. 2010; 56:111-117.
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Exclusion criteria
•
•
•
•
•
•
•
•
•
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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Study outcomes
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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Study population
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
575 Assigned to receive
Amlodipine-based treatment
558 Completed follow-up
1 Withdrew consent
16 Lost to follow up
575 Included in efficacy analysis
575 Included in safety analysis
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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Baseline characteristics 1
Variables
Age, mean (SD), y
Women, n (%)
Body mass index, mean (SD), kg/m2
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)
Amlodipine
(n = 575)
63 (8)
199 (35)
25 (4)
104 (18)
253 (44)
156 (27)
30 (5)
145 (18)
82 (13)
70 (11)
144 (19)
81 (13)
71 (12)
470 (82)
105 (18)
472 (82)
103 (18)
Baseline characteristics 2
Variables, mean (SD)
Valsartan Amlodipine
(n = 575)
(n = 575)
Glycosylated hemoglobin (HbA1c) *, %
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
7.0 (1.4)
8.2 (3.0)
1.9 (1.2)
1.6 (0.4)
3.5 (1.0)
328 (83)
5.6 (1.5)
60 (18)
6.9 (1.1)
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.
Medications at baseline
Variables, n (%)
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
Valsartan
(n = 575)
171
54
258
125
12
15
17
20
(30)
(9)
(45)
(22)
(2)
(3)
(3)
(4)
Amlodipine
(n = 575)
168
44
275
147
17
10
13
25
(29)
(8)
(48)
(26)
(3)
(2)
(2)
(4)
141 (25)
40 (7)
196 (34)
134 (23)
36 (6)
198 (34)
157 (27)
227 (40)
162 (28)
217 (38)
(mmHg)
Changes in blood pressure and glycemic status
180
Valsartan
Amlodipine
160
Systolic blood pressure (mmHg)
140
120
100
Diastolic blood pressure (mmHg)
80
(%)
10.0
60
Glycosylated hemoglobin (%)
40
8.0
20
6.0
0
4.0
0
6
12
18
24
30
36
42
48
54
60
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)
HRs
54 (9.4%)
56 (9.7%)
0.97
7 (1.2%)
3 (0.5%)
2.33
13 (2.3%)
16 (2.8%)
0.81
10 (1.7%)
11 (1.9%)
0.90
Primary outcome
Composite cardiovascular event
Components
Acute myocardial infarction
Stroke
Ischemic stroke
Intracerebral hemorrhage
2 (0.3%)
4 (0.7%)
0.50
Subarachnoid hemorrhage
1 (0.2%)
1 (0.2%)
1.00
29 (5.0%)
26 (4.5%)
1.12
Congestive heart failure
3 (0.5%)
15 (2.6%)
0.20
Sudden cardiac death
4 (0.7%)
4 (0.7%)
1.00
22 (3.8%)
16 (2.8%)
1.37
Coronary revascularization
Secondary outcome
All-cause death
Safety outcomes
Adverse events (n≥3)
Solid cancer
Dizziness
Liver dysfunction
Aortic aneurysm
Headache
Rashes / Zoster
Benign tumor
Fracture
Face flush
Fatigue
Hyperkalemia
Atrioventricular block
Gastric ulcer
Pruritis
Total
Valsartan
(n = 575)
Amlodipine
(n = 575)
22
14
4
4
3
4
3
2
1
1
3
0
0
0
23
10
5
4
5
2
3
2
3
3
0
3
3
3
106
112
Summary
 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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Discussion
IDNT
n = 1146
Secondary outcome
Hazard ratio
Favours ARB
Favours CCB
Cardiovascular composite
Cardiovascular death
Myocardial infarction
Congestive heart failure
Cerebrovascular accident
Cardiac revascularization
0.25
0.5
1
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.
Primary composite CV outcome
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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Study Limitations
 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
Variables
Favours 1st
Favours 2nd
HR
95% CI
Polyvascular disease vs. risk factors only
1.99
(1.78-2.24)
Congestive heart failure, yes vs. no
1.71
(1.60-1.83)
Ischemic event ≤1y vs. no ischemic event
1.71
(1.57-1.85)
History of diabetes, yes vs. no
1.44
(1.36-1.53)
Ischemic event >1y vs. no ischemic event
1.41
(1.32-1.51)
Single vascular territory disease vs. risk factors only
1.39
(1.25-1.54)
Body mass index <20, yes vs. no
1.30
(1.14-1.49)
Current smoker vs. former or never
1.30
(1.20-1.41)
Eastern Europe and Middle East vs. other regions*
1.28
(1.19-1.39)
Atrial fibrillation/flutter, yes vs. no
1.28
(1.18-1.38)
Sex, male vs. female
1.14
(1.07-1.21)
Age, per 1-year increase
1.04
(1.03-1.04)
Aspirin, yes vs. no
0.93
(0.87-0.98)
Statins, yes vs. no
0.73
(0.69-0.77)
Japan vs. other regions*
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.
Conclusions
 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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Acknowledgments
 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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