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

Comparison between valsartan and amlodipine regarding cardiovascular

morbidity and mortality in hypertensive patients with glucose intolerance:

NAGOYA HEART Study

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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The NAGOYA Castle

Golden Shachi-hoko= Symbol of Nagoya City

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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JNC72003

ADA2004

ESC-ESH2007

JSH2009

ACEIs ◎ ◎ ◎ ◎

ARBs ◎ ◎ ◎ ◎

CCBs ○ △ ○ ○

β-blockers ○ ○ ○ ○

α-blockers NA △ △ NA

Diuretics ○ ○ ○ ○◎ Recommended as a First-Choice Agent, ○ Available as an Alternative Agent, △ Not

Recommended

Many guidelines recommend ACEIs / ARBs as the first-line antihypertensive medications for diabetic hypertensive patients.

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BackgroundTrials n DM Control CV outcomes HRs (95% CIs)

LIFEDM-subgroup

(2001)

1195 100%

BB CompositeCV deathAcute MIStroke

0.760.630.830.79

(0.6-0.98)(0.4-0.95)(0.6-1.3)(0.6-1.1)

IDNTCV outcomes-

analysis(2003)

1146 100%

CCB CompositeCV deathAcute MIPCI/CABG

Heart FailureStroke

0.901.361.540.930.651.55

(0.7-1.1)(0.9-2.1)(0.97-2.5)(0.6-1.6)(0.5-0.9)(0.8-2.9)

VALUE(2004)

15245

34% CCB CompositeCV deathAcute MI

Heart Failure

1.041.011.200.89

(0.9-1.2)(0.9-1.2)(1.0-1.4)(0.8-1.03)

CASE-J(2008)

4728 43% CCB CompositeSudden death

Acute MIStrokeAngina

Heart Failure

1.010.730.951.280.571.25

(0.8-1.3)(0.3-1.6)(0.5-1.8)(0.9-1.9)(0.2-1.4)(0.7-2.4)

Previous major trials comparing ARBs vs. other active treatments

Irbesartan Diabetic Nephropathy Trial Collaborative Study Group. 　 Ann Intern Med 2003;138:542-9.

Irbesartan Diabetic Nephropathy Trial (IDNT)

Secondary endpoint

Congestive heart failure

Myocardial infarction

Cerebrovascular accident

Cardiovascular death

n = 1146

Cardiovascular composite

Cardiac revascularization

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Favours ARB

Favours CCB

Hazard ratio

10.50.25 2 4

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.ACC 2011, LBCT

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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Random allocationMinimization factors ： age, gender, statin use, smoking, and T2DM/IGT

Valsartan-based treatment

Amlodipine-based treatment

BP goal < 130/80 mmHg, median 3-years follow-up

Primary outcome: Composite CV events

Secondary outcome: All-cause mortality

T2DM or IGT*Hypertension30 to 75 y.o.

Trial scheme of the Nagoya Heart Study

and and

PROBE

1 : 1

*T2DM and IGT were diagnoses by *ADA 2004 criteria

Treatment schedule

Amlodipine 10 mg + Other drugs*Amlodipine 10 mg + Other drugs*

Amlodipine 10 mg / dayAmlodipine 10 mg / day

Amlodipine 5 mg / dayAmlodipine 5 mg / day

Valsartan 80 mg / dayValsartan 80 mg / day

Valsartan 160 mg / dayValsartan 160 mg / day

0w 4w 8w 12w LastVisit

Valsartan 160 mg + Other drugs*Valsartan 160 mg + Other drugs*

*excluding ACEIs/ARBs, and other CCBs

*excluding ACEIs/other ARBs, and CCBs

Run-in

-4w

Randomization

Matsushita K, et al. J Cardiol. 2010; 56:111-117.ACC 2011, LBCT

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 enrollMatsushita K, et al. J Cardiol. 2010;56:111-117.

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Study outcomesPrimary outcome

Composite of cardiovascular eventsAcute myocardial infarctionStrokeCoronary revascularization (PCI or CABG)Admission due to heart failureSudden cardiac death

Secondary outcome

All-cause mortalityMatsushita K, et al. J Cardiol. 2010;56:111-117.

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Study population

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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

575 Assigned to receiveValsartan-based treatment

575 Assigned to receiveAmlodipine-based treatment

558 Completed follow-up 1 Withdrew consent 16 Lost to follow up

559 Completed follow-up 2 Withdrew consent 14 Lost to follow up

575 Included in efficacy analysis575 Included in safety analysis

575 Included in efficacy analysis575 Included in safety analysis

1150 Patients randomized

VariablesValsartan(n = 575)

Amlodipine(n = 575)

Age, mean (SD), y 63 (8) 63 (8)

Women, n (%) 197 (34) 199 (35)

Body mass index, mean (SD), kg/m2 25 (4) 25 (4)

Current smoker, n (%) 106 (18) 104 (18)

Dyslipidemia, n (%) 245 (43) 253 (44)

Prior cardiovascular diseases, n (%) 150 (26) 156 (27)

Prior cerebrovascular diseases, n (%) 24 (4) 30 (5)

Blood pressure 　 　 Systolic, mean (SD), mmHg 145 (18) 144 (19)

Diastolic, mean (SD), mmHg 82 (13) 81 (13)

Heart rates, mean (SD), /min 70 (11) 71 (12)

Status of glucose intolerance 　 　 Type 2 diabetes mellitus, n (%) 470 (82) 472 (82)

Impaired glucose tolerance, n (%) 105 (18) 103 (18)

Baseline characteristics 1

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 8.2 (3.0) 7.9 (2.6)Triglycerides, mmol/L 1.9 (1.2) 1.9 (1.2)HDL cholesterol, mmol/L 1.6 (0.4) 1.6 (0.4)LDL cholesterol, mmol/L 3.5 (1.0) 3.6 (1.0)Uric acid, μmol/L 328 (83) 333 (84)Blood urea nitrogen, mmol/L 5.6 (1.5) 5.6 (1.6)Serum creatinine, μmol/L 60 (18) 60 (17)

* Presented as National Glycohemoglobin Standardization Program (NGSP) value.

Baseline characteristics 2

Variables, n (%)Valsartan(n = 575)

Amlodipine(n = 575)

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

Medications at baseline

0 6 12 18 24 30 36 42 48 54 60 0

20

40

60

80

100

120

140

160

180

Valsartan Amlodipine

Systolic blood pressure (mmHg)

Diastolic blood pressure (mmHg)

(%)

4.0

6.0

8.0

10.0

Glycosylated hemoglobin (%)

(mmHg)

Months

Changes in blood pressure and glycemic status

No. at riskValsartanAmlodipine

575 562 549 536 492 443 343 253 206 165

575 567 555 540 493 445 336 250 197 159ACC 2011, LBCT

Follow-up median 3.2 (2.6-4.7) yearsHazard ratio 0.97 (95% CI, 0.66-1.40)

Primary composite CV outcome

Number of events (%)

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

2 (0.3%)

4 (0.7%) 0.50

1 (0.2%)

1 (0.2%) 1.00

29 (5.0%)

26 (4.5%) 1.12

3 (0.5%)

15 (2.6%) 0.20

4 (0.7%)

4 (0.7%) 1.00

22 (3.8%)

16 (2.8%) 1.37

Hazard ratios and 95% confidence intervals

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

0.25 0.5 1 2 4

Safety outcomes

Adverse events (n≥3)Valsartan Amlodipine(n = 575) (n = 575)

Solid cancer 22 23Dizziness 14 10Liver dysfunction 4 5Aortic aneurysm 4 4Headache 3 5Rashes / Zoster 4 2Benign tumor 3 3Fracture 2 2Face flush 1 3Fatigue 1 3Hyperkalemia 3 0Atrioventricular block 0 3Gastric ulcer 0 3Pruritis 0 3

Total 106 112

SummaryA 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 Collaborative Study Group. 　 Ann Intern Med 2003;138:542-9.

IDNT

Congestive heart failure

Myocardial infarction

Cerebrovascular accident

Cardiovascular death

n = 1146

Cardiovascular composite

Cardiac revascularization

Secondary outcome

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Favours ARB

Favours CCB

Hazard ratio

10.50.25 2 4

Percent of CCB administeredValsartan Group 51%Non-ARB Group 63%

Kyoto Heart StudyEur. Heart J. 2009;30:2461–2469.

HR=0.55, p=0.0000195% CI 0.42-0.72

Pri

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V o

utc

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Kaplan–Meier estimate and effect of treatment on all endpoints.

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

Bhatt DL, et al. JAMA 2010; 304(12): 1350-7.

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.

1o.5

2

Favours 1st Favours 2nd

ConclusionsThe 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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