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 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

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: * McMurray JJ, et al. N Engl J Med. 2010; 362: † HOPE Investigators. Lancet. 2000; 355: † Brenner BM, et al. N Engl J Med. 2001; 345: ACC 2011, LBCT

JNC ADA 2004 ESC-ESH 2007 JSH 2009 ACEIs ◎◎◎◎ ARBs ◎◎◎◎ CCBs ○ △ ○○ β-blockers ○○○○ α-blockers 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. ACC 2011, LBCT

Background TrialsnDMControlCV outcomesHRs(95% CIs) LIFE DM-subgroup (2001) %BBComposite CV death Acute MI Stroke ( ) ( ) ( ) ( ) IDNT CV outcomes-analysis (2003) %CCBComposite CV death Acute MI PCI/CABG Heart Failure Stroke ( ) ( ) ( ) ( ) ( ) ( ) VALUE (2004) %CCBComposite CV death Acute MI Heart Failure ( ) ( ) ( ) CASE-J (2008) %CCBComposite Sudden death Acute MI Stroke Angina Heart Failure ( ) ( ) ( ) ( ) ( ) ( ) Previous major trials comparing ARBs vs. other active treatments

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: NCT ACC 2011, LBCT

Random allocation Minimization 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*Hypertension 30 to 75 y.o. Trial scheme of the Nagoya Heart Study and PROBE 1 : 1 *T2DM and IGT were diagnoses by *ADA 2004 criteria

Treatment schedule Amlodipine 10 mg + Other drugs* Amlodipine 10 mg / day Amlodipine 5 mg / day Valsartan 80 mg / day Valsartan 160 mg / day 0w4w8w12w Last Visit 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: ACC 2011, LBCT

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: ACC 2011, LBCT

Study population ACC 2011, LBCT 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 receive Valsartan-based treatment 575 Assigned to receive Amlodipine-based treatment 558Completed 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 analysis 575 Included in safety analysis 575 Included in efficacy analysis 575 Included in safety analysis 1150 Patients randomized

Variables Valsartan (n = 575) Amlodipine (n = 575) Age, mean (SD), y63 (8) Women, n (%)197 (34)199 (35) Body mass index, mean (SD), kg/m 2 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), mmHg145 (18)144 (19) Diastolic, mean (SD), mmHg82 (13)81 (13) Heart rates, mean (SD), /min70 (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/L8.2 (3.0)7.9 (2.6) Triglycerides, mmol/L1.9 (1.2) HDL cholesterol, mmol/L1.6 (0.4) LDL cholesterol, mmol/L3.5 (1.0)3.6 (1.0) Uric acid, μmol/L328 (83)333 (84) Blood urea nitrogen, mmol/L5.6 (1.5)5.6 (1.6) Serum creatinine, μmol/L60 (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 blockers171 (30)168 (29) Angiotensin converting enzyme inhibitors54 (9)44 (8) Calcium channel blockers258 (45)275 (48) β-Blockers125 (22)147 (26) α-Blockers12 (2)17 (3) Anti-aldosterone agents15 (3)10 (2) Thiazides17 (3)13 (2) Other diuretics20 (4)25 (4) Treatment for glucose intolerance Sulfonylurea141 (25)134 (23) Insulin40 (7)36 (6) Other hypoglycemic agents196 (34)198 (34) Other medication Aspirin157 (27)162 (28) Statins227 (40)217 (38) Medications at baseline

(%) Glycosylated hemoglobin (%) (mmHg) Months Changes in blood pressure and glycemic status

No. at risk Valsartan Amlodipine ACC 2011, LBCT Follow-up median 3.2 ( ) years Hazard ratio 0.97 (95% CI, ) Primary composite CV outcome

Number of events (%) Valsartan (n = 575) Amlodipine (n = 575) HRs 54 (9.4%) 56 (9.7%) (1.2%) 3 (0.5%) (2.3%) 16 (2.8%) (1.7%) 11 (1.9%) (0.3%) 4 (0.7%) (0.2%) (5.0%) 26 (4.5%) (0.5%) 15 (2.6%) (0.7%) (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

Safety outcomes Adverse events (n≥3) ValsartanAmlodipine (n = 575) Solid cancer2223 Dizziness1410 Liver dysfunction45 Aortic aneurysm44 Headache35 Rashes / Zoster42 Benign tumor33 Fracture22 Face flush13 Fatigue13 Hyperkalemia30 Atrioventricular block03 Gastric ulcer03 Pruritis03 Total106112

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, ], 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, ], p = 0.01) ACC 2011, LBCT

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. ACC 2011, LBCT

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. ACC 2011, LBCT

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. ACC 2011, LBCT