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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). ACC 2011, LBCT 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. ACC 2011, LBCT NAGOYA City The NAGOYA Castle Golden Shachi-hoko = Symbol of Nagoya City ACC 2011, LBCT 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. ACC 2011, LBCT 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 ACC 2011, LBCT 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. ACC 2011, LBCT 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. ACC 2011, LBCT 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. 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 enroll Matsushita K, et al. J Cardiol. 2010;56:111-117. 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;56:111-117. ACC 2011, LBCT 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 ACC 2011, LBCT 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 ACC 2011, LBCT 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) ACC 2011, LBCT 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. ACC 2011, LBCT 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% 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 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. 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