toyoaki murohara, takashi muramatsu, kunihiro matsushita, kentaro yamashita, takahisa kondo, kengo...

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  • Slide 1
  • 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
  • Slide 2
  • Presenter disclosure information Toyoaki Murohara, MD, PhD. Lecturers fee from Daiichi-Sankyo, Novartis Pharma, Pfizer, and Takeda (Modest). ACC 2011, LBCT
  • Slide 3
  • 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
  • Slide 4
  • The NAGOYA Castle Golden Shachi-hoko = Symbol of Nagoya City NAGOYA City ACC 2011, LBCT
  • Slide 5
  • 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
  • Slide 6
  • JNC7 2003 ADA 2004 ESC-ESH 2007 JSH 2009 ACEIs ARBs CCBs -blockers -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
  • Slide 7
  • Background TrialsnDMControlCV outcomesHRs(95% CIs) LIFE DM-subgroup (2001) 1195100%BBComposite 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) IDNT CV outcomes-analysis (2003) 1146100%CCBComposite 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) VALUE (2004) 1524534%CCBComposite CV death Acute MI Heart Failure 1.04 1.01 1.20 0.89 (0.9-1.2) (1.0-1.4) (0.8-1.03) CASE-J (2008) 472843%CCBComposite 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) Previous major trials comparing ARBs vs. other active treatments
  • Slide 8
  • 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 ACC 2011, LBCT Favours ARBFavours CCB Hazard ratio 10.50.2524
  • Slide 9
  • 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
  • Slide 10
  • 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
  • Slide 11
  • 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
  • Slide 12
  • 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; 56:111-117. ACC 2011, LBCT
  • Slide 13
  • 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 mol/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
  • Slide 14
  • 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
  • Slide 15
  • 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
  • Slide 16
  • 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
  • Slide 17
  • 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, mol/L328 (83)333 (84) Blood urea nitrogen, mmol/L5.6 (1.5)5.6 (1.6) Serum creatinine, mol/L60 (18)60 (17) * Presented as National Glycohemoglobin Standardization Program (NGSP) value. Baseline characteristics 2
  • Slide 18
  • 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) -Blockers125 (22)147 (26) -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
  • Slide 19
  • (%) 4.0 6.0 8.0 10.0 Glycosylated hemoglobin (%) (mmHg) Months Changes in blood pressure and glycemic status
  • Slide 20
  • 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 Follow-up median 3.2 (2.6-4.7) years Hazard ratio 0.97 (95% CI, 0.66-1.40) Primary composite CV outcome
  • Slide 21
  • 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%) 1.00 29 (5.0%) 26 (4.5%)1.12 3 (0.5%) 15 (2.6%)0.20 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 0.250.5124
  • Slide 22
  • Safety outcomes Adverse events (n3) ValsartanAmlodipine (n = 575) Solid cancer2223 Dizziness1410 Liver dysfunction45 Aortic aneurysm44 Headache35 Rash

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