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Toyoaki Murohara, Takashi Muramatsu , Kunihiro Matsushita ,

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 ,

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Toyoaki Murohara, Takashi Muramatsu , Kunihiro Matsushita ,

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  1. 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

  2. Presenter disclosure information Toyoaki Murohara, MD, PhD. Lecturer’s fee from Daiichi-Sankyo, Novartis Pharma, Pfizer, and Takeda (Modest). ACC 2011, LBCT

  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

  4. NAGOYA City The NAGOYA Castle Golden Shachi-hoko = Symbol of Nagoya City ACC 2011, LBCT

  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

  6. Many guidelines recommend ACEIs / ARBs as the first-line antihypertensive medications for diabetic hypertensive patients. ◎ Recommended as a First-Choice Agent, ○ Available as an Alternative Agent, △ Not Recommended ACC 2011, LBCT

  7. Background Previous major trials comparing ARBs vs. other active treatments

  8. Irbesartan Diabetic Nephropathy Trial (IDNT) Secondary endpoint n = 1146 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 Irbesartan Diabetic Nephropathy Trial Collaborative Study Group.Ann Intern Med 2003;138:542-9. ACC 2011, LBCT

  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

  10. Study design of the NHS • Aninvestigator-initiatedtrial. • 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

  11. Trial scheme of the Nagoya Heart Study and and Hypertension T2DM or IGT* 30 to 75 y.o. Random allocation Minimization factors： age, gender, statin use, smoking, and T2DM/IGT PROBE Valsartan-based treatment Amlodipine-based treatment 1 : 1 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

  12. Treatment schedule *excluding ACEIs/ARBs, and other CCBs Amlodipine 10 mg + Other drugs* Amlodipine 10 mg / day Amlodipine 5 mg / day Run-in Valsartan 80 mg / day Valsartan 160 mg / day Valsartan 160 mg + Other drugs* *excluding ACEIs/other ARBs, and CCBs 0w 4w 8w 12w Last Visit -4w Randomization Matsushita K, et al. J Cardiol.2010; 56:111-117. ACC 2011, LBCT

  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 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

  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

  15. 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 • 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 analysis 575 Included in safety analysis 575 Included in efficacy analysis 575 Included in safety analysis ACC 2011, LBCT

  16. Baseline characteristics 1

  17. Baseline characteristics 2 * Presented as National Glycohemoglobin Standardization Program (NGSP) value.

  18. Medications at baseline

  19. (mmHg) Changes in blood pressure and glycemic status (%) 10.0 8.0 Glycosylated hemoglobin (%) 6.0 4.0 Months

  20. 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

  21. Safety outcomes

  22. 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

  23. Discussion

  24. IDNT n = 1146 Hazard ratio Secondary outcome 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

  25. Kyoto Heart Study Eur. Heart J. 2009;30:2461–2469. Kaplan–Meier estimate and effect of treatment on all endpoints. HR=0.55, p=0.00001 95% CI 0.42-0.72 Primary composite CV outcome Percent of CCB administered Valsartan Group 51% Non-ARB Group 63% ACC 2011, LBCT

  26. 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

  27. Favours 1st Favours 2nd Multivariable Predictors of CV death, MI, or Stroke o.5 1 2 • Other regions were North America, Latin America, Western Europe, and Asia. Bhatt DL, et al. JAMA 2010; 304(12): 1350-7.

  28. 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

  29. 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

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