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Massie - 3320 I-PRESERVE Trial Irbesartan in heart failure with preserved EF Co-PIs: Barry Massie and Peter Carson Executive Committee M. Komajda, R. McKelvie, J. McMurray, M. Zile, M. Donovan, C. Staiger, A. Ptaszynska, C. Staiger On Behalf of the I-PRESERVE Committees and Investigators Background Massie - 3320 • Approximately 50% of heart failure patients have preserved EF (≥ 45%), and this proportion is growing. • In the US, HFPEF is responsible for approximately 500,000 heart failure hospitalizations and 25,000 deaths. • HFPEF affects primarily women and older patients, and in contrast to low EF heart failure, hypertension is the primary underlying condition and CAD is relatively infrequent. • Currently no evidence-based treatment to improve patient outcomes. • Objective • To determine whether treatment with the angiotensin receptor blocker irbesartan reduces mortality and morbidity in patients with HFPEF. • Primary endpoint: All cause mortality and protocol-specified CV hospitalizations (for heart failure, MI, stroke, arrhythmia). • Secondary endpoints: – – – – HF death or hospitalization QOL (Minnesota) Death, MI or stroke CV death Massie - 3320 I-PRESERVE Entry Criteria Age 60 years Current HF symptoms LVEF 0.45 NYHA class II - IV CHF hosp. 6 months NYHA Class III/IV CXR congestion ECG (LVH, LBBB) Echo (LVH, LAE) Exclusions: Prior EF <40%; ACS or stroke ≤ 3m, hypertrophic or restrictive CM, pericardial or valvular disease, cor pulmonale, SBP >160 or <100, Scr >2.5, Hb <11, other conditions limiting life expectancy, characteristics that might interfere with study protocol. Massie - 3320 I-PRESERVE Study Design Irbesartan 75 mg* 150 mg 300 mg N=4,128 Enrollment Single-blind 2 weeks Only 1/3 pts could enter on an ACEI R Forced titration W2 W4 Maintenance W8 M6 M 10 M 14–end Q4 months Placebo Randomized, double-blind, placebo controlled trial Follow-up continued until 1,440 primary endpoints occurred Massie - 3320 I-Preserve Patient Characteristics I-Preserve (n=4,128) Cohort & Epi Studies 72 75 Women 60% 65-70% EF 59% 60% HTN (1° cause) 88%(63%) 80-90% (60%) Prior MI 23%(25%) <20% (25%) CABG/PCI 13% <20% Stroke/TIA 10% na Atrial fib 29% 20-30% Diabetes 27% 20-30% ACE I on entry 25% Beta-blocker 60% Spironolactone 18% Age (mean) I-PRESERVE: Primary Endpoint Massie - 3320 Death or hospitalization for heart failure, MI, stroke, or arrhythmia I-Preserve: Major Secondary Endpoints Cardiovascular mortality HR 1.02(0.87-1.19) P=0.85 Massie - 3320 Heart failure death or hospitalization HR 1.01 (0.88-1.16) P=0.89 Irbesartan n=306 Placebo N= 296 Placebo n=445 Irbesartan n=436 Massie - 3320 I-PRESERVE: Conclusions • Largest trial conducted in patients with HFPEF, and successfully enrolled patients similar to those in the community. • Irbesartan was unsuccessful in achieving its primary or secondary outcomes. • Irbesartan was generally safe and well tolerated. • Our results are consistent the 2 previous trials in patients with HFPEF that did not demonstrate a positive effect. • For this large group of patients there is no specific evidence-based therapy. • In order for this field to move forward, a better understanding of the mechanisms underlying this syndrome and the potential targets for treatment is required.