1. 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

2. Massie - 3320 Background 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

3. Massie - 3320 Age  60 years Current HF symptoms LVEF  0.45 NYHA Class III/IV  Echo (LVH, LAE)  ECG (LVH, LBBB)  CXR congestion I-PRESERVE Entry Criteria NYHA class II - IV  CHF hosp.  6 months Exclusions: Prior EF 160 or 2.5, Hb <11, other conditions limiting life expectancy, characteristics that might interfere with study protocol.

4. Massie - 3320 Placebo Forced titrationMaintenance Enrollment Single-blind 2 weeks W 2 W 4W 8M 6 M 10 M 14–end Q4 months 75 mg*150 mg 300 mg Randomized, double-blind, placebo controlled trial Follow-up continued until 1,440 primary endpoints occurred N=4,128 I-PRESERVE Study Design Irbesartan R Only 1/3 pts could enter on an ACEI

5. Massie - 3320 I-Preserve Patient Characteristics I-Preserve (n=4,128) Cohort & Epi Studies Age (mean)7275 Women60%65-70% EF59%60% HTN (1° cause)88%(63%)80-90% (60%) Prior MI23%(25%)<20% (25%) CABG/PCI13%<20% Stroke/TIA10%na Atrial fib29%20-30% Diabetes27%20-30% ACE I on entry25% Beta-blocker60% Spironolactone18%

6. Massie - 3320 I-PRESERVE: Primary Endpoint Death or hospitalization for heart failure, MI, stroke, or arrhythmia

7. Massie - 3320 I-Preserve: Major Secondary Endpoints Cardiovascular mortality HR 1.02(0.87-1.19) P=0.85 Irbesartan n=306 Placebo N= 296 HR 1.01 (0.88-1.16) P=0.89 Placebo n=445 Irbesartan n=436 Heart failure death or hospitalization

8. 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.