Massie BM. I-PRESERVE. NEJM 4 Dec 2008; 359: 2456-67.
BACKGROUND: 50% of patients with heart failure have an ejection fraction > 45%. The renin-aldosterone-angiotensin system is involved in many processes associated with this syndrome - HTN, LVH, myocardial fibrosis, and vascular dysfunction. Inhibition of this system could possibly serve as a therapeutic intervention.
RESULTS
Randomization: 4564 patients screened, 4128 underwent randomization. 2067 assigned to receive Irbersartan, 2061 received placebo.
Baseline: Mean age 72y, 60% women, hypertensive heart disease 64%, HTN 88%, atrial fibrillation 29%, DM 27%, obese 41%, baseline NT-proBNP 339 pg/mL, diuretic use 83%, beta-blocker use 59%, CCB use 70%, spironolactone use 45%, ACEi use 25%
Primary Outcome: Composite end-point
All patients: 36% vs 37%, no significant differences between the two groups
All subgroups: no significant differences between the two groups
Secondary Outcomes: no significant differences between the two groups
Predetermined subgroup analysis: no significant differences between the two groups
Adverse Events: no significant differences between the two groups
Discussion: At the end of the study, 73% taking beta-blockers, 40% using ACEi which possibly leaves little room for more improvement. 34% discontinued drug use in both groups, consistent with other trials of this duration.
METHODS
Sponsors: Bristol-Myers Squibb & Sanofi-Aventis
Study Type: 2 week run-in phase with placebo before randomization, then randomized and stratified to ACEi use. 293 sites, 25 countries (Europe, North America, South America, South Africa, and Australia).
Inclusion: (a) 60y +, (b) heart failure symptoms and LVEF > 45%, (c) required hospitalization for heart failure symptoms in last 6 months with NYHA class II, III, or IV, (d) if not hospitalized, had to have NYHA class III or IV with corroborative evidence (pulmonary congestion on CXR, LVH or LAE on echocardiogram, LVH or LBBB on ECG), (e) ACEi permitted when essential for indication other than uncomplicated hypertension.
Exclusion: (a) prior intolerance to ARB, (b) alternative problem causing symptoms, e.g. pulmonary disease, (c) any previous LVEF < 40%, (d) h/o ACS, coronary revascularization, or stroke in the last 3 months, (e) substantial valvular disease, (f) hypertrophic or restrictive cardiomyopathy, (g) pericardial disease, (h) cor pulmonale or other RHF, (i) SBP < 100 mm Hg or > 160 mm Hg, (j) DBP > 95 mm Hg, (k) life expectancy < 3y, (l) Hb < 11 g/dL, (m) Cr > 2.5 mg/dL, (n) increased LFTs.
Time Frame: June 2002 to April 2005
Treatment: (1) Irbesartan 75 mg PO daily, doubled to 150 mg after 1-2wks, then doubled to 300mg after 1-2 wks, versus (2) placebo.
Primary Outcome: Composite of death from any cause or hospitalization for cardiovascular cause (worsening heart failure, MI, stroke, unstable angina, ventricular or atrial dysrhythmia, or MI or stroke during any hospitalization).
Secondary Outcome: (1) death from any cause, (2) hospitalization for cardiovascular cause, (3) composite heart failure (death from heart failure, sudden death, or hospitalization for worsening heart failure), (4) change in Minnesota Living with Heart Failure scale at 6m, (5) change in plasma level of NT-proBNP at 6m, (6) composite cardiovascular event (death from cardiovascular cause, nonfatal MI, or nonfatal stroke, (7) death from cardiovascular cause
Predefined Subgroup Analysis: (1) Age <65y, 65y to 75y, >75y, (2) sex, (3) EF < 59% and > 59%, (4) ACEi use, (5) beta blocer use, (6) diabetes, (7) hospitalization for heart failure in the last 6 months, (8) geographic region
ADDITIONAL READING
Leave a comment