No benefit from irbesartan in patients with normal ejection fraction heart failure

The I-PRESERVE study (Irbesartan in Heart Failure with Preserved Ejection Fraction) assessed the efficacy of the angiotensin II receptor blocker (AIIRB) irebesartan on mortality and cardiovascular morbidity in patients with heart failure and a preserved LVEF. This was a multi-centre international trial which enrolled 4128 patients with a minimum age of 60 years and NYHA Class II-1V heart failure with an LVEF of at least 45%). Patients were randomly assigned to receive 300mg irbesartan or placebo each day. The primary composite outcome was death from any cause or hospitalisation for any cardiovascular cause. Secondary outcomes included death from heart failure or hospitalisation for heart failure, death from any cause and from cardiovascular causes, and quality of life.

Patients were followed up for a mean of 49.5 months. The primary end-point occurred in 742 patients in the irbesartan arm and 763 in the placebo arm. Primary event rates in the irbesartan and placebo groups were 100.4 and 105.4 /1000 patient years respectively (HR 0.95, 95% CI 0.86-1.05, p = 0.35). Overall rates of death were 52.6 and 52.3 /1000 patient years respectively (HR 1.00, 95%CI 0.88-1.14, p = 0.98). Rates of hospitalisation for cardiovascular causes contributing to the primary outcome were 70.6 and 74.3 /1000 patient years respectively (HR 0.95, 95%CI 0.85-1.08, p = 0.44).

Treatment with irbesartan did not reduce the risk of either the primary or any of the secondary end-points. This contrasts with the clear benefit of blockade of the RAAS in patients with heart failure and low ejection fraction, but these findings are consistent with those from two other studies involving patients with heart failure and preserved ejection fraction: CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) and PEP-CHF (Perindopril in Elderly People with Chronic Heart Failure). The reasons for this lack of benefit are uncertain. The authors postulate whether a 300mg dose of irbesartan (despite this being the highest approved dose) is insufficient for efficacy in this disease. However such a dose has been shown to decrease both systolic and diastolic blood pressure by a mean of 4/2 mmHg and to reduce the onset of heart failure in patients with diabetic nephropathy. The TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) Trial is ongoing and may shed further light on this question.

  • Massie BM, Carson PE, McMurray JJ et al. Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction. N Engl J Med 2008;359 (on-line early)

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