The I-PRESERVE study found no evidence to support the routine use of an A2RA in patients with heart failure and a preserved left ventricular ejection fraction.
This data provides no evidence to support the widespread use of A2RAs in addition to standard therapy for patients with heart failure and a preserved left ventricular ejection fraction (LVEF). The optimum management of patients with heart failure and a preserved LVEF is uncertain. Treatment is perhaps best guided by symptomatic response, and the SIGN guideline recommends identifying and treating those conditions that that commonly occur alongside HF with preserved LVEF, e.g. myocardial ischaemia, hypertension and myocardial hypertrophy.
What is the background to this?
As many as 35–50% of patients with heart failure (HF) have a preserved LVEF, according to recent SIGN guidance. Evidence for how best to treat patients with this condition is limited. Although use of drugs that act on the renin-angiotensin-aldosterone system [RAAS] (e.g. ACE inhibitors, A2RAs, beta-blockers, spironolactone) have been shown to improve outcomes in patients with left ventricular systolic dysfunction, no drugs have been shown to be effective in improving outcomes in patients with a preserved LVEF. The I-PRESERVE study investigated whether the addition of an A2RA, irbesartan, added to standard treatment, improved the outcome of patients with HF and preserved LVEF.
What does this study claim?
This large study in 4128 patients with HF and preserved LVEF found that irbesartan 300 mg/day did not improve outcomes for patients compared with placebo. Over a mean of about four years, there was no significant difference between groups in the primary end point (death from any cause or hospitalisation for specified cardiovascular [CV] causes). This outcome occurred in 36% of the patients who received irbesartan (100.4 per 1000 patient-years) and 37% of the patients who received placebo (105.4 per 1000 patient-years): HR 0.95, 95%CI 0.86 to 1.05, P=0.35. There was also no difference in the occurrence of the individual components of this composite outcome, or for any other pre-specified outcomes. Irbesartan was not associated with more discontinuations from the study. Patients receiving irbesartan were significantly more likely to have a doubling of their serum creatinine level or a raised potassium level (above 6mmol/L) compared with placebo. However, there were no differences in the rates of serious adverse events between groups.
How does this relate to other studies?
Two previous, smaller randomised controlled trials (PEP-CHF and CHARM-Preserved) evaluated the effects of an ACE inhibitor, perindopril, or an A2RA, respectively, in patients with heart failure and preserved LVEF. Neither showed any effects on their primary outcomes (a composite of hospitalisation from heart failure and either all-cause mortality [PEP-CHF] or death from CV causes [CHARM-Preserved]). In view of the absence of evidence for their effectiveness, no recommendations for treatment of HF with preserved LVEF are made for drugs affecting the RAAS system in the NICE (2003), SIGN (2007) or European Society of Cardiology Guidelines (2008) for HF.
The SIGN guideline recommends identifying and treating those conditions that that commonly occur alongside HF with preserved LVEF, e.g. myocardial ischaemia, hypertension and myocardial hypertrophy.
Many of the patients in the I-PRESERVE study were already taking other drugs that affect the RAAS system at baseline (i.e. ACE inhibitors, beta-blockers, spironolactone) and the use of these increased during the study. The authors suggest that, it is possible that the failure to show any benefit for irbesartan in this study was because the high concomitant use of other RAAS drugs in the study might have left little room for further benefit from the addition of the A2RA. However, no significant differences were seen between subgroups of patients who did or did not use any of the drugs affecting the RAAS system. The results appear just to confirm the lack of benefit for drugs of this type in patients with HF with preserved LVEF shown in PEP-CHF and CHARM-Preserved studies; the study provides no justification for the routine use of an A2RA in patients with HF and preserved LVEF.
Design: Randomised double-blind placebo controlled trial. Allocation was concealed.
Patients: 4128 patients, at least 60 years of age (mean age 72 years); 60% female; NYHA class II–IV (77% class III); LVEF >45%, ACE inhibitors permitted only if for conditions other than uncomplicated hypertension. Baseline medications included diuretics (83%, including 52% who were taking a loop diuretic), beta-blockers (59%), calcium-channel blockers (40%), spironolactone (15%), and ACE inhibitors (25%).
Intervention: Irbesartan 300mg daily (75mg initially with doubling of doses every 1–2 weeks to 300mg if tolerated) or placebo.
Comparison: Irbesartan group vs. placebo group (ITT population); Kaplan Meier estimates (log-rank test) and supportive Cox proportional-hazards model to calculate HRs.
Outcomes: Primary endpoint – composite of death from any cause or hospitalisation for a CV cause (HF, MI, unstable angina, arrhythmia, stroke); secondary outcomes included death from heart failure or hospitalisation for heart failure, death from any cause and from CV causes, and quality of life.
Results: During a mean follow-up of 49.5 months, the primary outcome occurred in 742 patients in the irbesartan group (n=2067) and 763 in the placebo group (n= 2061). Primary event rates in the irbesartan and placebo groups were 100.4 and 105.4 per 1000 patient-years, respectively (HR 0.95; 95%CI 0.86 to 1.05; P=0.35). Overall rates of death were 52.6 and 52.3 per 1000 patient-years, respectively (HR 1.00; 95%CI 0.88 to 1.14; P=0.98). Rates of hospitalisation for CV causes that contributed to the primary outcome were 70.6 and 74.3 per 1000 patient-years, respectively (HR 0.95; 95%CI, 0.85 to 1.10; P=0.44). There were no significant differences in the other pre-specified outcomes including the Minnesota Living with Heart Failure scale, a measure of quality of life. The rates of discontinuations were similar between groups. Doubling of serum creatinine levels (6% vs. 4%, P<0.0001) and raised potassium serum levels above 6mmol/L (3% vs. 2%, P=0.01), on at least one measurement, were more common in the patients who received irbesartan compared with placebo. There were no differences in the rates of serious adverse events between groups.
Sponsorship: This study was supported by Bristol-Myers Squibb and Sanofi-Aventis.