New England Journal of Medicine December 04, 2008

Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction

Barry M. Massie et al.

Bottom Line

In patients with heart failure and a preserved ejection fraction, the angiotensin receptor blocker irbesartan did not significantly improve cardiovascular outcomes or reduce overall mortality compared to placebo.

Key Findings

1. During a mean follow-up of 49.5 months, the primary composite outcome of death from any cause or hospitalization for a cardiovascular cause occurred in 742 patients (36%) in the irbesartan group and 763 patients (37%) in the placebo group.

2. Primary event rates were 100.4 per 1000 patient-years for irbesartan versus 105.4 per 1000 patient-years for placebo (Hazard Ratio [HR] 0.95; 95% CI 0.86-1.05; P=0.35).

3. Overall rates of death were not significantly different between the groups, occurring at 52.6 per 1000 patient-years in the irbesartan group and 52.3 per 1000 patient-years in the placebo group (HR 1.00; 95% CI 0.88-1.14; P=0.98).

4. Rates of hospitalization for cardiovascular causes were 70.6 and 74.3 per 1000 patient-years in the irbesartan and placebo groups, respectively (HR 0.95; 95% CI 0.85-1.08; P=0.44).

Study Design

Design

RCT

Double-Blind

Sample

4,128

Patients

Duration

49.5 mo

Median

Setting

Multicenter, International

Population Patients aged 60 years or older with New York Heart Association (NYHA) class II, III, or IV heart failure and a left ventricular ejection fraction of at least 45%.

Intervention Irbesartan 300 mg daily.

Comparator Matching placebo.

Outcome A composite of death from any cause or hospitalization for a cardiovascular cause (heart failure, myocardial infarction, unstable angina, arrhythmia, or stroke).

Study Limitations

• A substantial number of patients received off-protocol open-label ACE inhibitors or ARBs during the trial, which may have diluted any potential therapeutic effect.

• The patient population had high rates of non-cardiovascular morbidities, resulting in non-cardiovascular deaths acting as a competing risk to cardiovascular endpoints.

• The inclusion criterion of an ejection fraction of at least 45% represents mildly reduced ejection fraction by modern classification, creating a potentially heterogeneous study population.

• Many enrolled patients had only mild symptoms at baseline, which may have contributed to a lower-than-expected overall event rate.

Clinical Significance

The I-PRESERVE trial demonstrated that irbesartan is ineffective at altering the natural history of heart failure with preserved ejection fraction (HFpEF). It solidified the clinical paradigm that, unlike in heart failure with reduced ejection fraction (HFrEF) where RAAS inhibition provides profound mortality benefits, neurohormonal blockade with ARBs does not offer disease-modifying benefits in HFpEF and should be reserved primarily for blood pressure control and concomitant conditions.

Historical Context

Following the CHARM-Preserved (2003) and PEP-CHF (2006) trials, which showed equivocal or very modest benefits of RAAS inhibitors in HFpEF, I-PRESERVE was designed as a definitive, large-scale trial to evaluate the ARB irbesartan. Its neutral findings confirmed the difficulty in treating HFpEF and contributed to a prolonged therapeutic stalemate in this condition, which lasted until the breakthrough success of SGLT2 inhibitors over a decade later.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Why might blocking the renin-angiotensin-aldosterone system (RAAS) with an ARB like irbesartan be highly effective in reducing mortality for heart failure with reduced ejection fraction (HFrEF) but fail to show the same benefit in heart failure with preserved ejection fraction (HFpEF)?

Key Response

HFrEF involves eccentric hypertrophy and significant neurohormonal overdrive leading to adverse remodeling, which ARBs directly counteract. HFpEF is driven more by systemic inflammation, microvascular endothelial dysfunction, and myocardial fibrosis/stiffness, making simple RAAS blockade insufficient to alter the disease trajectory.

Resident

A 72-year-old patient with HFpEF and hypertension is currently taking irbesartan. Based on the I-PRESERVE trial, should this medication be discontinued, or are there still valid clinical indications to keep the patient on this ARB?

Key Response

While I-PRESERVE showed irbesartan does not improve primary HFpEF outcomes, ARBs remain guideline-directed therapy for managing comorbid hypertension in these patients. Controlling blood pressure is a critical component of HFpEF management to prevent further diastolic dysfunction, so the ARB should be continued for BP control.

Fellow

The I-PRESERVE trial required patients to have an LVEF of at least 45 percent. How does the heterogeneity of the HFpEF phenotype, particularly the 'mildly reduced' EF category (HFmrEF, 41-49 percent), complicate the interpretation of neutral trials like I-PRESERVE when compared to later trials?

Key Response

Patients at the lower end of the LVEF spectrum (HFmrEF) often behave more like HFrEF patients and may derive benefit from RAAS inhibitors. Lumping true HFpEF (EF > 50 percent) with HFmrEF dilutes the ability to see differential treatment effects across the EF continuum.

Attending

For decades, trials of neurohormonal blockade in HFpEF, including I-PRESERVE, yielded neutral results. What paradigm shift in our understanding of HFpEF pathophysiology was necessary to move away from the 'HFrEF-lite' treatment approach and ultimately lead to the successful use of SGLT2 inhibitors?

Key Response

The failure of trials like I-PRESERVE taught us that HFpEF is not just 'HFrEF with a normal EF' driven by RAAS/SNS overdrive. Recognizing HFpEF as a systemic syndrome driven by cardiometabolic inflammation and endothelial dysfunction paved the way for therapies with pleiotropic metabolic effects like SGLT2 inhibitors.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The I-PRESERVE trial was an event-driven study. How might competing risks, specifically the high rate of non-cardiovascular mortality in the elderly HFpEF population, attenuate the statistical power to detect a significant difference in the primary cardiovascular composite endpoint?

Key Response

HFpEF patients are older with multiple comorbidities. If a significant proportion dies from non-CV causes (competing risk), the accrual of the primary CV endpoints is slowed, reducing statistical power and potentially masking a small but real cardiovascular benefit of the intervention.

Journal Editor

In reviewing the inclusion criteria for I-PRESERVE, how does the reliance on echocardiographic criteria and clinical signs versus the mandatory use of elevated natriuretic peptides impact diagnostic certainty, and how might this threaten the trial's internal validity?

Key Response

Earlier trials like I-PRESERVE heavily relied on clinical signs, potentially enrolling patients with non-cardiac causes of dyspnea like obesity or COPD. Modern trials mandate elevated natriuretic peptides to ensure a true heart failure phenotype; lacking this could mean I-PRESERVE included patients without true HFpEF, diluting treatment effect.

Guideline Committee

Given the neutral primary outcome of I-PRESERVE alongside similar results from PEP-CHF, what Level of Evidence and Class of Recommendation do current ACC/AHA guidelines assign to ARBs for HFpEF, and what is their primary role?

Key Response

Current ACC/AHA guidelines assign a Class 2b recommendation for ARBs in HFpEF, noting they might be considered to decrease hospitalizations, but primarily emphasize their use for treating comorbidities like hypertension. The neutral mortality data prevents a Class 1 recommendation for HFpEF itself.

Clinical Landscape

Noteworthy Related Trials

2003

CHARM-Preserved

n = 3,023 · Lancet

Tested

Candesartan

Population

Patients with symptomatic heart failure and LVEF > 40%

Comparator

Placebo

Endpoint

Composite of cardiovascular death or heart failure hospitalization

Key result: Candesartan reduced the number of hospital admissions for heart failure but did not significantly reduce cardiovascular mortality compared to placebo.

2014

TOPCAT Trial

n = 3,445 · NEJM

Tested

Spironolactone

Population

Patients with symptomatic heart failure and LVEF >= 45%

Comparator

Placebo

Endpoint

Composite of cardiovascular death, aborted cardiac arrest, or hospitalization for heart failure

Key result: Spironolactone did not significantly reduce the primary composite endpoint, although there was a significant reduction in heart failure hospitalizations.

2021

EMPEROR-Preserved

n = 5,988 · NEJM

Tested

Empagliflozin 10mg daily

Population

Patients with heart failure and LVEF > 40%

Comparator

Placebo

Endpoint

Composite of cardiovascular death or hospitalization for heart failure

Key result: Empagliflozin significantly reduced the combined risk of cardiovascular death or hospitalization for heart failure, driven primarily by a reduction in hospitalizations.

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