"Valsartan in Heart Failure Patients Already Treated with ACE Inhibitors". The New England Journal of Medicine. 2001. 345:1667-1675. PubMed • Full text • PDF

Contents

1 Clinical Question
2 Bottom Line
3 Major Points
4 Guidelines
5 Design
6 Population
6.1 Inclusion Criteria
6.2 Exclusion Criteria
6.3 Baseline Characteristics
7 Interventions
8 Outcomes
8.1 Primary Outcomes
8.2 Secondary Outcomes
9 Criticisms
10 Funding
11 Further Reading

Clinical Question

In patients with heart failure already treated with prescribed therapy including ACE inhibitors and beta-blockers, does the addition of valsartan improve mortality and morbidity?

Bottom Line

Valsartan significantly reduced the combined endpoint of mortality and morbidity in heart failure patients when added to prescribed therapy, without affecting overall mortality. However, it had an adverse effect on mortality in the subgroup receiving valsartan in combination with both an ACE inhibitor and a beta-blocker.

Major Points

Despite the use of angiotensin-converting–enzyme (ACE) inhibitors and beta-blockers, heart failure remains a major cause of hospitalization and mortality. Valsartan, an angiotensin-receptor blocker, was tested to see if it could further reduce morbidity and mortality in heart failure patients already on optimal therapy.



A post hoc analysis raised safety concerns about the specific combination of valsartan, an ACE inhibitor, and a beta-blocker, showing an adverse effect on mortality and morbidity in this subgroup.

Guidelines

Design

- Randomized, placebo-controlled, double-blind, parallel-group trial
- N=5,010 patients with heart failure of NYHA class II, III, or IV
- Interventions:
- Valsartan (n=2,511), initiated at 40 mg twice daily, up titrated to a target of 160 mg twice daily
- Placebo (n=2,499)
- Primary outcomes: Mortality and the combined endpoint of mortality and morbidity

Population

Inclusion Criteria

- Aged ≥18 with heart failure for at least three months
- NYHA class II, III, or IV
- Clinically stable on fixed-dose heart failure medication regimen for at least two weeks
- Left ventricular ejection fraction <40%
- Left ventricular dilatation

Exclusion Criteria

- Contraindications to valsartan
- Current use of angiotensin-receptor blockers

Baseline Characteristics

- Mean age: 61.8 years
- 23% female
- Approx. 93% on ACE inhibitors, 35% on beta-blockers at baseline

Interventions

- Valsartan or placebo, with the dose progressively titrated to target based on blood pressure, absence of hypotension symptoms, and kidney function.

Outcomes

Primary Outcomes

- Overall mortality similar in two groups
- Combined endpoint of mortality and morbidity 13.2% lower with valsartan (P=0.009)

Secondary Outcomes

- Reduction in hospitalizations for heart failure with valsartan
- Improvements in NYHA class, ejection fraction, signs and symptoms of heart failure, and quality of life (P<0.01)

Criticisms

- The unexpected post hoc finding of an increased risk of mortality in the subgroup receiving valsartan, an ACE inhibitor, and a beta-blocker raises concerns about the safety of this combination.

Funding

Supported by a grant from Novartis Pharma, Basel, Switzerland.

Further Reading

N/A