Val-HeFT

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Cohn JN, et al. "A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure". New England Journal of Medicine. 2001. 345(23):1667-75.
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Clinical Question

In patients with HFrEF and NHYA class II-IV symptoms, what is the efficacy of valsartan in addition to standard therapy in decreasing morbidity and mortality?

Bottom Line

In a time when HFrEF therapy included ACE inhibitors but not beta blockers, addition of valsartan to standard HFrEF therapy did not improve survival but reduced the incidence of the composite endpoint of morbidity and mortality, largely through a decrease in HF hospitalizations.

Major Points

ACE inhibitors became the standard of care in HFrEF management following publication of CONSENSUS (1987) and SOLVD (1991). Beta blockers joined a decade later with publication of CIBIS-II (1999), MERIT-HF (1999), and COPERNICUS (2002). The role of ARBs was not clear in this disease.

The 2001 Valsartan Heart Failure Trial (Val-HeFT) provided an interesting window to the role of ARB therapy in HFrEF. The trial randomized 5,010 with LVEF <40% to valsartan or placebo. >90% of the patients were on ACE-inhibitors but only 25% were on metoprolol or carvedilol. Addition of valsartan did not provide a survival benefit but did reduce a combined morbidity outcome, though it was driven by a reduction in HF hospitalizations. A post-hoc subgroup analysis found increased mortality in individuals on valsartan, ACE inhibitor therapy, and beta blockers.

The 2003 CHARM-Added trial studied the use of ACE inhibitors plus the ARB candesartan in patients with HFrEF. The population in this trial had a higher rate of beta blocker use. Add-on ARB therapy was found to reduce CV mortality or HF hospitalizations over ACE inhibitor therapy alone.

Guidelines

AHA/ACCF Heart Failure (2013, adapted)[1]

  • ACE inhibitors in patients with HFrEF with present or former symptoms unless contraindicated (class I, level A)
  • ARBs for above if ACE inhibitor intolerant unless contraindicated (class I, level A)
  • ARBs are reasonable as first-line agents for HFrEF (class IIa, level A)
  • ARBs can be added to ACE inhibitor and beta blocker for those in which an aldosterone antagonist is not indicated or is poorly tolerated (class IIb, level A)
  • Routine combined ACE inhibitor and ARB use is potentially harmful in HFrEF (class III, level C)

Design

  • Multicenter, double-blinded, parallel-group, randomized, placebo-controlled trial
  • N=5,010
    • Valsartan (n=2,511)
    • Placebo (n=2,499)
  • Setting: 302 centers in 16 countries
  • Mean follow-up: 23 months
  • Primary outcomes:
    • All-cause mortality
    • All-cause mortality, cardiac arrest with resuscitation, HF hospitalization, IV inotropic agents, or IV vasodilator therapies

Population

Inclusion Criteria

  • Age ≥18 years
  • History and exam findings of HF ≥3 months prior to screening
  • NYHA class II-IV with compensated heart failure
  • Receipt of a fixed dose of medical therapy (ACE inhibitors, diuretics, digoxin, and/or beta blockers) for ≥2 weeks
  • EF <40% and LV dilatation

Exclusion Criteria

  • Pregnancy, nursing mothers, or women of child-bearing potential not using contraception, postpartum cardiomyopathy
  • Cor pulmonale
  • Decompensated HF
  • ACS
  • Cardiac surgery or PCTA within past 3 months
  • History of heart transplant or listed for heart transplant
  • CAD likely to require intervention
  • Sustained VT with syncope within past 3 months
  • Hemodynamically significant valvular disease
  • Hypertrophic cardiomyopathy
  • Stroke within 3 months
  • Clinically significant renal failure (Cr >2.5), hepatic failure, or hematologic disorder
  • Malignancies limiting 5 year survival
  • <5 year life expectancy
  • Contraindication to ARBs
  • Prior double-blind treatment in a valsartan HF trial
  • Any investigational drug trial within 30 days
  • Noncompliance
  • Treatment with class 1C agents, IV inotropes or vasodilators, or AII antagonists in past 3 months.

Baseline Characteristics

From the valsartan group except where specified. Groups were similar.

  • Demographics: Age 62 years, male 80%, White race 90%, Black race 7%
  • PMH: DM 26%, AF 12%
  • Baseline health data: BP 123/76 mmHg
  • HF data:
    • LVEF 27%
    • LV internal diastolic diameter 3.7 cm/m2
    • Etiology: CAD 58%, idiopathic 31%, HTN 6%, other 5%
    • NYHA class: II 62%, III 36%, IV 2%
  • Baseline medications: Diuretic 86%, digoxin 67%, beta blocker 34% (carvedilol 15%, metoprolol 12%, atenolol 3%), ACE inhibitor 93%
    • Daily ACE inhibitor doses (all patients): Enalapril 17 mg, lisinopril 19 mg, captopril 80 mg, ramipril 6 mg, quinapril 23 mg

Interventions

  • Single-blind run-in with twice daily placebo
  • Randomization to a group with stratification to beta blocker use:
    • Valsartan - Begun at 40 mg PO BID then doubled every 2 weeks until target dose of 160 mg PO BID was achieved
    • Placebo - Similar increase in dosing
  • Intervention doses were uptitrated if SBP ≥90 mmHg while standing, no hypotension symptoms, serum creatinine <2.0 mg/dL or <50% increase from baseline

Outcomes

Comparisons are valsartan vs. placebo.

Primary Outcomes

All-cause mortality
19.7% vs. 19.4% (RR 1.02; 95% CI 0.88–1.18; P=0.80)
All-cause mortality, cardiac arrest with resuscitation, HF hospitalization, IV inotropic agents, or IV vasodilator therapies
28.8% vs. 32.1% (RR 0.87; 95% CI 0.77–0.97; P=0.009)

Secondary Outcomes

HF hospitalizations
13.8% vs. 18.2% (P<0.001)
Cardiac arrest with resuscitation
0.6% vs. 1.0%
IV inotropic or IV vasodilator therapies
0.2% vs. 0.2%
Risk of hospitalization
RR 0.83 (P<0.001)
EF change
4% vs. 3.2% (P=0.001)
NYHA class
Improvement: 23.1% vs. 20.7% (P<0.001)
Worsening: 10.1% vs. 12.8% (P<0.001)
Dyspnea, fatigue, edema, rales
Improved with valsartan (P<0.01)
Score change on Minnesota Living with Heart Failure questionnaire
No change vs. 1.9 points worse (P=0.005)

Additional Analyses

Dose achieved
254 vs. 283 mg
SBP change
Four months: -5.2 vs. -1.2 mmHg (significant, no P given)
One year: -5.2 vs. -1.3 mmHg (significant, no P given)
Change in laboratory values
Potassium: +0.12 vs. -0.07 mmol/L (P<0.001)
Creatinine: +0.18 vs. +0.10 mg/dL (P<0.001)
BUN: +5.9 vs. +3.3 mg/dL (P<0.001)

Subgroup Analysis

There was no significant interaction for the combined primary outcome when comparing age, sex, DM, CAD, LVEF above or below median, NYHA class, or race.

Mortality
Baseline therapy +ACE, -beta-blocker: No difference
Baseline therapy +ACE, +beta-blocker: Placebo better (P=0.009)
Baseline therapy -ACE, -beta-blocker: Valsartan better (P=0.012)
Baseline therapy -ACE, +beta-blocker: No difference

Adverse Events

Adverse event leading to discontinuation
9.9% vs. 7.2% (P<0.001)
Dizziness: 1.6% vs. 0.4% (P<0.001)
Hypotension: 1.3% vs. 0.8% (P=0.124)
Renal impairment: 1.1% vs. 0.2% (P<0.001)

Criticisms

  • Unclear clinical relevance of increased rate of hypotension leading to discontinuation in the valsartan group[2]
  • Measurement of of angiotensin II levels may help delineate individuals unlikely to benefit to add-on ARB therapy on other HF regimens[2]
  • Low dosing of ACE inhibitors at baseline[2]

Funding

Novartis Pharmaceuticals, the makers of Diovan (the brand name of valsartan)

Further Reading

  1. Yancy CW, et al. "2013 ACCF/AHA guideline for the management of heart failure." Circulation. 2013;128:e240-e327.
  2. 2.0 2.1 2.2 Multiple authors. "Correspondence: Valsartan in chronic heart failure." The New England Journal of Medicine. 2002;346:1173-1174.