Relationship of background ACEI dose to benefits of candesartan in the CHARM-Added trial

CHARM-Added: Study design

McMurray JJV et al. Lancet. 2003;362:761-71.

Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Added

Randomized, double-blindNYHA class II–IV, LVEF ≤40%, stable ACEI dose for ≥30 days

N = 2548

Candesartan 32 mg qdn = 1276

Placebo n = 1272

Median follow-up: 41 months

Primary outcome: CV death or hospitalization for HF

ACEI = angiotensin-converting enzyme inhibitor

CHARM-Added: Baseline characteristics by ACEI dose

<FDA maximum dose(n = 2019)

≥FDA maximum dose(n = 529)

Male (%)Mean BP (mm Hg) NYHA class (%)

IIIIIIV

Medical history (%)HF hospitalizationMIAngina HypertensionDiabetes

78125/75

25723.2

7757534629

81126/75

22762.5

7650525634

McMurray JJV et al. Am Heart J. 2006;151:985-91.

CHARM-Added: Daily ACEI dose

McMurray JJV et al. Am Heart J. 2006;151:985-91.

*Based on European Society of Cardiology guidelines †Not indicated for heart failure

ACEI(86% of patients)

Meandose

(mg/day)% onRx

Meandose

(mg/day)Patients

(%)

Meandose

(mg/day)Patients

(%)

Enalapril 17 27 20 52 40 10

Lisinopril 18 19 20 52 20 52

Captopril 83 17 150 21 300 2

Ramipril 7 11 10 39 10 39

Trandolapril 2.5 6 2 90 4 27

Perindopril† 4 6 4 83 16 1

Subgroup analysis, most commonly used ACEIs

≥Recommended(CHARM prespecified)*

(n = 1291)

≥Maximum (FDA)

(n = 529)All patients(N = 2548)

CHARM-Added: Primary outcome of CV death or HF hospitalizationN = 2548

McMurray JJV et al. Am Heart J. 2006;151:985-91.

Recommended dose of ACEICHARM prespecified

Maximum dose of ACEIFDA 2005

CHARM-Added

CHARM-Alternative

Pooled results (low LVEF patients)

NoYes

NoYes

12571291

2019529

2548

2028

4576

0.26

0.29

Patients (n)

Candesartan better

Placebo better

P value for interaction

0.6 0.8 1 1.2

Hazard ratio (95% Cl)

CHARM-Added: Primary outcome in patients taking a -blocker

McMurray JJV et al. Am Heart J. 2006;151:985-91.

n = 1413

CV death or HF hospitalizationRecommended dose of ACEI CHARM prespecified

Maximum dose of ACEI FDA 2005

All patients

NoYes

NoYes

692721

1100313

1413

0.69

0.64

Patients (n)

Candesartan better

Placebo better

P value for interaction

0.6 0.8 1 1.2

Hazard ratio (95% Cl)

Summary: CHARM-Added

• Candesartan reduced CV death or HF hospitalization in patients taking no ACEI, a moderate ACEI dose, or a high ACEI dose

• Benefits of candesartan in HF patients were not modified by either ACEI dose or concomitant therapy with a -blocker

• ACEIs and angiotensin receptor blockers (ARBs) have distinct and complementary mechanisms of action

• Combined use of an ACEI and the ARB, candesartan, improved outcomes in patients with HF vs ACE inhibition alone

McMurray JJV et al. Am Heart J. 2006;151:985-91.