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

1
Relationship of background ACEI dose to benefits
of candesartan in the CHARM-Added trial
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CHARM-Added Study design
Candesartan in Heart failure Assessment of
Reduction in Mortality and morbidity (CHARM)-Added
Randomized, double-blind NYHA class IIIV, LVEF
40, stable ACEI dose for 30 days N 2548
Candesartan 32 mg qd n 1276
Placebo n 1272
Median follow-up 41 months
Primary outcome CV death or hospitalization for
HF
ACEI angiotensin-converting enzyme inhibitor
McMurray JJV et al. Lancet. 2003362761-71.
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CHARM-Added Baseline characteristics by ACEI dose
ltFDA maximum dose (n 2019) FDA maximum dose (n 529)
Male () Mean BP (mm Hg) NYHA class () II III IV Medical history () HF hospitalization MI Angina Hypertension Diabetes 78 125/75 25 72 3.2 77 57 53 46 29 81 126/75 22 76 2.5 76 50 52 56 34

McMurray JJV et al. Am Heart J. 2006151985-91.
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CHARM-Added Daily ACEI dose
Subgroup analysis, most commonly used ACEIs
All patients(N 2548)
Recommended(CHARM prespecified)(n 1291)
Maximum (FDA)(n 529)
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
Based on European Society of Cardiology
guidelines Not indicated for heart failure
McMurray JJV et al. Am Heart J. 2006151985-91.
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CHARM-Added Primary outcome of CV death or HF
hospitalization
N 2548
Patients (n)
Candesartan better
Placebo better
P value for interaction
0.26 0.29
Recommended dose of ACEI CHARM
prespecified Maximum dose of ACEI FDA
2005 CHARM-Added CHARM-Alternative Pooled results
(low LVEF patients)
No Yes No Yes
1257 1291 2019 529 2548 2028 4576
0.6
0.8
1
1.2
Hazard ratio (95 Cl)
McMurray JJV et al. Am Heart J. 2006151985-91.
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CHARM-Added Primary outcome in patients taking a
?-blocker
n 1413
Patients (n)
Candesartan better
Placebo better
P value for interaction
0.69 0.64
CV death or HF hospitalization Recommended dose
of ACEI CHARM prespecified Maximum dose of
ACEI FDA 2005 All patients
No Yes No Yes
692 721 1100 313 1413
0.6
0.8
1
1.2
Hazard ratio (95 Cl)
McMurray JJV et al. Am Heart J. 2006151985-91.
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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. 2006151985-91.