CHARM-Preserved:Candesartan in Heart failure: Assessment of

Reduction in Mortality and morbidity - Preserved

Purpose

To determine whether the angiotensin II receptor blocker candesartan is beneficial in patients with chronic heart failure (CHF) and preserved left ventricular systolic function

ReferenceYusuf S, Pfeffer MA, Swedberg K, et al. for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved trial. Lancet 2003;362:777–81.

CHARM-Preserved:Candesartan in Heart failure: Assessment of

Reduction in Mortality and morbidity - Preserved- TRIAL DESIGN -

DesignMulticenter, multinational, randomized, double-blind, placebo-controlled

Patients3023 patients aged >18 years with symptomatic CHF (NYHA class II–IV), who had left ventricular ejection fraction >40%

Follow up and primary endpointPrimary endpoint: cardiovascular death or hospital admission for CHF. Median 36.6 months follow up.

TreatmentPlacebo or candesartan titrated to 32 mg once daily

CHARM-Preserved:Candesartan in Heart failure: Assessment of

Reduction in Mortality and morbidity - Preserved- TRIAL DESIGN continued-

Age (years)a

Male

NYHA class:IIIIIIV

LVEF41–49%50–59%>60%

BP (mmHg)a

SystolicDiastolic

HistoryMIDiabetes mellitusHypertension

Baseline characteristics (%)

67.1

136.377.8

59

60391

363431

Placebo(n=1509)

67.2

136.077.8

61

62372

353629

Candesartan(n=1514)

Yusuf et al. Lancet 2003;362:777–81.aMean

MedicationsACE inhibitorBeta-blockerSpironolactoneAspirinLipid-lowering drug

Heart failure causeIschemicIdiopathicHypertensive

442864

Placebo(n=1509)

1956125943

57923

452965

2056115841

56922

Candesartan(n=1514)

CHARM-Preserved:Candesartan in Heart failure: Assessment of

Reduction in Mortality and morbidity - Preserved- RESULTS -

• Nonsignificant trend to reduction in primary outcome of cardiovascular death or hospital admission for CHF in candesartan group compared with placebo (22 vs. 24.3%, P=0.118)

• Secondary outcomes – composites of primary outcome and MI, nonfatal stroke and coronary revascularization – also showed nonsignificant trend

• Total number of hospital admissions for CHF significantly reduced in candesartan group (402 vs. 566, P=0.014)

• All-cause mortality similar in both groups (244 vs. 237 patients)• Permanent discontinuation due to adverse event or laboratory

abnormality more frequent with candesartan (17.8 vs. 13.5%, P=0.001)

CHARM-Preserved: Candesartan in Heart failure: Assessment of

Reduction in Mortality and morbidity - Preserved- RESULTS continued -

Years after randomization

Proportionwith event

(%)

00

1.0 2.0 3.0 3.5

10

20

30

40

50

Cardiovascular death or hospital admission for CHF

Yusuf et al. Lancet 2003;362:777–81.

Hazard ratio 0.89(95% CI 0.77–1.03)P = 0.118

Placebo

Candesartan

CHARM-Preserved: Candesartan in Heart failure: Assessment of

Reduction in Mortality and morbidity - Preserved- RESULTS continued -

P

Cardiovascular death orhospital admission for CHF

0.89 (0.77–1.03) 0.118

Primary and secondary outcomes

333

No.

(22.0)

(%)

Candesartan(n=1514)

366

No.

(24.3)

Cardiovascular death 0.99 (0.80–1.22) 0.918170 (11.2)170 (11.3)Hospital admission for CHF 0.85 (0.72–1.01) 0.072241 (15.9)276 (18.3)

Cardiovascular death, hospitaladmission for CHF, or MI

0.90 (0.78–1.03) 0.126365 (24.1)399 (26.4)

Cardiovascular death, hospitaladmission for CHF, MI,or stroke

0.88 (0.77–1.01) 0.078388 (25.6)429 (28.4)

Cardiovascular death, hospitaladmission for CHF, MI, stroke,or coronary revascularization

0.91 (0.80–1.03) 0.123460 (30.4)497 (32.9)

(%)

Placebo(n=1509) Hazard ratio

(95% CI)

Yusuf et al. Lancet 2003;362:777–81.

CHARM-Preserved:Candesartan in Heart failure: Assessment of

Reduction in Mortality and morbidity - Preserved- RESULTS continued -

PCause of discontinuation

Discontinuation because of adverse events

No. (%)

Candesartan(n=1514)

No.

Hypotension 0.00937 (2.4)17 (1.1)

Increase in creatinine 0.000572 (4.8)36 (2.4)

Hyperkalemia 0.02922 (1.5)9 (0.6)

Any adverse event or laboratory abnormality 0.001270 (17.8)204 (13.5)

(%)

Placebo(n=1509)

Yusuf et al. Lancet 2003;362:777–81.

CHARM-Preserved:Candesartan in Heart failure: Assessment of

Reduction in Mortality and morbidity - Preserved- SUMMARY -

In patients who had symptomatic CHF and preserved left ventricular systolic function, with candesartan there was no significant reduction of the following, although the trend was favorable:

• Cardiovascular death or hospitalization for CHF• Secondary outcomes that combined these with MI, stroke and

coronary revascularization procedures

However, the total number of hospital admissions for CHF was significantly reduced in the candesartan group.