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

1
CHARM Added Candesartan in Heart failure
Assessment of Reduction in Mortality and
morbidity - Added

• Purpose
• To determine whether addition of the angiotensin
  II receptor blocker candesartan is beneficial in
  patients with chronic heart failure (CHF) who are
  taking angiotensin converting enzyme (ACE)
  inhibitors
• Reference
• McMurray JJV, Östergren J, Swedberg K, et al.
  for the CHARM Investigators and Committees.
  Effects of candesartan in patients with chronic
  heart failure and reduced left-ventricular
  systolic function taking angiotensin-converting-en
  zyme inhibitors the CHARM-Added trial. Lancet
  200336276771.

2
CHARM Added Candesartan in Heart failure
Assessment of Reduction in Mortality and
morbidity - Added- TRIAL DESIGN -

• Design
• Multicenter, multinational, randomized,
  double-blind, placebo-controlled
• Patients
• 2548 patients aged gt18 years with symptomatic
  CHF (NYHA class IIIV), who had left ventricular
  ejection fraction lt40 and were receiving ACE
  inhibitors
• Follow up and primary endpoint
• Primary endpoint cardiovascular death or
  hospital admission for CHF. Median 41 months
  follow up.
• Treatment
• Placebo or candesartan titrated to 32 mg once
  daily

3
CHARM Added Candesartan in Heart failure
Assessment of Reduction in Mortality and
morbidity - Added- TRIAL DESIGN continued-
Baseline characteristics ()

Age (years)a
History
MI
Male
Diabetes mellitus
NYHA class
II
Hypertension
III
IV
Medications
Systolic BP (mmHg)a
ACE inhibitor
Diuretic
Heart failure cause
Beta-blocker
Ischemic
Spironolactone
Idiopathic
Hypertensive
Aspirin
McMurray et al. Lancet 200336276771.
a
Mean
4
CHARM Added Candesartan in Heart failure
Assessment of Reduction in Mortality and
morbidity - Added- RESULTS -

• Primary outcome of cardiovascular death or
  hospital admission for CHF significantly reduced
  in candesartan group compared with placebo (37.9
  vs. 42.3, hazard ratio 0.85, 95 CI 0.750.96,
  P0.011) each component was reduced
  significantly
• Secondary outcomes composites of primary
  outcome and MI, nonfatal stroke and coronary
  revascularization also significantly reduced
• All-cause mortality not significantly reduced (30
  vs. 32, hazard ratio 0.89, 95 CI 0.771.02,
  P0.086)
• Benefits similar in patients taking beta-blockers
  and those who were not (P0.14 for treatment
  interaction), and regardless of whether
  recommended dose of ACE inhibitor achieved
  (P0.26)
• Permanent discontinuation due to adverse event or
  laboratory abnormality more frequent with
  candesartan (24.2 vs. 18.3, P0.0003)

5
CHARM Added Candesartan in Heart failure
Assessment of Reduction in Mortality and
morbidity - Added- RESULTS continued -
Cardiovascular death or hospital admission for CHF
Proportion
50
with event
()
40
30
20
Hazard ratio 0.85 (95 CI 0.750.96)
10
P 0.011
0
0
1.0
2.0
3.0
3.5
Years after randomization
McMurray et al. Lancet 200336276771.
6
CHARM Added Candesartan in Heart failure
Assessment of Reduction in Mortality and
morbidity - Added- RESULTS continued -
Primary and secondary outcomes
Candesartan
Placebo
Hazard ratio
P
(n1276)
(n1272)
(95 CI)
No.
()
No.
()
Cardiovascular death or
0.85 (0.750.96)
0.011
483
(37.9)
538
(42.3)
hospital admission for CHF
Cardiovascular death, hospital
0.85 (0.760.96)
0.010
495
(38.8)
550
(43.2)
admission for CHF, or MI
Cardiovascular death, hospital
0.87 (0.770.98)
0.020
512
(40.1)
559
(43.9)
admission for CHF, MI,
or stroke
Cardiovascular death, hospital
0.87 (0.770.97)
0.015
548
(42.9)
596
(46.9)
admission for CHF, MI, stroke,
or coronary revascularization
McMurray et al. Lancet 200336276771.
7
CHARM Added Candesartan in Heart failure
Assessment of Reduction in Mortality and
morbidity - Added- RESULTS continued -
Cardiovascular death or hospital admission for
CHF in relation to
concomitant treatment at baseline
Candesartan
Placebo
P for treatment interaction
Candesartan better
Placebo better
No. of events/n
No. of events/n
ß-blocker
Yes
223/702
0.14
274/711
No
260/574
264/561
Recommended dose
of ACE inhibitor
Yes
232/643
0.26
275/648
No
251/633
263/624
All patients
483/1276
538/1272
0.8
0.6
1.0
1.2
McMurray et al. Lancet 200336276771.
8
CHARM Added Candesartan in Heart failure
Assessment of Reduction in Mortality and
morbidity - Added- SUMMARY -

• In patients with symptomatic CHF who were taking
  ACE inhibitors, candesartan reduced
• Cardiovascular death and hospitalization for CHF
• Secondary outcomes that combined these with MI,
  stroke and coronary revascularization procedures
• Benefit was independent of concurrent
  beta-blocker therapy and ACE inhibitor dose