Mortality and morbidity reduction with Candesartan in patients with chronic heart failure and left ventricular systolic dysfunction: results of the CHARM low-left ventricular ejection fraction trials.
BACKGROUND
Patients with symptomatic chronic heart failure (CHF) and reduced left ventricular ejection fraction (LVEF) have a high risk of death and hospitalization for CHF deterioration despite therapies with angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and even an aldosterone antagonist. To determine whether the angiotensin-receptor blocker (ARB) candesartan decreases cardiovascular mortality, morbidity, and all-cause mortality in patients with CHF and depressed LVEF, a prespecified analysis of the combined Candesartan in Heart Failure Assessment of Reduction in Mortality and morbidity (CHARM) low LVEF trials was performed. CHARM is a randomized, double-blind, placebo-controlled, multicenter, international trial program.


RESULTS
New York Heart Association (NYHA) class II through IV CHF patients with an LVEF of < or =40% were randomized to candesartan or placebo in 2 complementary parallel trials (CHARM-Alternative, for patients who cannot tolerate ACE inhibitors, and CHARM-Added, for patients who were receiving ACE inhibitors). Mortality and morbidity were determined in 4576 low LVEF patients (2289 candesartan and 2287 placebo), titrated as tolerated to a target dose of 32 mg once daily, and observed for 2 to 4 years (median, 40 months). The primary outcome (time to first event by intention to treat) was cardiovascular death or CHF hospitalization for each trial, with all-cause mortality a secondary end point in the pooled analysis of the low LVEF trials. Of the patients in the candesartan group, 817 (35.7%) experienced cardiovascular death or a CHF hospitalization as compared with 944 (41.3%) in the placebo group (HR 0.82; 95% CI 0.74 to 0.90; P<0.001) with reduced risk for both cardiovascular deaths (521 [22.8%] versus 599 [26.2%]; HR 0.84 [95% CI 0.75 to 0.95]; P=0.005) and CHF hospitalizations (516 [22.5%] versus 642 [28.1%]; HR 0.76 [95% CI 0.68 to 0.85]; P<0.001). It is important to note that all-cause mortality also was significantly reduced by candesartan (642 [28.0%] versus 708 [31.0%]; HR 0.88 [95% CI 0.79 to 0.98]; P=0.018). No significant heterogeneity for the beneficial effects of candesartan was found across prespecified and subsequently identified subgroups including treatment with ACE inhibitors, beta-blockers, an aldosterone antagonist, or their combinations. The study drug was discontinued because of adverse effects by 23.1% of patients in the candesartan group and 18.8% in the placebo group; the reasons included increased creatinine (7.1% versus 3.5%), hypotension (4.2% versus 2.1%), and hyperkalemia (2.8% versus 0.5%), respectively (all P<0.001).


CONCLUSIONS
Candesartan significantly reduces all-cause mortality, cardiovascular death, and heart failure hospitalizations in patients with CHF and LVEF < or =40% when added to standard therapies including ACE inhibitors, beta-blockers, and an aldosterone antagonist. Routine monitoring of blood pressure, serum creatinine, and serum potassium is warranted.
Young
James B
JB
Division of Medicine, The Cleveland Clinic Foundation and Kaufman Center for Heart Failure, 9500 Euclid Avenue T-13, Cleveland, OH 44195, USA. youngj@ccf.org
Dunlap
Mark E
ME
Pfeffer
Marc A
MA
Probstfield
Jeffrey L
JL
Cohen-Solal
Alain
A
Dietz
Rainer
R
Granger
Christopher B
CB
Hradec
Jaromir
J
Kuch
Jerzy
J
McKelvie
Robert S
RS
McMurray
John J V
JJ
Michelson
Eric L
EL
Olofsson
Bertil
B
Ostergren
Jan
J
Held
Peter
P
Solomon
Scott D
SD
Yusuf
Salim
S
Swedberg
Karl
K
D000368:Aged; D047228:Angiotensin II Type 1 Receptor Blockers / Q000037:antagonists & inhibitors*; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D002303:Cardiac Output, Low / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality*; D002908:Chronic Disease; D005260:Female; D006760:Hospitalization; D006801:Humans; D008297:Male; D016032:Randomized Controlled Trials as Topic; D013318:Stroke Volume; D013599:Systole; D013777:Tetrazoles / Q000627:therapeutic use*; D018487:Ventricular Dysfunction, Left / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality*
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; C081643:candesartan