Published online before print October 18, 2004, doi: 10.1161/01.CIR.0000146819.43235.A9
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(Circulation. 2004;110:2618-2626.)
© 2004 American Heart Association, Inc.
Heart Failure |
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
From The Cleveland Clinic Foundation and Kaufman Center for Heart Failure, Cleveland, Ohio (J.B.Y.); Case Western Reserve University, Cleveland (M.E.D.); Brigham and Women’s Hospital, Boston, Mass (M.A.P., S.D.S.); University of Washington, Seattle (J.L.P.); Hopital Beaujon, Clichy, France (A.C.-S.); Max-Delbrueck-Center Berlin-Buch, Berlin, Germany (R.D.); Duke University Medical Center, Durham, NC (C.B.G.); Charles University, Prague, Czech Republic (J.H.); Warsaw School of Medicine, Poland (J.K.); Hamilton General Hospital, Hamilton, Calif (R.M., S.Y.); University of Glasgow, UK (J.J.V.M.); AstraZeneca LP, Wilmington, Del (E.L.M.); AstraZeneca R&D Molndal, Sweden (B.O., P.H.); Karolinska Hospital, Stockholm, Sweden (J.O.); Sahlgrenska University Hospital/Ostra, Göteberg, Sweden (K.S.).
Correspondence to Dr James B. Young, Chairman, Division of Medicine, The Cleveland Clinic Foundation, 9500 Euclid Avenue T-13, Cleveland, OH 44195. E-mail youngj{at}ccf.org
Received June 30, 2004; revision received June 30, 2004; accepted August 4, 2004.
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, ß-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.
Methods and Results— New York Heart Association (NYHA) class II through IV CHF patients with an LVEF of 
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, ß-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%), respectivelyt (all P<0.001).
Conclusion— Candesartan significantly reduces all-cause mortality, cardiovascular death, and heart failure hospitalizations in patients with CHF and LVEF 40% when added to standard therapies including ACE inhibitors, ß-blockers, and an aldosterone antagonist. Routine monitoring of blood pressure, serum creatinine, and serum potassium is warranted.
Key Words: heart failure • ventricles • angiotensin-converting enzyme inhibitors • adrenergic beta-antagonists • aldosterone antagonists
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