on October 18, 2004
Published online before print October 18, 2004, doi: 10.1161/01.CIR.0000146819.43235.A9
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Submitted on June 30, 2004
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.). * To whom correspondence should be addressed. E-mail: youngj{at}ccf.org.
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, Methods and Results--New York Heart Association (NYHA) class II through IV CHF patients with an LVEF of Conclusion--Candesartan significantly reduces all-cause mortality, cardiovascular death, and heart failure hospitalizations in patients with CHF and LVEF
Revised on June 30, 2004
Accepted on August 4, 2004
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
James B. Young MD*,
-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.
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, -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).40% when added to standard therapies including ACE inhibitors, -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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