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CLINICAL RESEARCH: HEART FAILURE

Incidence and Predictors of Hyperkalemia in Patients With Heart Failure

An Analysis of the CHARM Program

Akshay S. Desai, MD^_*,_*, Karl Swedberg, MD, PhD, FACC, John J.V. McMurray, MD, FACC, Christopher B. Granger, MD, FACC, Salim Yusuf, MD, Dphil, FACC^||, James B. Young, MD, FACC^¶, Mark E. Dunlap, MD, FACC^#, Scott D. Solomon, MD^_*, James W. Hainer, MD^_**, Bertil Olofsson, PhD, Eric L. Michelson, MD, FACC^_**, Marc A. Pfeffer, MD, PhD, FACC^_* on behalf of the CHARM Program Investigators

^_* Department of Cardiology, Brigham and Women’s Hospital, Boston, Massachusetts
Emergency and Cardiovascular Medicine, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden
Department of Cardiology, Western Infirmary, Glasgow, Scotland
Department of Cardiology, Duke University Medical Center, Durham, North Carolina
^|| Department of Medicine, HGM-McMaster Clinic, Hamilton, Ontario, Canada
^¶ Department of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio
^# Department of Cardiology, Case Western Reserve University and VA Medical Center, Cleveland, Ohio
^_** AstraZeneca LP, Wilmington, Delaware
AstraZeneca R&D, Mölndal, Sweden

Manuscript received June 19, 2007; revised manuscript received July 26, 2007, accepted July 31, 2007.

^_* Reprint requests and correspondence: Dr. Akshay S. Desai, PBB-A3, AB370, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115. (Email: adesai{at}partners.org).

Objectives: We explored the incidence and predictors of hyperkalemia in a broad population of heart failure patients.

Background: When used in optimal doses to treat patients with heart failure, renin-angiotensin-aldosterone system (RAAS) inhibitors improve clinical outcomes but can cause hyperkalemia.

Methods: Participants in the CHARM (Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity) (n = 7,599) Program were randomized to standard heart failure therapy plus candesartan or placebo, titrated as tolerated to a target of 32 mg once daily with recommended monitoring of serum potassium and creatinine. We assessed the incidence and predictors of hyperkalemia associated with dose reduction, study drug discontinuation, hospitalization, or death over the median 3.2 years of follow-up.

Results: Independent of treatment assignment, the risk of hyperkalemia increased with age 75 years, male gender, diabetes, creatinine 2.0 mg/dl, K⁺ 5.0 mmol/l, and background use of angiotensin-converting enzyme inhibitors or spironolactone. Candesartan increased the rate of aggregate hyperkalemia from 1.8% to 5.2% (difference 3.4%, p < 0.0001) and serious hyperkalemia (associated with death or hospitalization) from 1.1% to 1.8% (difference 0.7%, p < 0.001), with hyperkalemia associated with death reported in 2 (0.05%) candesartan patients and 1 (0.03%) placebo patient. The benefit of candesartan in reducing cardiovascular death or heart failure hospitalization (relative risk reduction 16%, p < 0.0001) was uniform in these subgroups, as was the incremental risk of hyperkalemia.

Conclusions: The risk of hyperkalemia is increased in symptomatic heart failure patients with advanced age, male gender, baseline hyperkalemia, renal failure, diabetes, or combined RAAS blockade. Although these groups derive incremental clinical benefit from candesartan, careful surveillance of serum potassium and creatinine is particularly important.

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   ARB = angiotensin receptor blocker   CI = confidence interval   CV = cardiovascular   eGFR = glomerular filtration rate estimated by the Modification of Diet in Renal Disease method   HF = heart failure   LVEF = left ventricular ejection fraction   OR = odds ratio   RAAS = renin-angiotensin-aldosterone system

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