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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).

	Abstract

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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

The CHARM (Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity) Program investigated the impact of treatment with the angiotensin receptor blocker (ARB) candesartan, both alone and in combination with an ACE inhibitor, across a broad spectrum of symptomatic HF patients, including those with both depressed and preserved left ventricular ejection fraction (LVEF) and those treated with various combinations of neurohumoral antagonists. Protocol-directed, serial monitoring of serum potassium and creatinine, as well as surveillance for serious adverse events (including hyperkalemia) permitted a quantitative assessment of risk in both placebo- and candesartan-assigned patients. We utilized the CHARM Program to investigate the incidence and predictors of hyperkalemia in a contemporary HF population managed with modern medical therapy.

	Methods

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The CHARM Program.   The design and overall results of the CHARM Program have been previously reported in detail (1). Eligible patients were women and men age 18 years or older who had symptomatic HF (New York Heart Association functional class II to IV) for at least 4 weeks’ duration. Major exclusion criteria included baseline serum creatinine 3 mg/dl (265 µmol/l); baseline serum potassium 5.5 mmol/l (mEq/l); history of marked ACE inhibitor-induced hyperkalemia resulting in either a serum potassium 6.0 mmol/l or a life-threatening adverse event; known bilateral renal artery stenosis, symptomatic hypotension, critical aortic or mitral stenosis; recent (within 4 weeks) myocardial infarction, stroke, or open heart surgery; and use of an ARB within 2 weeks of trial enrollment. Eligible, consented patients were enrolled into 1 of 3 trials according to LVEF higher than 40% (CHARM-Preserved, n = 3,023), 40% or lower and treated with an ACE inhibitor (CHARM-Added, n = 2,548), or 40% or lower and not treated with an ACE inhibitor due to prior intolerance (CHARM-Alternative, n = 2,028) (2–4). In CHARM-Added, investigators were instructed to use "individualized optimum doses" of ACE inhibitors based on doses proven effective in clinical outcomes trials and individual tolerability (2). Angiotensin-converting enzyme inhibitor use was left to the discretion of the investigator in CHARM-Preserved. The primary outcome for each of the component trials was cardiovascular (CV) death or unplanned admission to the hospital for management of worsening HF, which was also used as the primary outcome for this supplementary, retrospective analysis. Whereas serum creatinine and potassium were measured on the full cohort of 7,599 patients enrolled in CHARM-Overall, core laboratory values were recorded only for the subset of 2,675 patients enrolled from North America.

Study drug was dosed according to an incremental, biweekly, forced titration scheme. At randomization, study drug was initiated at 4 mg once daily (or at 8 mg once daily at the investigator’s discretion). The dose was then doubled every 2 weeks as tolerated up to a maximum target dose of 32 mg candesartan (or matching placebo) once daily. Visits were scheduled at 2, 4, and 6 weeks; 6 months; and then every 4 months until study end. Investigators were instructed to assess serum creatinine and potassium before drug initiation, within 2 weeks of dose escalation or completion of dose titration, yearly thereafter, and at their discretion. There were no prespecified mandates regarding the management of hyperkalemia. Follow-up was conducted over a minimum of 2 years, and a maximum of 4 years with median duration of 3.2 years.

For this analysis, the diagnosis of hyperkalemia was based not on a prespecified laboratory threshold, but on investigator assessments of when clinically important increases in serum potassium were present. Adverse events (serious or nonserious) that led to a dose reduction or discontinuation of study drug treatment, including hyperkalemia, were routinely reported on the case report forms. Narrative summaries of all hospitalization and death events in the CHARM Program were examined using a free text search to identify those that were associated with hyperkalemia, without regard to attribution of causality to treatment by the investigators. A post-hoc composite outcome of "clinically important hyperkalemia" was then defined to identify all hyperkalemia events requiring medical intervention, including hyperkalemia requiring study drug dose reduction, study drug discontinuation, or hospitalization or hyperkalemia causing death. This composite outcome was designed to reflect a more all-encompassing "worst-case" scenario definition for hyperkalemia in the absence of an effective monitoring strategy, making the conservative assumption that all dose reductions or discontinuations would have become serious events (hospitalization or death) had they not occurred.

Statistics.   We determined the incidence of clinically important hyperkalemia for both placebo- and candesartan-treated patients in CHARM-Overall and in each of the component CHARM trials. Odds ratios (ORs) and 95% confidence intervals (CIs) comparing treatments, stratified by trial and by subgroups, were derived using the Mantel-Haenszel method. Incidence rates (per 1,000 patient-years) were also calculated to account for variable exposure duration across the different CHARM trials. The composite hyperkalemia outcome and the clinical efficacy outcome of CV death or HF hospitalization were examined in subgroups according to baseline demographic factors and clinical features previously reported to increase risk for hyperkalemia (5) (age 75 years, male gender, diabetes, concurrent ACE inhibitor or spironolactone use, baseline creatinine 2.0 mg/dl, and baseline potassium 5.0 mmol/l), using a test for heterogeneity to assess for interactions between subgroup and treatment assignment. As baseline values of creatinine and potassium were available from the case report forms only for patients enrolled in North America, the analysis for these subgroups was confined to the North American study population. The time to development of clinically important hyperkalemia (and serious hyperkalemia) was analyzed using Cox proportional hazards models and displayed in standard Kaplan-Meier plots. Finally, Cox models including age 75 years, male gender, diabetes, ACE inhibitor or spironolactone use, and treatment assignment were utilized to examine the multivariate predictors of clinically important hyperkalemia. Models were extended to include baseline potassium and renal function (measured as both serum creatinine and as glomerular filtration rate estimated by the Modification of Diet in Renal Disease Method [eGFR] [6]) in the subset of patients for whom laboratory data were available. All analyses were conducted using SAS statistical software (Cary, North Carolina).

	Results

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The breakdown of adverse events associated with hyperkalemia reported for the overall CHARM Program is displayed in Table 1. Overall, clinically important hyperkalemia was noted in 1.8% of placebo-treated (6.6 events/1,000 patient-years) and 5.2% of candesartan-treated patients (18.5 events/1,000 patient-years) in CHARM-Overall, reflecting an excess absolute risk of 3.4% with candesartan therapy (11.9 events/1,000 patient-years). The excess of serious hyperkalemia events (hospitalization or death) was 0.7% (1.8% vs. 1.1% for placebo), reflecting a difference of 2.7 events/1,000 patient-years. Hyperkalemia associated with death was rare in the CHARM Program, and was reported for only 3 (0.04%) patients in the overall program, including 2 (0.05%) patients assigned to candesartan in the CHARM-Added trial, and 1 patient (0.03%) assigned to placebo in the CHARM-Alternative study.

View larger version (24K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Impact of Candesartan on Hyperkalemia Risk in CHARM-Overall, by Subgroups Subgroups assigned according to patient characteristics at baseline. Baseline values for serum potassium and creatinine were available only for the subset of patients enrolled in North America. ACE = angiotensin-converting enzyme.

View larger version (17K): [in this window] [in a new window] [Download PPT slide]   Figure 2 Impact of Candesartan on CV Death or HF Hospitalization, by Subgroups, CHARM-Overall Subgroups are identical to those in Figure 1. CV = cardiovascular; HF = heart failure; other abbreviations as in Figure 1.

View larger version (19K): [in this window] [in a new window] [Download PPT slide]   Figure 3 Cumulative Incidence of Significant Hyperkalemia, CHARM-Overall Solid lines represent candesartan-treated patients and dashed lines represent placebo-treated patients. "Any Hyperkalemia" (black) indicates hyperkalemia associated with dose reduction, dose discontinuation, hospitalization, or death. "Serious Hyperkalemia" (red) refers only to those hyperkalemia events associated with hospitalization or death. HR = hazard ratio (95% confidence interval).

	Discussion

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Subgroups at highest risk for hyperkalemia in the CHARM Program were those with advanced age, diabetes, male gender, high potassium at baseline, renal dysfunction (identified by creatinine 2 mg/dl or eGFR <45 cc/min/1.73 m²), and those receiving background therapy with ACE inhibitors or spironolactone. After adjusting for baseline potassium and renal function in multivariable models (for the subset of patients in whom data were available), the addition of candesartan to standard medical therapy for HF was associated with 2- to 3-fold increase in risk that was further amplified by cotreatment with ACE inhibitors or spironolactone. Combination RAAS blockade, therefore, should provoke special concern for hyperkalemia among clinicians, especially on the backdrop of renal dysfunction.

The ability of the kidney to maintain potassium homeostasis is critically dependent on adequate renal perfusion and sodium delivery to the distal nephron, normal aldosterone production, and normal function of aldosterone-sensitive potassium channels in the cortical collecting duct. Increases in dietary potassium load (e.g., through potassium supplementation), reduction in the filtered sodium load (as a consequence of intrinsic renal disease, nephrotoxins, hypovolemia, or reduced cardiac output), diminished aldosterone production (as a result of old age, diabetes, or drugs that inhibit renin release), or attenuated tissue responsiveness to aldosterone or decreased skeletal muscle uptake of potassium (as a consequence of aldosterone-blockade or beta-2 receptor blockade) may therefore precipitate hyperkalemia in the vulnerable patient. Since aldosterone production is decreased in the elderly, patients with diabetes, and in patients receiving drugs that block the production or action of renin (nonsteroidal anti-inflammatory drugs, renin inhibitors including beta-blockers) and angiotensin II (ACE inhibitors and ARBs), these groups are particularly vulnerable to the development of hyperkalemia with additional perturbations of potassium homeostasis. Progressive decline in glomerular filtration rate as a consequence of age-related nephron loss and comorbid medical illness further enhances the risk of hyperkalemia.

Hyperkalemia is a well-known complication of medical therapy for symptomatic HF (7). When used in optimal doses, several inhibitors of the RAAS reduce morbidity and mortality in this population, but also reduce potassium excretion, especially in those with pre-existing renal dysfunction (8). Fortunately, increases in serum potassium are typically modest (<1 mEq/l), and severe or life-threatening hyperkalemia is uncommon (9). Increasingly, however, optimal medical therapy for patients with HF due to systolic dysfunction relies heavily on simultaneous treatment with multiple neurohormonal antagonists that collectively amplify the risk of significant hyperkalemia when used in effective doses, particularly in patients with diabetes or underlying renal disease.

Enhanced prescription of spironolactone, an aldosterone receptor antagonist, spurred by the results of the landmark RALES (Randomized Aldactone Treatment Evaluation Study) (10), was associated with a dramatic increase in the rates of hospitalization for hyperkalemia in a recently published large, community-based sample (11). This experience highlights the potential difference between the carefully controlled environment of a clinical trial and the broader application of new therapies to a "real world" population (12). Although an excess of serious hyperkalemia events was observed in 2.7 per 1,000 patient-years in CHARM, the number may have been as high as 11.9 per 1,000 patient-years had an effective monitoring strategy not been in place. However, even this more all-encompassing "worst-case scenario" of hyperkalemia in the CHARM Program likely underestimates the incidence in an unselected population of patients with HF in the community who may be more vulnerable due to age, comorbid medical illness (particularly renal failure), and less careful monitoring than that offered in the context of a clinical trial. Buttressing this concern, it has been observed that monitoring for hyperkalemia in patients treated with RAAS blockade remains poor, with nearly 30% to 60% of patients failing to receive recommended surveillance of serum potassium (13,14). Nonetheless, the increased risk of hyperkalemia associated with candesartan (and, presumably, other ARB) therapy in HF must be interpreted in the context of its clear benefits with regard to CV morbidity and mortality, even among populations at special risk for elevated potassium (15,16), and as well in the context of potentially reduced serious adverse events related to hypokalemia (0.4% in candesartan-treated patients versus 0.9% in placebo-treated patients in the CHARM Program).

Our analysis must be viewed with attention to its limitations. This was a retrospective analysis using a post-hoc definition of "clinically important hyperkalemia." The decision to report an adverse event of hyperkalemia and the management of hyperkalemic patients were left to the discretion of the individual investigators; as such, the actual serum potassium values and clinical context (such as electrocardiographic manifestations) at the time of adverse events were not available for analysis. Although guidelines for monitoring of serum potassium were provided to the CHARM investigators (particularly during dose titration), no regularly scheduled surveillance of serum potassium was mandated. It is possible therefore, that physicians may have intervened to manage potassium levels that would have been well tolerated by the patients, or alternatively, that hyperkalemia may have gone undetected because it was not associated with specific electrocardiographic or clinical manifestations. Finally, though hyperkalemia prompting study drug dose reduction or discontinuation was specifically reported in the case report forms for the trial, hospitalization or death associated with hyperkalemia was only identifiable from review of investigator-reported adverse events. Although we may as a consequence have included some hospitalizations that were not specifically due to hyperkalemia, we believe that our conservative assumption reflects the upper bound of the incidence of clinically important hyperkalemia in the CHARM study.

Additional studies of hyperkalemia in large community cohorts or registries are necessary to more accurately measure the incidence outside the context of a clinical trial. In the absence of such data, however, our data from the CHARM Program provide important reference points for practicing clinicians to gauge the risk for hyperkalemia in the management of patients with HF. Reassuringly, many hyperkalemia events in the CHARM Program could be adequately addressed by dose adjustment or discontinuation of the study drug, with the minority progressing to hospitalization or death. We conclude that periodic surveillance of serum potassium and creatinine (e.g., at baseline, within 1 to 2 weeks of a change in drug dosing, and at least annually thereafter) is critically important to limiting adverse events. The subset of older HF patients who have moderate or severe renal dysfunction (stage III chronic kidney disease or worse, many of whom were not eligible for the CHARM Program), those with high serum potassium at baseline, and those who receive combination RAAS antagonists are particularly vulnerable, necessitating even closer monitoring. As well, in all patients with HF, strategies to limit the toxicity of RAAS antagonists, such as restriction of potassium supplements (and in some cases, dietary potassium), elimination of drugs that may impair renal potassium excretion (e.g., nonsteroidal anti-inflammatory drugs, herbal remedies, licorice), and careful assessment of baseline renal function to identify those at especially high risk (e.g., eGFR <45 cc/min/1.73 m²), should be routinely considered (17). The addition of candesartan to standard HF therapy should be undertaken cautiously, if at all, where adequate monitoring of potassium and renal function is not possible. Although candesartan provides important incremental benefits with regard to CV morbidity and mortality over standard medical therapy for HF, a favorable balance of benefit and risk requires clinical vigilance and regular laboratory surveillance, particularly among patients at high baseline risk for hyperkalemia.

	Acknowledgments

 
The authors wish to acknowledge Elizabet Hemlin, AstraZeneca, for her assistance in abstracting the data.

	Footnotes

 
The CHARM Program was funded by AstraZeneca. Drs. Pfeffer, Swedberg, McMurray, Yusuf, Granger, Young, Solomon, and Dunlap have served as consultants to or received research grants and honoraria from AstraZeneca and/or other major pharmaceutical companies. Drs. Michelson, Hainer, and Olofsson are employees of AstraZeneca.

	References

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2. McMurray JJ, Ostergren J, Swedberg K, et al. CHARM Investigators and Committees Effects of candesartan in patients with chronic heart failure and reduced left ventricular systolic function treated with an ACE inhibitor: the CHARM-Added trial Lancet 2003;362:767-771.[CrossRef][Web of Science][Medline]

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10. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failureRandomized aldactone evaluation study investigators. N Engl J Med 1999;341:709-717.[Abstract/Free Full Text]

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This Article Abstract Figures Only Full Text (PDF) All Versions of this Article: j.jacc.2007.07.067v1 50/20/1959    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Desai, A. S. Search for Related Content PubMed Articles by Desai, A. S.